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Strategies for Implementing Occupational eMental Health Interventions: Scoping Review
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Strategies for Implementing Occupational eMental Health Interventions: Scoping Review
Background:The implementation of eMental health interventions, especially in the workplace, is a complex process. Therefore, learning from existing implementation strategies is imperative to ensure improvements in the adoption, development, and scalability of occupational eMental health (OeMH) interventions. However, the implementation strategies used for these interventions are often undocumented or inadequately reported and have not been systematically gathered across implementations in a way that can serve as a much-needed guide for researchers.Objective:The objective of this scoping review was to identify implementation strategies relevant to the uptake of OeMH interventions that target employees and detail the associated barriers and facilitation measures.Methods: A scoping review was conducted. The descriptive synthesis was guided by the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework and the Consolidated Framework for Implementation Research.Results: A total of 31 of 32,916 (0.09%) publications reporting the use of the web-, smartphone-, telephone-, and email-based OeMH interventions were included. In all, 98 implementation strategies, 114 barriers, and 131 facilitators were identified. The synthesis of barriers and facilitators produced 19 facilitation measures that provide initial recommendations for improving the implementation of OeMH interventions.Conclusions:This scoping review represents one of the first steps in a research agenda aimed at improving the implementation of OeMH interventions by systematically selecting, shaping, evaluating, and reporting implementation strategies. There is a dire need for improved reporting of implementation strategies and combining common implementation frameworks with more technology-centric implementation frameworks to fully capture the complexities of eHealth implementation. Future research should investigate a wider range of common implementation outcomes for OeMH interventions that also focus on a wider set of
# Introduction
Background Mental health problems experienced by the working population are a global public health issue. Worldwide, more than 210 million people, representing 70% of those affected by common mental health disorders (eg, anxiety and mood disorders) are employed . Several risk factors, including working conditions, workplace culture, and the nature of work, have been linked to occupational mental health [bib_ref] Health care workers' mental health and quality of life during COVID-19: results..., Young [/bib_ref] [bib_ref] Pilot Work Related Stress (WRS), effects on wellbeing and mental health, and..., Cahill [/bib_ref]. Public health emergencies, such as the COVID-19 pandemic, are linked to specific stressors, including the threat of infection, social distancing measures, stigma, and job insecurity, which considerably increase the prevalence of mental health problems in the working population [bib_ref] COVID-19 and employees' mental health: stressors, moderators and agenda for organizational actions, Hamouche [/bib_ref].
Occupational eMental health (OeMH) interventions significantly improve mental health in work settings. OeMH interventions use information and communication technology, including internet-and web-based services, mobile apps, and wearable technologies, to deliver knowledge and services such as psychoeducation, workplace health promotion, psychological and medical treatment, and return to work assistance to employees [bib_ref] Theme issue on e-mental health: a growing field in internet research, Riper [/bib_ref] [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref]. OeMH interventions have the potential to be more available, accessible, and scalable than traditional interventions [bib_ref] Designing a scalable, accessible, and effective mobile app based solution for common..., Ha [/bib_ref] [bib_ref] Making mental health more accessible in light of COVID-19: scalable digital health..., Rodriguez-Villa [/bib_ref] , especially in public health emergencies, leading to physical-distancing policies to contain the spread of threatening conditions such as COVID-19.
However, implementing OeMH interventions is a complex process characterized by unique challenges involving adherence to new and crude regulatory frameworks, interoperability and compatibility with existing systems and procedures, threats to employees, organizational privacy and security, and associated costs. Newly introduced working arrangements in response to public health emergencies, such as the COVID-19 pandemic, could also compound existing implementation challenges and persist after the pandemic ends. Carefully developing and planning implementation strategies, which can be defined as a method or technique used to enhance the adoption, execution plan, and sustainability of an intervention [bib_ref] Implementation strategies: recommendations for specifying and reporting, Proctor [/bib_ref] , is therefore essential to guarantee the sustainable uptake of OeMH interventions by employers and employees.
Nonetheless, it is difficult to establish a best practice for the implementation of OeMH interventions. Implementation strategies are often inadequately documented and seldom evaluated and published [bib_ref] Implementation strategies: recommendations for specifying and reporting, Proctor [/bib_ref] [bib_ref] A compilation of strategies for implementing clinical innovations in health and mental..., Powell [/bib_ref] , especially in comparison with studies on the effectiveness of interventions. Even when reported, implementation strategies have been discussed within a general context, and researchers have called for more tailored implementation strategies that focus on specific contexts [bib_ref] Leveraging implementation science to understand factors influencing sustained use of mental health..., Connolly [/bib_ref] , for instance health care [bib_ref] Implementation strategies for digital mental health interventions in health care settings, Graham [/bib_ref]. Context encompasses the environment, broad setting, and circumstances (eg, systems and structures) in which an intervention is implemented and its associated characteristics [bib_ref] Context, complexity and process in the implementation of evidence-based innovation: a realist..., Dryden-Palmer [/bib_ref]. It is a key component of several widely adopted implementation frameworks, as evident in the Consolidated Framework for Implementation Research (CFIR) [bib_ref] Fostering implementation of health services research findings into practice: a consolidated framework..., Damschroder [/bib_ref]. Currently, those implementing new OeMH interventions are likely insufficiently informed about the procedure, strengths, and weaknesses of poorly documented implementation strategies, or uninformed about many potentially useful facilitators in this context. Furthermore, replicating positive results from similar implementations or overcoming barriers encountered in similar contexts would be challenging to achieve [bib_ref] Implementation strategies to enhance the implementation of eHealth programs for patients with..., Varsi [/bib_ref] [bib_ref] EMPOWER: The European platform to promote wellbeing and health in the workplace...., Pinnock [/bib_ref].
Objectives Therefore, a compilation of possible implementation strategies for OeMH interventions is critical to fostering improvements in their uptake and can serve as a reference for identifying and overcoming likely barriers and informing the future development of best practices. The objective of this scoping review was to identify implementation strategies relevant to the uptake of OeMH interventions that target employees and detail the associated barriers and facilitation measures. This scoping review would achieve these objectives by mapping the existing literature on the implementation of OeMH interventions and identifying gaps for future research. This work was conducted under the EMPOWER (European Platform to Promote Well-being and Health in the Workplace) project, funded by the European Commission, which investigates the impact of an eMental health platform aimed at preventing common mental health problems and reducing psychological distress in the workplace . It is also one of the series of review papers on different aspects of the knowledge base related to the development of the EMPOWER platform.
# Methods
## Overview
A scoping review was conducted to identify implementation strategies relevant to the implementation of OeMH interventions and to describe related barriers and associated facilitation measures. The scoping review is an established method for assessing and mapping the extent of evidence to address and inform practice in a topic area [bib_ref] Scoping reviews: time for clarity in definition, methods, and reporting, Colquhoun [/bib_ref] [bib_ref] Scoping studies: advancing the methodology, Levac [/bib_ref] [bib_ref] Scoping studies: towards a methodological framework, Arksey [/bib_ref] [bib_ref] An evidence-based approach to scoping reviews, Khalil [/bib_ref]. The review proceeded through five stages as developed by Arksey and O'Malley [bib_ref] Scoping studies: towards a methodological framework, Arksey [/bib_ref] , extended by Levac et al [bib_ref] Scoping studies: advancing the methodology, Levac [/bib_ref] , and further modified by Westphaln et alto accommodate a team-based approach: (1) identifying the research question; [bib_ref] Health care workers' mental health and quality of life during COVID-19: results..., Young [/bib_ref] identifying relevant studies; (3) selecting studies; (4) charting the data; and [bib_ref] COVID-19 and employees' mental health: stressors, moderators and agenda for organizational actions, Hamouche [/bib_ref] collating, summarizing, and reporting the results. Accordingly, this scoping review provides an overview of the existing evidence without a formal assessment of the methodological quality. It is conducted and reported in accordance with the widely adopted PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) [bib_ref] PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation, Tricco [/bib_ref] to help ensure a high level of methodological rigor and reporting quality.
## Search strategy
Electronic bibliographic databases, including MEDLINE, Scopus, CINAHL Complete, PsycINFO, and Web of Science Core Collection, were searched to find eligible peer-reviewed and gray literature. Search terms were based on concepts related to mental health, digital tools, the workplace, and implementation strategies (Multimedia Appendix 1). The MEDLINE search strategy (Multimedia Appendix 1) was adapted for other databases using relevant syntax and keywords in consultation with all coauthors who are also experienced researchers in the area. Hand searching of the reference lists of included articles was also completed for further relevant literature not identified during the search of databases. Members of the EMPOWER Consortium (ie, mental health researchers, clinicians, and experts focusing on well-being in the workplace) were also requested to suggest potentially eligible references via email.
## Eligibility criteria
Publications were eligible for inclusion if they described implementation strategies (ie, according to Proctor et al [bib_ref] Implementation strategies: recommendations for specifying and reporting, Proctor [/bib_ref] or related barriers or facilitation measures relevant to the uptake of OeMH interventions targeting employees. For example, all other eligibility criteria being met, approaches with the following characteristics would be considered: aim to introduce and encourage continued use of an intervention; prescribe actions in support of the intervention (eg, adaptations, fiscal strategies, and testing); and ensure that interventions can deliver intended benefits to the relevant organization over time, for instance, creating routine organizational policies or best practices. OeMH interventions are broadly defined here as mental health information and services delivered by information and communication technologies to employees [bib_ref] Theme issue on e-mental health: a growing field in internet research, Riper [/bib_ref] [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref]. This definition is consistent with the definition of eHealth [bib_ref] What is e-health?, Eysenbach [/bib_ref] , as well as the broader term digital health. Studies with employed participants aged ≥18 years, that were written in English. and published between January 2010 and May 2021 were considered. Primary research studies, systematic reviews, books, and gray literature (eg, conference proceedings, theses, government documents, and professional publications) were considered. Gray literature, such as commentaries, letters to editors, and editorials, were excluded.
## Eligibility assessment
A total of 10 researchers (AO-T, AR, CdM, CT, CMvdFC, DM-K, KS, MdM, MTP, and RMB), including psychologists, health scientists, and health economists, were involved in screening. To ensure consistency across researchers, they attended a web-based training workshop to practice the skills needed to reliably execute screening using the web and an app-based service Rayyan, Qatar Computing Research Institute. A training set of 100 publications was screened by all workshop attendees. Screening decisions (ie, include, maybe, or exclude) were reviewed and discussed to clarify any misunderstandings and identify difficulties using Rayyan QCRI. Instructions not to use the natural language processing-, artificial intelligence (AI)-, and machine learning-based features offered in Rayyan QCRI as well as tips to overcome minor usability shortcomings were given. Screeners were randomly assigned a screening set, and a screener performed a second screening of 20% of titles, abstracts, and full texts, and 100% of the publications that received a maybe screening decision. All screenings were conducted independently to reduce the likelihood of reviewer biasand inconsistencies in screening decisions were resolved in reconciliation meetings.
## Data extraction and synthesis of results
In all, 5 researchers (AR, CdM, CT, MdM, and RMB), including psychologists and health scientists, of the 10 (50%) screeners, were involved in data extraction and attended a web-based training workshop focused on developing consistency across researchers by practicing the skills needed to reliably execute data extraction using a web-based data extraction form. The form was reviewed and improved for clarity regarding the questions asked, user friendliness, and efficiency of data entry. For instance, it was clarified that single-component implementation strategies were to be extracted, and any bundling of strategies (ie, multifaceted strategies) in publications to address a goal were to be noted. Each researcher was randomly assigned an equal number of included records, and a researcher reviewed the extracted data for all the included publications.
A descriptive synthesis was performed, where identified implementation strategies, barriers, and facilitators were collated and later summarized. The synthesis was conducted by 3 (CT, MdM, and RMB, ie, psychologists and health scientists) of the 6 (50%) researchers involved in data extraction and guided by the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework [bib_ref] Evaluating the public health impact of health promotion interventions: the RE-AIM framework, Glasgow [/bib_ref] [bib_ref] Understanding and applying the RE-AIM framework: clarifications and resources, Holtrop [/bib_ref] and the CFIR [bib_ref] Fostering implementation of health services research findings into practice: a consolidated framework..., Damschroder [/bib_ref] and further informed by the Expert Recommendations for Implementing Change [bib_ref] A refined compilation of implementation strategies: results from the Expert Recommendations for..., Powell [/bib_ref]. RE-AIM and CFIR were chosen as they are widely used frameworks in implementation research (IR) [bib_ref] Scoping review identifies significant number of knowledge translation theories, models, and frameworks..., Strifler [/bib_ref] and were deemed by the authors to be the most comprehensive of the recently reviewed implementation frameworks [bib_ref] Scoping review identifies significant number of knowledge translation theories, models, and frameworks..., Strifler [/bib_ref] and most applicable to our objectives. The RE-AIM was originally developed as a framework for reporting findings regarding health promotion and disease management interventions in various settings. RE-AIM is used here to highlight essential strategy components with respect to its five steps: reach-the number of people who are willing to participate in a given initiative; effectiveness-the impact of an intervention on important outcomes (eg, individualistic and economic); adoption-the number of people or organizations who are willing to initiate and deliver an intervention; implementation-fidelity of delivery for the intervention including adaptations, costs, and consistency of delivery; and maintenance-sustained delivery and effects of an intervention after the associated initiative has ended. The CFIR unifies implementation theories to help build a robust implementation knowledge base across a wide range of studies, settings, contexts, and processes. The CFIR was used to provide a comprehensive view of multiple implementation contexts in which factors that might influence intervention implementation and effectiveness could be well detailed. Both frameworks determined the data for extraction: key publication characteristics, strategy definitions, key strategy implementation tasks, implementation processes, barriers and facilitators to strategy implementation, and any other data that holistically captured the complex and multilevel nature of strategy implementation were considered for data collection. Further synthesis of the identified barriers and facilitators produced recommendations for each relevant CFIR construct to improve the implementation of OeMH interventions.
# Results
A total of 31 publications were included in this scoping review [fig_ref] Table 1: Characteristics of included publications and interventions [/fig_ref]. [fig_ref] Figure 1: PRISMA [/fig_ref] details the methodological process followed, and a detailed itemization of the presented findings is provided in Multimedia Appendices 2 and 3. To develop, implement, and evaluate the intervention; survey (503), interviews [bib_ref] EMPOWER: The European platform to promote wellbeing and health in the workplace...., Pinnock [/bib_ref] , and focus groups[36], 2020 manage; workplace stress and mental well-being Web-based and smartphone app
Step-by-Step F; improve; depressive symptoms and anxiety symptoms China; human health and social work activities; 1
To describe the intervention's implementation; protocol-pilot randomized controlled trial (106) [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] , a 2020
Web-based and telephone With us in balance; prevent; stress-related disorders, anxiety disorders, mood disorders, sub-Germany; agriculture, forestry, and fishing; N/A c To describe the evaluation of the intervention's implementation;
protocol-focus groups (N/R b ) [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] , a 2020 stance-related and addictive disorders, insomnia, and chronic pain Smartphone app mWorks; support; common mental disorders Sweden; N/R; N/A To examine perspectives on the role and legitimacy of the intervention; interviews (32) and focus group [bib_ref] Leveraging implementation science to understand factors influencing sustained use of mental health..., Connolly [/bib_ref] [39], 2020 Smartphone app Anchored app; assess, improve, and monitor; depression, work-Australia; N/S d ; N/R To conduct preliminary evaluation of the intervention; pilot-usability study[40], a 2020 place stress, and mental well-being Web-based Psychological Well-being in Healthcare Workers: Mitigating United Kingdom; human health and social work activities; N/R To rapidly develop and evaluate the intervention; stakeholder consultation groups (97), peer [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] , a 2020 the Impacts of COVID-19; supreview panel [bib_ref] Making mental health more accessible in light of COVID-19: scalable digital health..., Rodriguez-Villa [/bib_ref] , and interven-port and manage; workplace stress and mental well-being tion fidelity and implementation testing [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] Web-based Self-confidence webinar program; improve; mood disorders and depression United Kingdom; public administration and defense and compulsory social security; 2
To evaluate the feasibility, outcome, and acceptability of the intervention; proof-of-concept-survey To compare engagement with(out) a discussion group; pilot-3-arm randomized controlled trial (84) To investigate users' views on two different technologies for an OeMH intervention; survey within randomized controlled trial (637) [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] , 2014
Web-based N/R; assess, improve, monitor, and promote; mental well-being Sweden; information and communication; public administration and defense; compulsory social security; education; and arts, entertainment, and recreation; 9
To contrast the role of differing managerial levels during the implementation of an OeMH; interviews[62], a 2014 The Netherlands; financial and insurance activities; professional, scientific, and technical activities; public administration and defense; compulsory social security; and education; 6
To assess the feasibility of the intervention and explore barriers and /facilitators for the implementation of the intervention; process evaluation alongside a randomized controlled trial (116)
## Publication characteristics
The 31 included publications comprised 28 journal articles [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Acceptance and barriers to access of occupational e-mental health: cross-sectional findings from..., Hennemann [/bib_ref] [bib_ref] Process evaluation of a digital platform-based implementation strategy aimed at work stress..., Havermans [/bib_ref] [bib_ref] Correlates of expected eMental Health intervention uptake among Filipino domestic workers in..., Hall [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] , 2 book chapters [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] , and a doctoral dissertation [fig_ref] Table 1: Characteristics of included publications and interventions [/fig_ref]
## Intervention characteristics
A total of 24 interventions were reported in 27 studies [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] [fig_ref] Table 3: Summary of intervention characteristics [/fig_ref]. These interventions were largely web-based (n=16, 67%%) [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Process evaluation of a digital platform-based implementation strategy aimed at work stress..., Havermans [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] and most aimed to improve (n=19, 79%) [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] and, to a lesser extent, educate users about mental health problems. Most interventions have focused on stress-related disorders and symptoms (n=17, 71%) [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref] [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Acceptance and barriers to access of occupational e-mental health: cross-sectional findings from..., Hennemann [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Correlates of expected eMental Health intervention uptake among Filipino domestic workers in..., Hall [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] , but a wide range of mental health problems (eg, burnout, anxiety disorders, and substance-related disorders) have also been covered to some extent. Where reported [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] , these interventions (n=19, 79%) largely targeted employees in professional occupations (eg, teachers and physicians). Most of these interventions were made available in specific countries, mainly in Europe (n=15, 63%%) [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] , except for one that was available internationally (n=1, 4%) [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref]. Standardized information about these 24 interventions, including year of launch, language, number of employees and employers interested in and who adopted the app, organizational size, and internal policies, was not clearly reported where relevant and could not be accurately extracted in detail. [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] 16 [bib_ref] Facebook as an effective recruitment strategy for mental health research of hard..., Kayrouz [/bib_ref] Web [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Process evaluation of a digital platform-based implementation strategy aimed at work stress..., Havermans [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] 1 (4) Web and smartphone [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] 1 (4) Web and telephone [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] 1 (4) Email [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] Aim 4 [bib_ref] Fostering implementation of health services research findings into practice: a consolidated framework..., Damschroder [/bib_ref] Assess [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] 1 (4) Educate [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] 19 [bib_ref] Digital mental health interventions for depression, anxiety, and enhancement of psychological well-being..., Lattie [/bib_ref] Improve [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] 5 [bib_ref] Scoping reviews: time for clarity in definition, methods, and reporting, Colquhoun [/bib_ref] Manage [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Acceptance and barriers to access of occupational e-mental health: cross-sectional findings from..., Hennemann [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] 6Monitor [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] 4 (17) Prevent [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] 7Promote [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] 3 (13) Support [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] Target mental health problem 2 (8) Anxiety disorders and symptoms [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] 1 (4) Burnout1 (4) Chronic pain [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] 1 (4) Common mental disorders [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] 8 [bib_ref] Understanding and applying the RE-AIM framework: clarifications and resources, Holtrop [/bib_ref] Mood disorders and symptoms [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] 1 (4) Return to work [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] 3 [bib_ref] A compilation of strategies for implementing clinical innovations in health and mental..., Powell [/bib_ref] Sleep problems [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] 2 (8) Substance-related and addictive disorders [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] 1 (4) Stigma and discrimination [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] 17 (71) Stress-related disorders and symptoms [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref] [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Acceptance and barriers to access of occupational e-mental health: cross-sectional findings from..., Hennemann [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Correlates of expected eMental Health intervention uptake among Filipino domestic workers in..., Hall [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] 7Well-being problems [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] Country of implementation 2 (8) Australia [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] 1 (4) Canada [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] 1 (4) China [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] 2 (8) Germany [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] 1 (4) International [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] 3 [bib_ref] A compilation of strategies for implementing clinical innovations in health and mental..., Powell [/bib_ref] The Netherlands [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] 1 (4) New Zealand [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] 5 [bib_ref] Scoping reviews: time for clarity in definition, methods, and reporting, Colquhoun [/bib_ref] Sweden [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] 5 [bib_ref] Scoping reviews: time for clarity in definition, methods, and reporting, Colquhoun [/bib_ref] United Kingdom [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] 4 [bib_ref] Fostering implementation of health services research findings into practice: a consolidated framework..., Damschroder [/bib_ref] United States [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] Target occupational groups 2 (8) Armed forces occupations [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] 4 [bib_ref] Fostering implementation of health services research findings into practice: a consolidated framework..., Damschroder [/bib_ref] Clerical support worker [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] 1 (4) Elementary occupations (eg, cleaners and laborers) [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] 3 [bib_ref] A compilation of strategies for implementing clinical innovations in health and mental..., Powell [/bib_ref] Managers (eg, chief executive officer) [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] 5 [bib_ref] Scoping reviews: time for clarity in definition, methods, and reporting, Colquhoun [/bib_ref] Not reported [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] 1 (4) Plant and machine operators and assemblers [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] 10 (42) Professionals (eg, teachers and physicians) [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] 3 [bib_ref] A compilation of strategies for implementing clinical innovations in health and mental..., Powell [/bib_ref] Service and sales workers [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] 1 (4) Social workers (ie, specifically child and family social workers) [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] 2 (8) Skilled agricultural, forestry, and fishery workers [bib_ref] Implementing Internet-and tele-based interventions to prevent mental health disorders in farmers, foresters..., Freund [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] 6 (25) Technicians and associate professionals [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref]
## Implementation strategies
## Overview
Overall, 98 examples of implementation strategies were identified (Multimedia Appendix 2). Effectiveness, implementation, and maintenance Improve maintenance and adherence through the timely presentation of findings from monthly user feedback surveys where after follow-up actions can be immediately applied to the intervention [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] Develop and organize implementation quality monitoring systems and act on insights in a timely manner where feasible; 17 (17) Reach, effectiveness, implementation, and maintenance Filled knowledge gaps surrounding the effectiveness of eMental health interventions in the workplace by conducting systematic reviews on relevant topics [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] Assess for readiness and tailor strategies to address identified barriers and benefit from facilitators; 13 [bib_ref] A compilation of strategies for implementing clinical innovations in health and mental..., Powell [/bib_ref] Reach Users were recruited by sharing information about the intervention through advertisements distributed via email and the organizations' intranet and magazine [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] Use mass media to increase reach; 9 [bib_ref] Designing a scalable, accessible, and effective mobile app based solution for common..., Ha [/bib_ref] Reach, effectiveness, adoption, implementation, and maintenance A consultation process was carried out with users, clinical psychologists, psychiatrists, information technology professionals, and design and user experience specialists to ensure the app's content and design appealed to a broad range of workers from different industries [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] Capture local knowledge from implementation sites and involve users early in the implementation and intervention development effort; 8 [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref] Reach, effectiveness, adoption, implementation, and maintenance
Interventions were improved and adapted to each participating organization based on user feedback [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] Promote adaptability in the intervention to meet local needs without compromising fidelity; 8 (8)
## Implementation
Automatic email reminders were sent based on user-determined intervals and user inactivity [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] Send reminders; 7 (7) Implementation Users were able to contact the intervention coach at any time to ask for feedback, additional help, or advice and the coach would respond within 24 hours [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] Provide support to users during the intervention; 6 (6)
## Reach, adoption, and implementation
Senior and middle management-led introductory seminars with employees that aimed to explain the intervention, secure acceptance, provide answers to questions, and inspire their participation [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] Conduct educational meetings; 5 [bib_ref] COVID-19 and employees' mental health: stressors, moderators and agenda for organizational actions, Hamouche [/bib_ref] Reach and implementation Users received a certificate of completion and the training was recognized as continuing education toward the renewal of their professional certification [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] Provide incentives; 5 [bib_ref] COVID-19 and employees' mental health: stressors, moderators and agenda for organizational actions, Hamouche [/bib_ref] Reach, adoption, implementation, and maintenance Identification of champions at the implementation site facilitated organizational and employee buy-inIdentify and prepare organizational champions who will dedicate themselves to supporting, marketing, and driving the implementation; 4 (4)
Reach, adoption, implementation, and maintenance
The program was developed as a quality improvement project by the hospital and all research procedures (ie, retrospectively reviewing these outcomes) were approved by the institutional review board at the hospital [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] Involve senior management; 4 (4) Implementation Participants received immediate and automatic tailored feedback and could monitor their own responses and trends over time [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] Provide opportunities for users to obtain feedback on progress; 4 (4)
## Effectiveness and implementation
Conducted a pilot study aimed at assessing the usability, feasibility, acceptability, and preliminary effects of an app-based intervention designed to target depressive symptoms in a stressed working population [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] Stage implementation scale-up; 4 (4)
Reach and adoption When recruitment efforts did not attract enough participants, executives with the largest workforces in the region and industry were contacted directly via telephone and offered enrollment [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] Customize recruitment activities to enhance reach; 3 (3)
Reach, adoption, and implementation All participants who returned the consent form received an email welcoming them to the study and explaining how to log in and use their personal webpage for the stress management program [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] Develop and distribute educational materials; 3
Reach and adoption Management representatives were offered spots to enroll their organizations immediately after educational meetings about the intervention or to enroll at a later time [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] Provide immediate opportunities to demonstrate commitment; 3 (3) Relevant RE-AIM domains Example strategy Discrete implementation strategies-proportion of strategy examples; n (%) Implementation Systematic feedback was sought from researchers, expert clinicians, and veterans on the program and its content [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] Use advisory boards and workgroups to provide input and advice on implementation and improvements; 3 (3)
## Reach
Mass media services were mainly used to increase reach (9/27, 33%). Examples include email [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] , industry publications [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] , targeted web-based advertisements (eg, Facebook) [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] , and the organizations' intranet [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref]. The provision of attractive incentives for participation included monetary remuneration [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] , vouchers [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] , points for employee reward schemes [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] , educational credits for professional certifications [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] , and additional medical benefits [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref]. Other strategies included engaging potential users through educational meetings [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] and materials [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] (2/27, 7%), employees tasked with the responsibility of supporting the implementation of the intervention [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] (2/27, 7%), and well-timed opportunities to commit [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] (2/27, 7%). Local barriers to increasing reach among target users were identified through consultations with implementation sites, eligible users, and literature [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] (3/27, 11%), and recruitment activities were later modified to avoid or overcome these barriers where possible [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] (4/27, 15%).
## Effectiveness
Strategies to improve the effectiveness of the intervention mainly relied on insights obtained from a diverse group of professionals in relevant fields, representatives of implementation sites, target users, and intervention use data . This insight was captured through stakeholder consultations [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] , steering group interviews and focus groups with target users [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] , peer review panels [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] , and user experience research [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] throughout the implementation process. Several strategies adopted an incremental approach to implementation [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] (3/19, 16%), fostered adaptability in the intervention to adequately meet the local needs [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] (2/19, 11%), or implemented measures to avoid or mitigate identified barriers that could negatively impact the effectiveness of the particular intervention [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] (2/19, 11%).
## Adoption
Sharing and discussing details about the proposed intervention with decision-makers was the most commonly used adoption strategy. This involved conducting educational meetings [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] (4/17, 24%) and distributing educational materials about the intervention [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] (1/17, 6%). Engaging senior management and others from the organization to identify necessary adaptations for intervention to succeed in the organization was also common. These strategies involved organizational stakeholders early in the intervention development process [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] (2/17, 12%) to adapt the intervention to meet special organizational needs without compromising fidelity [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] (1/17, 6%) and address other identified barriers [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] (1/17, 6%). Some strategies also identified staff members who could dedicate themselves to supporting, marketing, and driving the implementation within the organization, as this was expected to increase the likelihood of success [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] (2/17, 12%). The provision of immediate opportunities for decision-makers to confirm their commitment to adopt the intervention was also used [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] (1/17, 6%).
## Implementation
Implementation strategies focused on adapting interventions and customizing the implementation process to implementation settings, monitoring the consistency of delivery, and providing various forms of support as needed. Implementers underwent training, subscribed to a common protocol, and had their work reviewed to help ensure fidelity. Some implementation strategies were continuously monitored using both qualitative and quantitative methods, including surveys, implementation reviews, process evaluations, and other similar methods and be notified when their participation level was too low [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Adherence to Internet-based mobile-supported stress management: a pooled analysis of individual participant..., Zarski [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] or when new updates became available [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref].
## Maintenance
Maintenance strategies involved changes at the organizational level, where accommodating work conditions [bib_ref] Participant engagement in and perspectives on a web-based mindfulness intervention for 9-1-1..., Kerr [/bib_ref] [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] (2/8, 25%) and support staff [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] (1/8, 13%) were sometimes arranged. Embedding interventions within existing employee programs was also expected to help sustain the use of the intervention [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] (1/8, 13%). Special monitoring measures (eg, postintervention acceptability surveys and opportunities for monthly user feedback) were also established to provide insight into how benefits to users could be sustained after the initiative had officially ended [bib_ref] A digital mental health intervention to reduce depressive symptoms among overseas Filipino..., Liem [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] (2/8, 25%).
## Barriers and facilitators
## Overview
The included publications reported 114 barriers and 131 facilitation measures (Multimedia Appendix 3), and 28 barriers were accompanied by facilitation measures. There were no notable differences between barriers and facilitators extracted from publications that focused on the implementation of OeMH interventions (108/217, 49.8%) or that reported results or noted implications related to their implementation (109/217, 50.2%) so these will be reported together. Examples of barriers and facilitators organized by the relevant CFIR domains and associated constructs are provided in the corresponding tables. Most of the 217 identified barriers and facilitation measures were related to key attributes of interventions that influence successful implementation (103/217, 47.5%), followed by the inner setting of the organization (87/217, 40.1%), individual characteristics of target users (25/217, 11.5%), and the outer setting of the organization (2/217, 0.9%). The highest number of barriers were categorized under the inner setting (54/114, 47.4%), followed by intervention characteristics .7%), individual characteristics of target users .3%), and the outer setting of the organization (2/114, 1.8%) domains. The highest number of facilitators were categorized under intervention characteristics (77/131, 58.8%), followed by inner setting (44/131, 33.6%), individual characteristics of target users (9/131, 6.9%), and outer setting of the organization (1/131, 0.8%) domains.
## Intervention characteristics
Numerous barriers and facilitators were identified regarding how the interventions were bundled, presented, and assembled (ie, design quality and packaging) . Participants from several studies considered web-based platforms to be an impersonal medium (eg, no face-to-face contact or human interaction) [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] , and some saw its use as inappropriate for helping with sensitive topics such as mental health problems [bib_ref] Addressing police discrimination regarding mental distress using a service user-led and interpersonal..., Davey [/bib_ref]. Several usability issues (eg, poor accessibility, technical issues, unclear navigational elements and user interface, and overly effortful tasks) have also emerged as barriers [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref]. Accordingly, ensuring good usability [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref] [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] and considering individual factors (eg, high impulsivity benefits from continuous motivational components) [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] in the design were also often reported as facilitators.
The stakeholders' perceptions of the evidence supporting the effectiveness of the proposed occupational mental interventions were influenced by several factors. The barriers included between-group contamination due to limited randomization at the individual level, unrepresentativeness of samples used for the general workforce, use of new or adapted measures with low reliability [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] , and type 1 errors [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref]. Identified facilitators focused on the including diverse samples (eg, including underrepresented industries and occupations) [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] , collecting comparable demographic data [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] , including comprehensive engagement measures [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] , presenting interventions based on credible information highly relevant to target employees [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] , using control conditions when evaluating effectiveness [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] , providing evidence from similar interventions that demonstrate effectiveness [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] , and conducting comprehensive and ongoing process evaluations to inform implementation [bib_ref] Line managers' influence on employee usage of a web-based system for occupational..., Frykman [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref].
## Table 5. examples of barriers and facilitators organized under the intervention characteristics consolidated framework for implementation research domain (n=217).
## Example of identified facilitators example of identified barriers relevant associated construct-proportion of barriers and facilitators; n (%) and brief description
Providing evidence from other programs and interventions could be a strategy (oral presentations or reading materials) to demonstrate likely effectiveness [bib_ref] Factors associated with high use of a workplace web-based stress management program..., Hasson [/bib_ref] Using newly created or adapted measures demonstrating low reliability negatively impacts the strength of findings [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] Evidence strength and quality; 15 (6.9); stakeholders' perceptions of the quality and validity of evidence supporting the belief that the intervention will have desired outcomes
The lack of a previous existing intervention for well-being in the organization, except for the intranet, which was difficult to use, so the app resulted to be a huge advantage for employees [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] Possible low motivation from employers and organization in their employees return to work as they came from small-to mediumsized companies that had insurance for the costs of sickness absence [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] Relative advantage; 2 (0.9); stakeholders' perception of the advantage of implementing the intervention versus an alternative solution Possibility to use the program at their own pace [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] Materials presented in a modular format that had to be completed start to finish in a single sitting or in a set order [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] Adaptability; 4 (1.8); the degree to which an intervention can be adapted, tailored, refined, or reinvented to meet local needs Improving usability based on participant and expert feedback [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] Usability was affected by unclear navigational elements and user interface [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] Design quality and packaging; 80 (36.9); perceived excellence in how the intervention is bundled, presented, and assembled
## Outer setting
Strict external policies and failure of interventions to meet patient needs erected several barriers to the implementation of OeMH interventions [fig_ref] Table 6: Examples of barriers and facilitators organized under the outer setting Consolidated Framework... [/fig_ref]. For example, strict legislation and policies regarding privacy and confidentiality were highlighted as potential reasons for the reduced adoption of interventions based on innovative technologies [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref]. Moreover, failure to maintain employees' confidentiality during these programs was believed to discourage the use of interventions for fear of being vulnerable to privacy breaches by employers [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref]. The sole facilitation measure identified for this CFIR domain also addresses this point by urging implementers to find ways to maintain employee confidentiality [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref].
## Example of identified facilitators example of identified barriers
Relevant associated construct-proportion of barriers and facilitators; n (%) and brief description a The surrounding legislation and policy regulation of privacy and confidentiality may make it difficult to use innovative technology [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] External policy and incentives; 1 (0.5); a broad construct that includes external strategies to spread interventions including policy and regulations (governmental or other central entity), external mandates, recommendations and guidelines, pay for performance, collaboratives, and public or benchmark reporting Maintaining confidentiality between employee and employer [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] Reluctancy of the potential participants in participating for fear of demonstrating vulnerability [bib_ref] Health-relevant personality traits in relation to adherence to a web-based occupational health..., Villaume [/bib_ref] Patient needs and resources; 1 (0.5); the extent to which patient needs, as well as barriers and facilitators to meet those needs, are accurately known and prioritized by the organization a No facilitator reported.
## Inner setting
Many publications have identified the lack of resources dedicated to implementation as a major barrier [fig_ref] Table 7: Examples of barriers and facilitators organized under the inner setting Consolidated Framework... [/fig_ref]. For example, there is a lack of time for employees to use the intervention [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Process evaluation of a digital platform-based implementation strategy aimed at work stress..., Havermans [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] , funds to meet additional costs [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] , unreliable systems that lead to data loss [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] , inflexible participation times [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] , lack of workspaces to avoid office distractions and private spaces [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] when completing interventions [bib_ref] Acceptability of online self-help to people with depression: users' views of MoodGYM..., Schneider [/bib_ref] , low technology (eg, computers and email) adoption by the organization [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] , little support from the app or implementor [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] , and insufficient resources for piloting [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref]. Some interventions were also inadequately adjusted to organizational processes [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] and insufficiently tailored to the work situation and culture [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Process evaluation of a digital platform-based implementation strategy aimed at work stress..., Havermans [/bib_ref] [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref]. Organizational restructuring has also been identified as a barrier to successful implementation and should be considered during implementation planning [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] [bib_ref] Process evaluation of a digital platform-based implementation strategy aimed at work stress..., Havermans [/bib_ref] [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref].
Several facilitators have also been identified. For example, it was recommended for employers to arrange dedicated time for employees to participate in the intervention [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] ; to allow employees flexibility regarding the time, place, and pace when completing the intervention [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] ; to offer an option for employees to use the intervention in a private workspace [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] ; to provide recordings of any live sessions with feedback options [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] ; and to encourage employee access to or ownership of technology (eg, smartphone) in use [bib_ref] Correlates of expected eMental Health intervention uptake among Filipino domestic workers in..., Hall [/bib_ref]. Intervention creators can also support employers with recruitment [bib_ref] Increasing engagement with an occupational digital stress management program through the use..., Carolan [/bib_ref] , by obtaining support from a dedicated organizational support group for implementation [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] , providing lower-cost intervention options (eg, email based) [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] , using reliable data storage methods [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] , and demonstrating cost-effectiveness of the proposed intervention [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref].
## Example of identified facilitators example of identified barriers relevant associated construct-proportion of barriers and facilitators; n (%) and brief description
Changes in the organizations should be considered (in light of resulting delays and communication problems) when planning intervention studies [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] Personnel shortage, turnover, and organizational restructuring hindered the use of the strategy considerably [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] Structural characteristics; 4 (1.8%); the social architecture, age, maturity, and size of an organization Conduct onsite testing before implementation [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] Restrictive internet security settings was a barrier for accessing the intervention [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] Networks and communications; 4 (1.8%); the nature and quality of webs of social networks and the nature and quality of formal and informal communications within an organization Embedding the intervention in a well-established wellness program to benefit from existing infrastructure to promote the intervention; users benefiting from incentive programs [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] Alignment with other stakeholders was absent and resulted in poor adherence to the recommended roles and tasks [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] Implementation climate; 17 (7.8); the absorptive capacity for change, shared receptivity of involved individuals to an intervention, and the extent to which use of that intervention will be rewarded, supported, and expected within their organization a Some stakeholders may be reluctant to implement new technology as it might threaten their ability to keep their job [bib_ref] Role of a digital return-to-work solution for individuals with common mental disorders:..., Engdahl [/bib_ref] Tension for change; 1 (0.5); the degree to which stakeholders perceive the current situation as intolerable or needing change Alignment to relevant stakeholders is also important and can be attained by offering ongoing support to leaders at all organizational levels during an implementation [bib_ref] Managing implementation: roles of line managers, senior managers, and human resource professionals..., Hasson [/bib_ref] It was not possible for employees to contact their occupational physician themselves by telephone outside their regular consultations. This could have caused difficulty when an employee struggled with a module in Re-turn@Work and wanted to ask the occupational physician for advice [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] Compatibility; 21 (9.7); the degree of tangible fit between meaning and values attached to the intervention by involved individuals; how those align with individuals' own norms, values, and perceived risks and needs; and how the intervention fits with existing workflows and systems -Complimentary gifts (eg, measuring tapes to be used by users with diabetes) with logos and information stimulate discussions and act as reminders [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] Organizational incentives and rewards; 2 (0.9); extrinsic incentives such as goal-sharing awards, performance reviews, promotions, and raises in salary and less tangible incentives such as increased stature or respect Consult review boards and consider these issues early in the data planning process [bib_ref] Improving the sleep of children's hospital employees through an email-based sleep wellness..., Smith [/bib_ref] Ensuring fidelity as coaches could not provide good feedback without supervision [bib_ref] Feasibility of a worker-directed Web-based intervention for employees with depressive symptoms, Geraedts [/bib_ref] Readiness for implementation; 6 (2.8); tangible and immediate indicators of organizational commitment to its decision to implement an intervention Adherence is better when managers are active and engaged [bib_ref] An automated and systematic Web-based intervention for stress management and organizational health..., Hasson [/bib_ref] Senior management was not engaged and too much responsibility for implementation was given to the team members who did not prioritize these activities [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] Leadership engagement; 7 (3.2); commitment, involvement, and accountability of leaders and managers with the implementation Supporting statement from the employers which will suggest to all employees who participate in the study that they will have 1 hour per week over the 8-week period to complete the program [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] The intervention required all participants to allocate the same time slot and competed with other time commitments [bib_ref] Evaluating the feasibility of an innovative self-confidence webinar intervention for depression in..., Mohd Yunus [/bib_ref] Available resources; 25 ; the level of resources dedicated for implementation and ongoing operations including money, training, education, physical space, and time Email messages from the decision aid supported the occupational physicians when guiding employees. The email gave them sufficient information and the layout was visually attractive [bib_ref] Process evaluation of a blended Web-based intervention on return to work for..., Volker [/bib_ref] Access to knowledge and information; 2 (0.9); ease of access to digestible information and knowledge about the intervention and how to incorporate it into work tasks a No facilitator reported.
## Characteristics of individuals
Barriers were related to either the employer or the individual [fig_ref] Table 8: Examples of barriers and facilitators organized under the characteristics of individuals Consolidated... [/fig_ref]. Employer-related barriers included the perception of low organizational commitment to addressing issues targeted by the proposed intervention [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] , perceived stigma associated with intervention adoption [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] , and a lack of privacy (eg, sharing information disclosed within the intervention with employers) [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref]. Individual-related barriers included a general lack of motivation and interest in using the intervention [bib_ref] A pilot evaluation of a smartphone application for workplace depression, Collins [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref] , no opportunities to interact with others during the intervention [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] , poor consistency in using the intervention as directed [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] , poor digital skills [bib_ref] Occupational e-mental health: current approaches and promising perspectives for promoting mental health..., Lehr [/bib_ref] [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Process evaluation of a digital platform-based implementation strategy aimed at work stress..., Havermans [/bib_ref] [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] , difficulty relating to content [bib_ref] A Web-based self-management program for recent combat veterans with PTSD and substance..., Possemato [/bib_ref] , low work ability [bib_ref] Acceptance and barriers to access of occupational e-mental health: cross-sectional findings from..., Hennemann [/bib_ref] , and reduction in engagement and adoption due to symptoms associated with medical conditions [bib_ref] Preliminary effectiveness of a smartphone app to reduce depressive symptoms in the..., Deady [/bib_ref] [bib_ref] Employees' perspectives on the facilitators and barriers to engaging with digital mental..., Carolan [/bib_ref]. Proposed facilitators include willingness to seek mental health support [bib_ref] Correlates of expected eMental Health intervention uptake among Filipino domestic workers in..., Hall [/bib_ref] , prior experience using an eHealth intervention and interventions that are freely accessible [bib_ref] Acceptance and barriers to access of occupational e-mental health: cross-sectional findings from..., Hennemann [/bib_ref] , low technical skill requirement (eg, no authentication) [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] , and content that is available in multiple media formats (eg, printed versions) [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref].
## Example of identified facilitators example of identified barriers relevant associated construct-proportion of barriers and facilitators; n (%) and brief description
Maintaining confidentiality between employee and employer [bib_ref] Increasing engagement with, and effectiveness of, an online CBT-based stress management intervention..., Carolan [/bib_ref] Skepticism toward the independence of the project from the organization [bib_ref] Co-creating and evaluating an app-based well-being intervention: the HOW (healthier outcomes at..., Ravalier [/bib_ref] Knowledge and beliefs about the intervention; 7 (3.2); individuals' attitudes toward and the value placed on the intervention as well as familiarity with facts, truths, and principles related to the intervention The package developed in a free-to-access and simple format that does not require logging in to a system or any specific technical expertise [bib_ref] Mitigating the psychological impact of COVID-19 on healthcare workers: a digital learning..., Blake [/bib_ref] Lack of computer skills in team members [bib_ref] Effectiveness of a digital platform-based implementation strategy to prevent work stress in..., Havermans [/bib_ref] Self-efficacy; 12 (5.5); individual belief in their own capabilities to execute courses of action to achieve implementation goals Willingness to seek professional mental health services [bib_ref] Correlates of expected eMental Health intervention uptake among Filipino domestic workers in..., Hall [/bib_ref] Barriers reported by participants at high risk for a major depressive episode included perceived stigma, lack of interaction with others that is characteristic of eMental health, lack of time, and lack of knowledge [bib_ref] Preferred features of e-mental health programs for prevention of major depression in..., Wang [/bib_ref] Other personal attributes; 6 (2.8); a broad construct to include other personal traits such as tolerance of ambiguity, intellectual ability, motivation, values, competence, capacity, and learning style
## Summary of facilitation measures
The identified facilitation measures were further synthesized and organized by the associated CFIR construct . . Summary of potential facilitation measures organized by associated Consolidated Framework for Implementation Research (CFIR) construct.
## Facilitation measure associated cfir construct
Strategies must provide evidence of effectiveness regarding the proposed or similar interventions in similar contexts featuring a representative sample of employees and a control group, where feasible, using valid and reliable measures.
## Evidence strength and quality
Strategies must be perceived to provide an advantage over the implementation of an alternative or no solution. Relative advantage Strategies must allow flexibility on intervention completion times, the pace of progression, access options, and the format of provided materials.
## Adaptability
Strategies must ensure that the design of the intervention is based on an explicit understanding of users, their tasks, and environments and provides guidance (eg, reminders, knowledge base, progress tracking, and feedback); considers opportunities to integrate intervention features with organizational processes; creates personalized, informative, and nonstigmatizing content that encourages user participation; provides user adaptable content and tasks (ie, increased user control); allows access via additional modalities (eg, ability to print content) and formats (eg, video and audio); includes formative and summative usability testing and accessibility evaluations; highlights a strict approach to privacy and data security; and considers a multichannel recruitment strategy.
Design quality and packaging Strategies must identify and comply with applicable privacy legislation and policy regulations. External policy and incentives Strategies must consider the capacity of stakeholders to complete assigned tasks and account for turnover and other restructuring activities.
## Structural characteristics
Strategies must involve all stakeholders, include onsite testing of required technology, and establish clear communication procedures at the planning stage.
## Networks and communications
Strategies must be cohesive and compatible with the organization's culture (eg, high turnover and highly active working environment), ensure that interventions can be used in distraction-free environments (ie, free from excessive noise), account for prior negative experiences with similar interventions, secure support from senior management for strategy implementation, and leverage existing programs by embedding interventions into them.
## Implementation climate
Strategies must consider the impact of implementation on-the-job security of stakeholders and how that affects their perception of proposed changes.
## Tension for change
Strategies must adequately reflect the implementation needs of the organization and its existing processes and policies; be aligned with stakeholders at different organizational levels; provide adequate separation between work and working with the intervention; and avoid stigmatization, especially of employees with mental health conditions.
## Compatibility
Strategies should offer incentives for using the intervention and consider incorporating gamification components to offer these incentives.
## Organizational incentives and rewards
Strategies must ensure that stakeholders are involved in strategy development, aware of the strategy and their role in it, equipped with the necessary tools and access, and adequately trained to implement the strategy.
## Readiness for implementation
Strategies must secure support from all stakeholders, especially an active and engaged senior management who strongly sanctions and advocates for the intervention.
## Leadership engagement
Strategies must provide organizational support for implementation, intervention support for users, dedicated time and private spaces for completing interventions in the workplace, less time-intensive interventions, alternative options to live-participation activities (eg, live webinar recording), low-cost technology-based options (eg, email) for interventions, reliable cloud data storage, access from varying device types, and implementation cost estimates with demonstrated cost-effectiveness.
## Available resources
Strategies must provide information that sets realistic expectations about the intervention and how to implement it.
## Access to knowledge and information
Strategies must clearly articulate the role of the organization in the development of the intervention and address privacy and stigmatization concerns associated with using mental health interventions.
Knowledge and beliefs about the intervention Strategies must accommodate users whose performance is affected by symptoms (eg, lack of motivation) associated with their health conditions (eg, depression) and a lack of confidence using technology.
## Self-efficacy
Strategies must consider users' perception of and level of commitment to the organization. Individual identification with organization Strategies must address a lack of motivation (eg, due to symptoms associated with health conditions) to adopt and consistently use interventions and to seek help.
## Other personal attributes
# Discussion
## Principal findings and comparison with prior work
The 31 included publications revealed 98 implementation strategies used when implementing OeMH interventions, 114 barriers, and 131 facilitators. The findings support observations [bib_ref] Implementation strategies: recommendations for specifying and reporting, Proctor [/bib_ref] [bib_ref] A compilation of strategies for implementing clinical innovations in health and mental..., Powell [/bib_ref] that the reporting of implementation strategies used for eHealth interventions is largely incomplete, nonsystematic, and unstructured. Nonetheless, the findings provide valuable insights into what is known and where knowledge gaps lie in the area.
## Implementation strategies
The OeMH knowledge base does not provide definitive answers regarding the implementation strategies to adopt and when and how it is most effective and efficient to adopt them. For example, the efficacy and cost-effectiveness of using innovative methods such as web-based targeted advertising compared with traditional methods (eg, posters) to increase reach is unclear [bib_ref] Integrative review of recruitment of research participants through Facebook, Reagan [/bib_ref] [bib_ref] Facebook as an effective recruitment strategy for mental health research of hard..., Kayrouz [/bib_ref] , despite the former's success in being more time-efficient [bib_ref] Facebook as an effective recruitment strategy for mental health research of hard..., Kayrouz [/bib_ref] and effective at recruiting hard-to-reach populations [bib_ref] Facebook as an effective recruitment strategy for mental health research of hard..., Kayrouz [/bib_ref] [bib_ref] The use of Facebook in recruiting participants for health research purposes: a..., Whitaker [/bib_ref]. Those responsible for implementation must use their judgment about which of the provided strategies would be most appropriate for their circumstances. These findings support the notion that the implementation of eHealth technology (eg, eMental health [eMH] interventions) is often narrowly seen as a postdevelopment activity rather than being a crucial part of the development process. Nonetheless, this could be partly a consequence of many included studies not specifically or comprehensively investigating implementation and therefore not reporting other details regarding implementation. Alternatively, publication restrictions [bib_ref] Standards for Reporting Implementation Studies (StaRI) statement, Pinnock [/bib_ref] (eg, strict word limits) and the multidisciplinary nature of digital health research [bib_ref] WHO mHealth Technical Evidence Review Group. Guidelines for reporting of health interventions..., Agarwal [/bib_ref] may prioritize other study information over details regarding implementation when reporting on digital health interventions.
## Barriers and facilitators
Similar to findings related to medical devices [bib_ref] Usability and user experience of medical devices: an overview of the current..., Bitkina [/bib_ref] , the findings here also suggest that usabilityappears to be the main design consideration in the evaluation of OeMH interventions, with little consideration given to other critical elements of the user experience. Findings regarding the CFIR inner setting domain highlight the need for researchers to articulate potential facilitators, including those that may have failed in one implementation context, as they might work in other contexts. Existing research [bib_ref] Difficulties encountered by people with depression and anxiety on the Web: qualitative..., Bernard [/bib_ref] [bib_ref] Barriers and facilitation measures related to people with mental disorders when using..., Bernard [/bib_ref] addresses many of the barriers (eg, associated with symptoms associated with mental health problems and limited digital literacy skills) categorized under the CFIR characteristics of individual domains and could provide an easy opportunity to improve implementation if given more consideration during the planning phase. Factors external to the organization (eg, external policies, partners, and competition) are known to greatly hinder or support the successful implementation of technology [bib_ref] Discovery of implementation factors that lead to technology adoption in long-term care, Schoville [/bib_ref] [bib_ref] Integrated technology implementation model: examination and enhancements, Schoville [/bib_ref] [bib_ref] Guiding healthcare technology implementation: a new integrated technology implementation model, Schoville [/bib_ref] but have been largely undocumented or overlooked by the included publications.
## Recency of work and coverage of technologies
Similar to recent eMH reviews focusing on college students [bib_ref] Digital mental health interventions for depression, anxiety, and enhancement of psychological well-being..., Lattie [/bib_ref] and user engagement [bib_ref] Barriers to and facilitators of user engagement with digital mental health interventions:..., Borghouts [/bib_ref] , this review also reported an increase since 2015 in eMH intervention studies meeting broad inclusion criteria. Recent reviews [bib_ref] Digital mental health interventions for depression, anxiety, and enhancement of psychological well-being..., Lattie [/bib_ref] [bib_ref] Barriers to and facilitators of user engagement with digital mental health interventions:..., Borghouts [/bib_ref] also found that the eMH interventions described in the included studies were primarily web-based despite the added benefits of mobile apps that are coded for a specific mobile operating system such as iOS and Android (eg, faster, functionality-rich, and offline access). This is perhaps because web-based interventions likely cost less to develop and could be accessed via more devices if they were developed in a responsive way. Emerging technologies, including AI, were considered in our search strategy, but were not used by the OeMH interventions described in the included studies. Nonetheless, this knowledge area is expected to increasingly feature the use of emerging technologies in the near future as the focus extends beyond nascent explorations of their applications for mental health and investigates the optimization of their implementation as well [bib_ref] What is the current and future status of digital mental health interventions?, Baños [/bib_ref].
## Implications and recommendations for practice and future research
Based on the findings of the scoping review, four practical recommendations could be considered to avoid and mitigate the identified barriers and improve the implementation of OeMH interventions:
1. Strategies must demonstrate a relative advantage over alternative solutions and promote flexibility in the delivery of interventions based on an explicit understanding of users, their tasks, and environments. 2. Strategies must promote the active engagement of organizational leadership, assess organizational readiness, and ensure compatibility with the organization's technological infrastructure and culture, in addition to providing desirable incentives and the necessary resources (eg, time and information about the intervention) for users to use the intervention as directed. 3. Strategies must ensure transparency regarding the intervention and implications of use and help users build confidence in their ability to benefit from the intervention. [bib_ref] CONSORT-EHEALTH: improving and standardizing evaluation reports of Web-based and mobile health interventions, Eysenbach [/bib_ref] [bib_ref] EHEALTH: implementation of a checklist for authors and editors to improve reporting..., Eysenbach [/bib_ref] [bib_ref] Expanding the CONSORT figure: increasing transparency in reporting on external validity, Glasgow [/bib_ref] and the implementation strategies used to achieve these outcomes (eg, Standards for Reporting Implementation Studies) [bib_ref] EMPOWER: The European platform to promote wellbeing and health in the workplace...., Pinnock [/bib_ref] [bib_ref] Standards for Reporting Implementation Studies (StaRI) statement, Pinnock [/bib_ref] need to be remedied for IR to be properly used in this area. Reporting could benefit from subscribing to technology-centric frameworks (eg, the mobile health evidence reporting and assessment checklist [bib_ref] WHO mHealth Technical Evidence Review Group. Guidelines for reporting of health interventions..., Agarwal [/bib_ref] and the integrated technology implementation model [bib_ref] Discovery of implementation factors that lead to technology adoption in long-term care, Schoville [/bib_ref] [bib_ref] Integrated technology implementation model: examination and enhancements, Schoville [/bib_ref] [bib_ref] Guiding healthcare technology implementation: a new integrated technology implementation model, Schoville [/bib_ref] that are more comprehensive in capturing key technology implementation factors (eg, accreditation, regulation, technology vendors, individual adoption factors, and interfacing systems). This should allow future studies to replicate and develop theories based on assessments of the implementation strategies used. In addition, any encountered or anticipated barriers and corresponding remedies that might be useful in avoiding these barriers or reducing their negative impact on implementation should also be reported. The development of an OeMH implementation checklist that includes comprehensive reporting guidelines and other prompts to ensure consistency and completeness when implementing these interventions would be beneficial. Future IR should also focus on investigating a wider range of common implementation outcomes (eg, cost-effectiveness and sustainability) [bib_ref] Outcomes for implementation research: conceptual distinctions, measurement challenges, and research agenda, Proctor [/bib_ref] facilitated by implementation strategies for OeMH interventions that also target more common mental health problems in the workplace (eg, anxiety, substance use, and addiction). Issues regarding lack of digital access and digital inequity are an ongoing challenge [bib_ref] Digital health equity and COVID-19: the innovation curve cannot reinforce the social..., Crawford [/bib_ref] , although not prominently featured in the results, and should be considered to avoid OeMH interventions contributing to any disparities. This study should also investigate how implementation strategies for OeMH interventions could benefit from emerging technologies. For instance, AI can use usage data to complement existing methods to better identify people who are at a high risk of mental health problems, support health decision-making, and offer resources that meet users' individual health needs [bib_ref] Digital interventions for mental disorders: key features, efficacy, and potential for artificial..., Ebert [/bib_ref]. This could have a profound positive impact on implementation through improvements in the effectiveness and maintenance of interventions.
# Limitations
Search results were limited to publications in English, and a publication date restriction was imposed from 2010 onwards; however, given the broad search strategy, it is not anticipated that many, if any, potentially eligible publications were missed as a result. The term eMental was coined in 2002, merely 8 years before this review's year restriction, and a recent review of 50 publications about OeMH interventionsincluded 11 publications that were published before 2010 and none were eligible for inclusion in this study. In addition, despite our exhaustive search strategy, 6 publications from 2010 to 2015 compared with 25 from the subsequent 5-year period were eventually included. Incomplete reporting also made it challenging to detail strategies (eg, their effectiveness), barriers, facilitators, and contextual data (eg, industry, organizational size, and employee level) from the included publications and to synthesize these data later. Nonetheless, all researchers involved in data extraction completed the training specifically for this review, followed the same thorough approach, and the extracted data were reviewed at least once by a second researcher. Interrater reliability was not calculated, and reasons for disagreement in screening decisions were not reported, which might have affected the reproducibility of this study [bib_ref] Interrater reliability in systematic review methodology: exploring variation in coder decision-making, Belur [/bib_ref]. However, this does not compromise the consistency and accuracy of the screening. Moreover, two 2-hour workshops were conducted with training sessions, and reconciliation meetings were consequently held when there were inconsistencies in screening decisions.
Although multiple implementation strategies can legitimately contribute to multiple RE-AIM domains, adopting a framework with more specificity could potentially be useful for the identification of more targeted strategies. Common implementation models (eg, RE-AIM and CFIR) predate the current development of eHealth, and concerns about their inability to fully capture the complexities of eHealth implementation have been raisedand persist [bib_ref] OeMH: Occupational eMental health PRISMA-ScR: Preferred Reporting Items for Systematic Reviews and..., Heinsch [/bib_ref] despite some recent updates [bib_ref] Expanding the CONSORT figure: increasing transparency in reporting on external validity, Glasgow [/bib_ref] and clarifications [bib_ref] Understanding and applying the RE-AIM framework: clarifications and resources, Holtrop [/bib_ref]. Nonetheless, these generic frameworks are useful for guiding data extraction and as tools for making valuable comparisons with other types of interventions. Similar to other scoping reviews, this review reports on the nature and features of the literature on the topic of focus and does not attempt to present a view regarding the appropriateness of the used methods and the strength or quality of evidence. Similarly, the provision of more detailed recommendations would have been premature and potentially misleading, as this was unsupported by the data collected. Further research is needed to determine valid facilitators and how they should be used in the process of OeMH development and delivery on a case-by-case basis while considering contextual factors such as industry, organizational size, employee level, and internal and external policies. Nevertheless, these recommendations could still be particularly relevant for OeMH interventions in comparison with similar interventions in different contexts. Consequently, readers should be mindful that the review cannot determine whether the included studies provide robust or generalizable findings.
# Conclusions
This scoping review represents one of the first steps in a research agenda aimed at improving the implementation of OeMH interventions by systematically selecting, shaping, evaluating, and reporting implementation strategies. It has identified 98 implementation strategies, 114 barriers, and 131 facilitation measures related to the implementation of these interventions. A synthesis of these findings offers 19 recommendations that provide initial guidance on how to improve the implementation of OeMH interventions. This scoping review also highlighted the need to combine common implementation models (eg, RE-AIM and CFIR) with more technology-centric frameworks (eg, integrated technology implementation model and the mobile health evidence reporting and assessment checklist) to fully capture the complexities of eHealth implementation. Despite yielding less detailed insight than hoped, owing to incomplete reporting and the adoption of incomprehensive frameworks by the included publications, this scoping review's findings can still be critically leveraged by discerning decision-makers to improve the reach, effectiveness, adoption, implementation, and maintenance of OeMH interventions.
[fig] Figure 1: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart of the review search, selection, and inclusion process. [/fig]
[table] Table 1: Characteristics of included publications and interventions. [/table]
[table] Table 2: Summary of study characteristics (N=31). [/table]
[table] Table 3: Summary of intervention characteristics (N=24). [/table]
[table] Table 4: categorizes these strategies into 17 discrete implementation strategies and maps them onto relevant RE-AIM domains based on the perceived intent of the themes. Each discrete implementation strategy is reported with the percentage and absolute number of defining strategy examples in relation to the 98 examples. Although evaluating effectiveness strategies is beyond the scope of this review, relevant effectiveness data could not be presented as they were largely absent or incomplete. A total of 36 examples of implementation strategies were extracted from publications that focused on the implementation of OeMH interventions, and 62 from publications that reported results or noted implications related to their implementation. There were no notable differences other than the larger number of examples extracted from the latter group so strategy examples would not be reported separately. Most strategy examples were organized under implementation (61/98, 62%), followed by reach (27/98, 28%), effectiveness (19/98), adoption (17/98, 17%), and maintenance (8/98, 8%). A couple of strategy examples were organized into multiple domains (6/98, 6%). The following sections provide a descriptive summary of the strategy examples categorized in each RE-AIM domain. [/table]
[table] Table 6: Examples of barriers and facilitators organized under the outer setting Consolidated Framework for Implementation Research domain (N=217). [/table]
[table] Table 7: Examples of barriers and facilitators organized under the inner setting Consolidated Framework for Implementation Research domain (N=217). [/table]
[table] Table 8: Examples of barriers and facilitators organized under the characteristics of individuals Consolidated Framework for Implementation Research domain (N=217). [/table]
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https://www.jmir.org/2022/6/e34479/PDF
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Background The implementation of eMental health interventions, especially in the workplace, is a complex process. Therefore, learning from existing implementation strategies is imperative to ensure improvements in the adoption, development, and scalability of occupational eMental health (OeMH) interventions. However, the implementation strategies used for these interventions are often undocumented or inadequately reported and have not been systematically gathered across implementations in a way that can serve as a much-needed guide for researchers. Objective The objective of this scoping review was to identify implementation strategies relevant to the uptake of OeMH interventions that target employees and detail the associated barriers and facilitation measures. Methods A scoping review was conducted. The descriptive synthesis was guided by the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework and the Consolidated Framework for Implementation Research. Results A total of 31 of 32,916 (0.09%) publications reporting the use of the web-, smartphone-, telephone-, and email-based OeMH interventions were included. In all, 98 implementation strategies, 114 barriers, and 131 facilitators were identified. The synthesis of barriers and facilitators produced 19 facilitation measures that provide initial recommendations for improving the implementation of OeMH interventions. Conclusions This scoping review represents one of the first steps in a research agenda aimed at improving the implementation of OeMH interventions by systematically selecting, shaping, evaluating, and reporting implementation strategies. There is a dire need for improved reporting of implementation strategies and combining common implementation frameworks with more technology-centric implementation frameworks to fully capture the complexities of eHealth implementation. Future research should investigate a wider range of common implementation outcomes for OeMH interventions that also focus on a wider set of common mental health problems in the workplace. This scoping review’s findings can be critically leveraged by discerning decision-makers to improve the reach, effectiveness, adoption, implementation, and maintenance of OeMH interventions.
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Neurofibromatosis Type 1 in Genetic Counseling Practice: Recommendations of the National Society of Genetic Counselors
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Neurofibromatosis Type 1 in Genetic Counseling Practice: Recommendations of the National Society of Genetic Counselors
The objective of this document is to provide recommendations for the genetic counseling of patients and families undergoing evaluation for neurofibromatosis type 1 (NF1) or who have received a diagnosis of NF1. These recommendations are the opinions of a multi-center working group of genetic counselors with expertise in the care of individuals with NF1. These recommendations are based on the committee's clinical experiences, a review of pertinent English language medical articles, and reports of expert committees. These recommendations are not intended to dictate an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of an individual patient.Our geneticist convinced us that in reality nothing had changed with our daughter when we walked through the door. We just had more information. She convinced us that although life was uncertain, we need to make sure that our child was given the opportunity to reach her full potential, no matter what that might be. Medically, if we were out having fun prior to the diagnosis, then that shouldn't change. We should continue to enjoy life and not let the information affect the child. In that sense, information can be harmful and NF will have already caused harm. I will say that we were still devastated, but her words helped us get through the process more quickly than if someone had just sat there and told us the facts and answered our questions. She set us out with goals in our life and a framework with which to use that information in our child's best interest.-Parent of a child with NF1, commenting on his experience with the genetic counseling process.
## Purpose
The purpose of these guidelines is to serve as a comprehensive resource for health care professionals providing genetic counseling to patients and families undergoing evaluation for neurofibromatosis type 1 (NF1) or who have received a diagnosis of NF1. In this document, we review the diagnosis, natural history, and genetics of NF1. We suggest relevant items to be included in the genetic counseling session. Specific medical management recommendations will not be discussed in this document.
## Disclaimer
These recommendations were approved in March 2007 by the National Society of Genetic Counselors (NSGC)-the leading voice, advocate and authority for the genetic counseling profession. This document is not intended to replace the judgment of an individual genetic counselor with respect to particular patients or special clinical situations and cannot be considered inclusive of all practices or exclusive of other practices reasonably directed at obtaining the same results. In addition, the practice of genetic counseling is subject to regulation by federal, state and local governments. In a subject jurisdiction, any such regulations will take precedence over this statement. NSGC expressly disclaims any warranties or guarantees, express or implied, and shall not be liable for damages of any kind, in connection with the information set forth in this document or for reliance on its contents.
Genetic counseling is a dynamic profession, which undergoes rapid change with the discovery of new genetic information and the development of new genetic tests and treatment options. Thus, NSGC will periodically review and, where appropriate, revise this statement as necessary for consistency with current practice information.
## Objectives
The goals of these recommendations are to:
1. Review the history, epidemiology, and genetics of NF1. 2. Summarize the current understanding of the natural history of NF1. 3. Provide a framework for the genetic counseling sessions of individuals and families with NF1. 4. Present a list of resources for patients and families with NF1.
# Materials and methods
The NF1 Working Group was composed of genetic counselors with experience in various NF1 Clinics through-out the United States. MEDLINE, PubMed and Internet databases were searched (using the key words neurofibromatosis type 1, NF1, neurofibromin) to locate relevant English language medical papers published between 1966 and 2007. The literature was reviewed and evaluated according to the following categories outlined by the US Preventive Services Task Force (1995):
I. Evidence obtained from at least one properly designed randomized controlled trial. II-1. Evidence obtained from well-designed controlled trials without randomization. II-2. Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. II-3. Evidence obtained from multiple time series, with or without the intervention. III. The opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The rating of supporting literature for this recommendation is Class III. Particular attention was paid to genetic counseling issues. Following the completion of the initial draft of the guidelines, the NF1 Working Group elicited opinions and feedback from noted medical experts in the field, as well as representatives of NF1 support and advocacy organizations (See "Patient Resources"). These recommendations were approved by the NSGC Board of Directors in March, 2007.
## Overview of neurofibromatosis type 1
Historical Background Over the centuries, NF1 has been known by many names, including peripheral neurofibromatosis, von Recklinghausen disease, and, erroneously, the "Elephant Man Disease." The history of NF1 is briefly summarized in [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref].
Historically, there has been confusion regarding the relationship between neurofibromatosis types 1 and 2. It was initially thought that these two conditions represented different manifestations of the same underlying entity. In 1930, Garner and Frazier first suggested that individuals with only central nervous system tumors should be differentiated from those with other manifestations of the condition. Genetic linkage to two distinct loci confirmed that these two conditions were not only clinically but also etiologically distinct [bib_ref] Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome..., Rouleau [/bib_ref].
Another historical confusion is the belief that the "Elephant Man" had neurofibromatosis. Joseph Merrick had a debilitating disfigurement originally presumed to be NF. His life was originally documented byLater, a play and a movie introduced this story to the public. Current knowledge suggests that Joseph Merrick had Proteus syndrome rather than NF [bib_ref] The Proteus syndrome: The elephant man diagnosed, Tibbles [/bib_ref]. However, the repercussions of the initial presumption persist, and many families continue to be misinformed that NF1 is the "Elephant Man Disease." Epidemiology NF1 is one of the most common genetic conditions with an estimated prevalence of 1 in 3,500 people [bib_ref] A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I...., Huson [/bib_ref] [bib_ref] Epidemiology of neurofibromatosis type 1 (NF1) in northern Finland, Poyhonen [/bib_ref] [bib_ref] NF1 gene and neurofibromatosis 1, Rasmussen [/bib_ref]. A distinct feature of the NF1 gene is the very high spontaneous mutation rate (1×10 −4 per gamete per generation), which is about 100-fold higher than the typical mutation rate for a single locus. This high mutation rate cannot be accounted for strictly by the size of the gene [bib_ref] The mutational spectrum in neurofibromatosis type 1 and its underlying mechanisms, Upadhyaya [/bib_ref]. NF1 affects all races, ethnicities, and genders.
## Diagnosis
Although the diagnosis of NF1 has historically been established by clinical evaluation, continued advances in the study of NF1 may lead to modification of diagnostic strategies. In recent years, advances in molecular testing offer another diagnostic approach.
## Clinical evaluation
Traditionally, NF1 has been a clinical diagnosis, based on a set of diagnostic criteria established in 1987 (NIH Consen-sus Development Conference 1988). These criteria are listed in [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref].
The appearance of many of the diagnostic manifestations of NF1 is age-dependent. This may make the diagnosis in a young child without a family history of the condition challenging. As a result, children may need to be followed for several years before the clinical diagnosis of NF1 can be confirmed. Approximately 90% of individuals with NF1 will have two or more diagnostic criteria by 6 years of age, 97% by age 8 and all do so by 20 years of age [bib_ref] Use of National Institutes of Health criteria for diagnosis of neurofibromatosis 1..., Debella [/bib_ref] [bib_ref] Diagnostic outcome in children with multiple caféau-lait spots, Korf [/bib_ref]. The most common NF1 referral indication is multiple café-au-lait spots; however, not all children with cafe-au-lait spots will be diagnosed with NF1.
## Molecular testing
Genetic testing is clinically available and identifies approximately 95% of mutations in individuals that fulfill the clinical diagnostic criteria [bib_ref] Exhaustive mutation analysis of the NF1 gene allows identification of 95% of..., Messiaen [/bib_ref]. Testing may be beneficial to individuals meeting only one of the diagnostic criteria or when the diagnosis is unclear. A positive DNA test result cannot predict the presence, age of onset, or severity of NF1 symptoms (See "Molecular Basis of Disease"). Likewise, a negative result, in the absence of a known familial mutation, cannot exclude the diagnosis.
## Natural history
Phenotypic Variability NF1 exhibits an extreme degree of inter-and intra-familial variability. Modifier genes may play a role in this variability [bib_ref] Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1), Szudek [/bib_ref]. One study estimated that two-thirds of individuals with NF1 are relatively mildly affected, not Molecular testing for NF1 identifies mutation in more than 95% of individuals meeting diagnostic criteria [bib_ref] Exhaustive mutation analysis of the NF1 gene allows identification of 95% of..., Messiaen [/bib_ref] [bib_ref] Historical Background and Information, Riccardi [/bib_ref] requiring major surgery or having life-threatening problems [bib_ref] Penetrance and variability in neurofibromatosis: A genetic study of 60 families, Carey [/bib_ref]. However, at the time this study was completed, many of the serious complications that are now known to be associated with NF1 had not yet been recognized. Therefore, this may represent an underestimate of the rate of serious complications of NF1.
Clinical Features [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref] lists the frequency and age of onset of common symptoms of NF1.
## Café-au-lait spots
Café-au-lait spots (CALS) are pigmentary lesions proportionately darker than one's skin color with uniform pigmentation and smooth borders. The presence of multiple CALS is one of the most well-recognized features of NF1. Ninety-nine percent of individuals with NF1 meet the CALS diagnostic criteria by 1 year of age [bib_ref] Use of National Institutes of Health criteria for diagnosis of neurofibromatosis 1..., Debella [/bib_ref]. In the newborn, typical CALS are oval-shaped lesions between 1 and 4 cm in diameter [bib_ref] The incidence and significance of birthmarks in a cohort of 4, 641..., Alper [/bib_ref]. As the child ages, the number and size of CALS may increase. In adults, CALS tend to fade and may be more difficult to identify.
## Freckling
Another characteristic but innocuous finding of NF1 is freckling, which is present in over 90% of patients by 7 years of age [bib_ref] Use of National Institutes of Health criteria for diagnosis of neurofibromatosis 1..., Debella [/bib_ref]. The freckles are similar in color to café-au-lait spots but are much smaller and often occur in clusters [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref]. They are most commonly found in the axillary and inguinal regions, but they can also occur in other areas of skin-toskin contact, such as the underside of the breast in female patients, between skin folds in obese patients, and on the back of the neck.
## Lisch nodules
Lisch nodules are a common feature of NF1. Lisch nodules are pigmented hamartomas of the iris that do not affect vision. They are typically not present at birth, but they develop during childhood. More than 95% of individuals with NF1 have Lisch nodules by the age of 20 [bib_ref] Iris hamartomata as a diagnostic criterion in neurofibromatosis, Flueler [/bib_ref] [bib_ref] Ophthalmic manifestations of neurofibromatosis, Huson [/bib_ref] [bib_ref] Lisch nodules in neurofibromatosis type 1, Lubs [/bib_ref]. Slit lamp examination by an ophthalmologist is necessary to determine the presence or absence of Lisch nodules as well as the distinction between these and iris nevi, which are not associated with NF1 [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref].
## Optic pathway gliomas
Optic pathway gliomas (OPG), or pilocytic astrocytomas of the optic nerve, are the most common central nervous system tumors seen in NF1 and typically present in early childhood (less than 6 years of age) [bib_ref] Intracranial gliomas in neurofibromatosis type 1, Listernick [/bib_ref] [bib_ref] Neurofibromatosis type 1 and sporadic optic gliomas, Singhal [/bib_ref]. It has been estimated that up to 70% of all OPGs are related to NF1 [bib_ref] Intracranial gliomas in neurofibromatosis type 1, Listernick [/bib_ref]. OPGs may be either unilateral or bilateral and may involve the optic nerve, the chiasm, or both. Approximately 15% of NF1 patients will develop an OPG, half of whom have no clinical symptoms [bib_ref] Natural history of optic pathway tumors in children with neurofibromatosis type 1:..., Listernick [/bib_ref] ; [bib_ref] Neurofibromatosis type 1 and sporadic optic gliomas, Singhal [/bib_ref]. Most NF1-related OPGs do not progress or metastasize. If progression does occur, presenting symptoms often include proptosis, precocious puberty or increased growth velocity. Other symptoms include loss of visual acuity, abnormal color vision, optic atrophy, and afferent pupillary defect. Some optic nerve tumors may spontaneously regress.
## Skeletal findings
Scoliosis is the most common skeletal finding in NF1 with an estimated frequency ranging from 10 to approximately 25% [bib_ref] Prevalence of scoliosis in neurofibromatosis, Akbarnia [/bib_ref] [bib_ref] Neurofibromatosis in children: The role of the orthopedist, Crawford [/bib_ref] [bib_ref] Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients, Friedman [/bib_ref] [bib_ref] Skeletal system, Riccardi [/bib_ref] [bib_ref] Orthopedic manifestations of neurofibromatosis in children. An update, Vitale [/bib_ref]. The scoliosis can be either dystrophic or nondystrophic [bib_ref] Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?, Alwan [/bib_ref]. The dystrophic type of scoliosis is associated with bony abnormalities evident on radiographic films and tends to be more severe with rapid progression. This form of scoliosis typically presents between 6 and 10 years of age, and, if not present by 10 years, is unlikely to develop [bib_ref] Skeletal system, Riccardi [/bib_ref]. The nondystrophic form of scoliosis has no apparent bony abnormalities and has findings similar to idiopathic scoliosis in individuals without NF1; it presents during adolescence and tends to be less severe. Kyphoscoliosis may also develop [bib_ref] Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?, Alwan [/bib_ref]. Occasionally, these spinal abnormalities may be caused by an underlying neurofibroma. Sphenoid dysplasia is present in 3-7% of NF1 patients and typically presents as a unilateral defect [bib_ref] Skeletal system, Riccardi [/bib_ref] [bib_ref] Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?, Alwan [/bib_ref]. Over 50% of cases of sphenoid dysplasia are associated with NF1. The lesions are usually asymptomatic and are diagnosed by skull radiographs or CT scans [bib_ref] Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?, Alwan [/bib_ref]. In rare instances, progression of a lesion may lead to medical complications such as enophthalmos and herniation of the brain into the orbit [bib_ref] Skeletal system, Riccardi [/bib_ref].
Lesions of the long bones are another feature of NF1 with a prevalence of 1-4% [bib_ref] Neurofibromatosis in children: The role of the orthopedist, Crawford [/bib_ref] [bib_ref] Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients, Friedman [/bib_ref] [bib_ref] Orthopedic manifestations of neurofibromatosis in children. An update, Vitale [/bib_ref]. The tibia is most frequently involved, although other long bones may also be affected [bib_ref] Congenital pseudarthrosis of the ulna due to neurofibromatosis, Ali [/bib_ref] [bib_ref] Congenital pseudarthrosis of the clavicle, Alldred [/bib_ref] [bib_ref] The elephant woman. Neurofibromatosis associated with pseudarthrosis of the humerus, Floyd [/bib_ref] [bib_ref] Pseudarthrosis of the radius associated with neurofibromatosis, Gregg [/bib_ref] [bib_ref] The fibula in congenital pseudarthrosis of the tibia: The EPOS multicenter study, Keret [/bib_ref] [bib_ref] Skeletal system, Riccardi [/bib_ref]. Congenital pseudarthrosis, or "false joint" abnormality, occurs in 1-2% of NF1 patients [bib_ref] Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients, Friedman [/bib_ref] [bib_ref] Skeletal system, Riccardi [/bib_ref]. These lesions are often detected during infancy or early childhood and present as bowing or fracturing of the affected bone [bib_ref] Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?, Alwan [/bib_ref]. Other potential abnormalities of the long bones include changes associated with a plexiform neurofibroma or localized lytic defects [bib_ref] Skeletal system, Riccardi [/bib_ref].
NF1 patients also have an increased risk for osteoporosis and osteopenia. [bib_ref] Decreased bone mineral density and content in neurofibromatosis type 1: Lowest local..., Kuorilehto [/bib_ref]. Other skeletal anomalies found in NF1 patients may include pectus deformities, genu varum, and genu valgum [bib_ref] Skeletal system, Riccardi [/bib_ref].
## Neurofibromas
Neurofibromas (NFs) are benign tumors that can occur anywhere in the body. They most commonly develop along peripheral nerves or less frequently in the deep nerves. Neurofibromas are typically multicellular in origin, composed of Schwann cells, axons, fibroblasts, mast cells, endothelial cells and perineurial cells [bib_ref] Cellular differentiation and expression of matrix genes in type 1 neurofibromatosis, Peltonen [/bib_ref]. Pruritis, or itching, is a somewhat common feature of NF1 and when localized, often precedes the development of cutaneous neurofibromas.
NFs can be classified into different types [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref] :
## Discrete neurofibromas
Discrete NFs are benign tumors that arise from a single site on a peripheral nerve. They are rarely present at birth, often appearing just before the time of puberty [bib_ref] Neurofibromatosis type I and pregnancy, Dugoff [/bib_ref]. The number of dermal neurofibromas tends to increase with age and varies widely between individuals. They may increase in size and number during pregnancy. Discrete NFs are encapsulated; they may grow in size and press on other tissues, but will not invade them.
Discrete Cutaneous Neurofibromas. Discrete cutaneous NFs usually protrude above the skin and are soft and fleshy. They may be flesh-colored, pink or purple. They may be sessile or pedunculated. They often initially appear on the chest, abdomen and back. Typically, these NFs are not painful, but may cause pruritis and often have a significant cosmetic burden. Discrete Subcutaneous Neurofibromas. Discrete subcutaneous NFs develop along nerves contained in deeper body tissue under the epidermis. They are usually firm and rubbery to palpation and can be distinguished from cutaneous neurofibromas because the skin can be moved over the nodule. These tumors may present clinically as beadlike nodules along the length of the nerve and they range in size from pea-sized to several centimeters. They may be painful or tender. Tumors in deeper nerves can compress a nerve root, causing radicular pain, weakness or loss of sensation.
## Plexiform neurofibromas
Plexiform NFs (PNFs) grow along the length of a peripheral nerve sheath. They are non-encapsulated and therefore may grow into healthy tissue and interfere with normal development of tissue or bone. These tumors tend to be supported by a network of blood vessels and therefore are usually difficult to surgically remove. Most PNFs are benign, but there is a risk for transformation to malignant peripheral nerve sheath tumors (MPNST) (See 'Tumors and Malignancy').
Diffuse Plexiform Neurofibromas. Diffuse PNFs are usually congenital, but may not be recognized until they increase in size or are found incidentally. They may spread out from the area of origin and develop numerous extensions that infiltrate extensively into adjacent normal tissues, making complete surgical removal difficult. They may also engulf nerves. The tumors can occur superficially, in deep tissues, or a combination thereof. With superficial involvement, skin may be thickened, redundant, and/or hyperpigmented. There may also be thick, coarse hair or localized hypertrophy over the affected area. Diffuse PNFs are described as having a "bag of worms" feel on palpation and most often develop in the head, neck and abdomen. They typically grow most rapidly during childhood, although they sometimes increase during adolescence and pregnancy. Nodular Plexiform Neurofibromas. Nodular PNFs are less common than diffuse PNFs and are discrete lesions that arise in peripheral nerve trunks. The most frequent site of involvement is along the spinal nerves. They cannot usually be detected by palpation. They vary in size and are sometimes painful. These types of NFs frequently cause neurological symptoms.
## Seizures
Although not common, there are some studies that suggest an increased frequency of seizures (range 3.5-7.3%) in NF1 [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref] [bib_ref] Neurofibromatosis type 1: Review of the first 200 patients in an Australian..., North [/bib_ref]. The seizures that are suggested to be associated with NF1 do not differ from those seen in the general population. When not associated with an intracranial lesion or stenosis, these seizures are generally well-controlled with routine antiepileptic drugs [bib_ref] Abnormalities of the nervous system, Gutmann [/bib_ref].
## Headaches
Individuals with NF1 have an increased frequency of headaches. These range from a mild "tension" headache to a true migraine [bib_ref] Neurofibromatosis: An overview and new directions in clinical investigations, Riccardi [/bib_ref]. Although common, a new onset of headaches or ones that are atypical for the patient and/or accompanied by neurologic deficits, may warrant investigations for other causes including brain tumors, pheochromocytomas or cerebrovascular etiologies [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref] [bib_ref] Neurofibromatosis: An overview and new directions in clinical investigations, Riccardi [/bib_ref].
## Ubos
Cranial MRI scans in NF1 patients often show focal areas of high signal intensity on T2 or FLAIR weighted images. They are typically referred to as Unidentified Bright Objects (UBOs) or "NF spots." They exert no mass effect and are not observed on CT scan. They often resolve with time and are rarely seen in NF1 patients over the age of 20 [bib_ref] Neurofibromatosis Types 1 & 2: Cranial MR findings, Aoki [/bib_ref]. Some researchers have suggested a connection between the presence of UBOs and lower IQ, language skills, visuospatial functioning and academic achievement [bib_ref] Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children..., Denckla [/bib_ref] , although this has not been found in other studies [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref].
## Growth
Individuals with NF1 tend to be below average in height and true short stature (<10th percentile) occurs in more than 40% of adults with NF1 [bib_ref] Growth, puberty, and endocrine functions in patients with sporadic or familial neurofibromatosis..., Carmi [/bib_ref]. One study found growth hormone deficiency in 3 of 122 children, although this does not appear to be the cause of short stature in most patients with NF1 [bib_ref] Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1, Cnossen [/bib_ref].
Macrocephaly, either relative or absolute, is present in 29-45% of individuals with NF1 and usually develops during childhood [bib_ref] Neurofibromatosis type 1 growth charts, Clementi [/bib_ref] [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref] [bib_ref] Skeletal system, Riccardi [/bib_ref] [bib_ref] Growth charts for young children with neurofibromatosis 1 (NF1), Szudek [/bib_ref]. Rarely, underlying hydrocephalus is identified [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref].
## Onset of puberty
Most individuals with NF1 undergo normal pubertal development [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref]. However, in approximately 1-4% of patients, puberty may be premature or delayed [bib_ref] Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients, Friedman [/bib_ref]. Precocious puberty typically results from an optic chiasm glioma or other tumor proximal to the region of the hypothalamus [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref] [bib_ref] Precocious puberty in children with neurofibromatosis type 1, Habiby [/bib_ref].
## Pregnancy and nf
Although NF1 appears to have no intrinsic effect on fertility, negative pregnancy outcome has been reported [bib_ref] Clinical and epidemiological features, Friedman [/bib_ref]. Early reports suggest a significant increase in complications including intrauterine growth retardation, preterm labor, and stillbirth [bib_ref] Neurofibromatosis and pregnancy: Report of a case complicated by intrauterine growth retardation..., Belton [/bib_ref] [bib_ref] Neurofibromatosis and severe hypertension in pregnancy, Edwards [/bib_ref] [bib_ref] Neurofibromatosis and pregnancy: An update, Weissman [/bib_ref]. However, these findings are controversial, and more recent studies suggest that most pregnancy outcomes for healthy women with NF1 are normal, although there appears to be an increased need for cesarean-sections [bib_ref] Neurofibromatosis type I and pregnancy, Dugoff [/bib_ref]. Pregnancy is frequently associated with an exacerbation of existing maternal symptoms as well as the new presentation or rapid increase in tumors and hypertension [bib_ref] Pregnancy and neurofibromatosis (von Recklinghausen's disease), Ansari [/bib_ref] [bib_ref] Neurofibromatosis type I and pregnancy, Dugoff [/bib_ref] [bib_ref] Neurofibromatosis in pregnancy, Swapp [/bib_ref]. A subsequent decrease in the size of the exacerbated neurofibromas in the postpartum period is sometimes seen [bib_ref] Neurofibromatosis type I and pregnancy, Dugoff [/bib_ref].
## Cardiovascular findings
Hypertension is a common finding in individuals with NF1. The incidence of hypertension increases with age and can lead to heart attack, stroke, kidney failure, and other medical problems. In most cases, the hypertension is essential. However, less common causes of hypertension include renal artery abnormalities, pheochromocytomas, and, in rarer instances, aortic coarctations or brain tumors [bib_ref] Vascular and endocrine abnormalities, Friedman [/bib_ref].
Congenital heart defects have been reported in patients with NF1 with an estimated frequency between 0.4 and 6.4% [bib_ref] Penetrance and variability in neurofibromatosis: A genetic study of 60 families, Carey [/bib_ref] [bib_ref] Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1, Lin [/bib_ref] [bib_ref] Summary of patient data from a multidisciplinary neurofibromatosis clinic, Schorry [/bib_ref]. The most common cardiac abnormality is valvar pulmonic stenosis [bib_ref] Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients, Friedman [/bib_ref] [bib_ref] Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1, Lin [/bib_ref]. This abnormality has been described in individuals with the Watson and the NF1-Noonan phenotypes as well as individuals with a large gene deletion (See "Variants of NF1"); however, the incidence of pulmonic stenosis is also increased in patients with NF1 without these variant phenotypes. Coarctation of the aorta and other heart defects have also been reported [bib_ref] Type 1 neurofibromatosis: A descriptive analysis of the disorder in 1,728 patients, Friedman [/bib_ref] [bib_ref] Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1, Lin [/bib_ref]. Several reports have identified NF1 patients with hypertrophic cardiomyopathy. Current evidence is insufficient to determine whether these reflect manifestations of NF1 or are simply coincidental.
Vasculopathies are a well-recognized cardiovascular complication of NF1 [bib_ref] Vascular and endocrine abnormalities, Friedman [/bib_ref]. They may be peripheral or cerebrovascular. The specific types of lesions include stenoses, dilations, aneurysms, and fistulas . Arterial involvement is most common, although venous involvement has also been reported [bib_ref] Neurofibromatosis presenting as a severe systemic vasculopathy, Lehrnbecher [/bib_ref]. These lesions frequently occur in the renal arteries, but may also occur in the cerebral or visceral arteries [bib_ref] Abdominal aortic coarctation, renovascular, hypertension, and neurofibromatosis, Criado [/bib_ref] [bib_ref] Ruptured pancreaticoduodenal artery aneurysms and pheochromocytoma in a pregnant patient with neurofibromatosis, Serleth [/bib_ref] [bib_ref] A 4-year old boy with neurofibromatosis and severe renovascular hypertension due to..., Westenend [/bib_ref]. The exact frequency of vasculopathy in patients with NF1 is unknown and many patients with vasculopathy remain asymptomatic throughout their lives . Symptomatic vascular lesions are most commonly detected in childhood or early adulthood and may be identified during a pregnancy [bib_ref] Neurofibromatosis and renovascular hypertension presenting in early pregnancy, Pilmore [/bib_ref]. A study by [bib_ref] Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1, Rosser [/bib_ref] identified a cerebrovascular abnormality in 2.5% of patients with NF1. These abnormalities may present with neurological symptoms secondary to cerebral ischemia .
## Pruritis
Pruritis, or chronic itching, is a relatively common feature of NF1. It may be generalized or restricted to a certain area of the body. When localized, the itching may precede the development of cutaneous neurofibromas. The itching is thought to be related to the large amount of mast cells in neurofibromas and is often relieved by anti-histamines [bib_ref] Neurofibromatosis: An overview and new directions in clinical investigations, Riccardi [/bib_ref].
## Tumors and malignancy
The malignancy rates in individuals with NF1 are higher than the general population risk, though precise risk estimates vary. Literature reports suggest that the risk for malignancy in individuals with NF1 is 5-15% higher than the general population risk [bib_ref] A prospective study of neurofibromatosis type I cancer incidence in the UK, Walker [/bib_ref]. On average, the onset of malignancy in NF1 patients appears to be earlier than the general population [bib_ref] Segmentally distributed neurofibromatosis associated with adenocarcinoma of the colon, Kim [/bib_ref] [bib_ref] A prospective study of neurofibromatosis type I cancer incidence in the UK, Walker [/bib_ref]. A prospective study by Walker et al. suggests that the increased malignancy rate comes primarily from a higher incidence of central nervous system and connective tissue malignancies [bib_ref] A prospective study of neurofibromatosis type I cancer incidence in the UK, Walker [/bib_ref].
## Malignant peripheral nerve sheath tumors
Approximately 4-13% of patients with NF1 will develop a malignant peripheral nerve sheath tumor (MPNST), also called malignant schwannoma or neurofibrosarcoma [bib_ref] From the archives of the AFIP: Abdominal neoplasms in patients with neurofibromatosis..., Levy [/bib_ref]. The most common locations of these tumors in NF1 patients are the abdominal paraspinal region, the extremities, and the head and neck regions [bib_ref] From the archives of the AFIP: Abdominal neoplasms in patients with neurofibromatosis..., Levy [/bib_ref]. Approximately 20-50% of patients with MPNSTs also have NF1 [bib_ref] From the archives of the AFIP: Abdominal neoplasms in patients with neurofibromatosis..., Levy [/bib_ref]. Compared to individuals without NF1, individuals with NF1 tend to be diagnosed with an MPNST at a younger age and have a poorer prognosis. Most of the time, MPNSTs in NF1 are associated with an underlying plexiform neurofibroma [bib_ref] From the archives of the AFIP: Abdominal neoplasms in patients with neurofibromatosis..., Levy [/bib_ref]. While plexiform neurofibromas may be very large tumors, the malignant component of the tumor may be very small and can easily be missed by a single biopsy. Symptoms commonly reported by patients with an MPNST include pain, enlarging tumor mass, and neurologic symptoms.
## Pheochromocytomas
Pheochromocytomas are catecholamine-secreting tumors that occur most often in the adrenal gland They occur in approximately 0.1-5.7% of NF1 patients. In the majority of cases, the NF1-related pheochromocytoma will be a single, unilateral tumor (84%). Roughly 10% of patients will have a bilateral pheochromocytoma and a small percentage (6%) will have an extra-adrenal pheochromocytoma [bib_ref] von Recklinghausen's disease and pheochromocytomas, Walther [/bib_ref]. Pheochromocytomas often lead to increased production of adrenaline which may cause hypertension and a variety of other associated symptoms such as headaches, cardiac palpitations, diaphoresis and tremors. They may become metastatic. [bib_ref] von Recklinghausen's disease and pheochromocytomas, Walther [/bib_ref].
## Gastrointestinal tumors
There is a wide spectrum and diverse nature of tumors that occur along the gastrointestinal (GI) tract in NF1 patients. Neurofibromas are the most common tumor of the gastrointestinal tract in patients with NF1, however most of these are benign and asymptomatic. When symptomatic, abdominal pain, constipation and bleeding are the most common presenting symptoms. The incidence of gastrointestinal carcinoids is higher in NF1 patients than in the general population; however, the malignancy rate is comparable between the two groups [bib_ref] From the archives of the AFIP: Abdominal neoplasms in patients with neurofibromatosis..., Levy [/bib_ref]. Gastrointestinal stromal tumors (GIST) are associated with NF1. Contrary to non-NF1 patients, NF1-related GIST occur primarily in the small intestine and typically present as either multiple tumors or are associated with other GI neoplasms [bib_ref] Gastrointestinal stromal tumors in patients with neurofibromatosis: Imaging features with clinicopathologic correlation, Levy [/bib_ref].
## Leukemia and lymphoma
There have been several reports suggesting an increased risk for acute lymphoblastic leukemia, non-Hodgkin lymphoma and juvenile myelomonocytic leukemia (JMML) in NF1 [bib_ref] Neurofibromatosis and childhood leukaemia/lymphoma: A population-based UKCCSG study, Stiller [/bib_ref] [bib_ref] Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia, Zvulunov [/bib_ref]. As many as 14% of individuals with JMML have NF1 [bib_ref] Chronic myelomonocytic leukemia in childhood: A retrospective analysis of 110 cases, Niemeyer [/bib_ref]. However, the risk of an individual with NF1 developing JMML is low. [bib_ref] Other malignancies, Gutmann [/bib_ref]. An association between leukemia and the cutaneous finding of juvenile xanthogranulomas (JXG) has been suggested, but this association has not been well-established [bib_ref] Juvenile zanthogranuloma associated with neurofibromatosis 1: 14 patients without evidence of hematologic..., Cambiaghi [/bib_ref] [bib_ref] Juvenile chronic granulocytic leukemia, juvenile xanthogranulomas, and neurofibromatosis. Case report and review..., Morier [/bib_ref].
## Gliomas
Optic gliomas are seldom malignant and are discussed earlier in this document. Other than optic gliomas, individuals with NF1 are at risk for other types of gliomas, including cerebellar astrocytomas, ependymomas, third ventricle astrocytomas, cerebral astrocytomas, brain stem gliomas, and spinal cord tumors. The risk of malignant transformation in these tumors in NF1 patients was found to be higher than in those without NF1 [bib_ref] Gliomas in neurofibromatosis: A series of 89 cases with evidence for enhanced..., Ilgren [/bib_ref].
## Embryonal tumors
Rhabdomyosarcomas are seen with disproportionately high frequency in individuals with NF1. An association of NF1 with neuroblastoma and Wilms tumor has been suggested but has not been confirmed [bib_ref] From the archives of the AFIP: Abdominal neoplasms in patients with neurofibromatosis..., Levy [/bib_ref].
## Breast cancer
Questions have been raised regarding a potentially increased risk for breast cancer in individuals with NF1 due to the possible role of neurofibromin in some breast cancers [bib_ref] A case of neurofibromatosis and breast cancer: Loss of heterozygosity of NF1..., Guran [/bib_ref]. This concern has been further supported by a prospective study suggesting an increased risk for early onset-breast cancer among women with NF1 [bib_ref] A prospective study of neurofibromatosis type I cancer incidence in the UK, Walker [/bib_ref]. Additional data and larger studies are necessary to determine whether the breast cancer risk in individuals with NF1 is truly increased.
## Miscellaneous tumors
A variety of other tumors occur in NF1 including leiomyosarcomas, ganglioneuromas and adenocarcinomas [bib_ref] From the archives of the AFIP: Abdominal neoplasms in patients with neurofibromatosis..., Levy [/bib_ref].
## Cognitive phenotype
The vast majority of individuals with NF1 have intelligence within the normal range. However, there is a documented leftward shift in the IQ curve, as well as an increased incidence of both mental retardation (MR) and learning disabilities as compared to the general population [bib_ref] Social skills of children with neurofibromatosis type 1, Barton [/bib_ref] [bib_ref] Neurofibromatosis: Implications for learning and behaviour, Eliason [/bib_ref] [bib_ref] Intellectual impairment in neurofibromatosis 1, Ferner [/bib_ref] [bib_ref] Language and reading deficits associated with neurofibromatosis type 1: Evidence for a..., Mazzocco [/bib_ref].
The incidence of MR in the NF1 population is estimated to be between 4.8 and 11% [bib_ref] Children and adolescents with neurofibromatosis 1: A behavioral phenotype, Dilts [/bib_ref] [bib_ref] Intellectual impairment in neurofibromatosis 1, Ferner [/bib_ref] [bib_ref] The nature and frequency of cognitive deficits in children with neurofibromatosis type..., Hyman [/bib_ref] [bib_ref] Cognitive function and academic performance in children with neurofibromatosis type 1, North [/bib_ref] [bib_ref] Neurofibromatosis in childhood: Neuropsychological aspects, Wadsby [/bib_ref]. Large NF1 gene deletions are a frequent finding in patients with MR, and patients with such deletions tend to exhibit a more severe phenotype overall [bib_ref] Example of somatic mosaicism in a series of de novo neurofibromatosis type..., Ainsworth [/bib_ref] (See "Variants of NF1"). Accordingly, MR is not typically expected in individuals without the deletion. The occurrence of MR in a patient with NF1 without a full gene deletion may warrant further evaluations to rule out other more common causes of MR, such as chromosomal duplications/deletions, and fragile X syndrome.
Learning disabilities are a much more common occurrence in NF1. Historically, most studies have estimated the incidence of learning disabilities to be between 40 and 60%, although the criteria for defining a "learning disability" have varied [bib_ref] The nature and frequency of cognitive deficits in children with neurofibromatosis type..., Hyman [/bib_ref] [bib_ref] Behavioral phenotype of neurofibromatosis, type 1. Mental Retardation and Developmental, Kayl [/bib_ref] [bib_ref] Cognitive Function and Academic Performance, North [/bib_ref] [bib_ref] Cognitive impairment in neurofibromatosis type 1, Ozonoff [/bib_ref] [bib_ref] Neurofibromatosis: A clinical and genetic study of 96 cases in Gothenburg, Samuelsson [/bib_ref] [bib_ref] Learning problems in neurofibromatosis patients, Stine [/bib_ref] [bib_ref] Neurofibromatosis in childhood: Neuropsychological aspects, Wadsby [/bib_ref]. The Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV) defines a specific learning disability as "the achievement on standardized tests that is more than two standard deviations below that expected for the individual's level of intelligence" (American Psychiatric Association 2000). Using this definition, a study by [bib_ref] The nature and frequency of cognitive deficits in children with neurofibromatosis type..., Hyman [/bib_ref] examined a cohort of 81 children with NF1, in which 81% of individuals showed some sort of cognitive impairment, but only 25% of individuals met the DSM IV diagnostic criteria for learning disabilities when controlling for IQ. Thus, some individuals with NF1 do not qualify for a formal diagnosis of a learning disability but will still require intervention for other neuropsychological deficits. These deficits can include but are not limited to visuospatial skills, executive function, expressive and receptive language, social skills and motor coordination [bib_ref] Social skills of children with neurofibromatosis type 1, Barton [/bib_ref] [bib_ref] Neurobehavioral profiles of children with neurofibromatosis 1 referred for learning disabilities are..., Chapman [/bib_ref] [bib_ref] Children and adolescents with neurofibromatosis 1: A behavioral phenotype, Dilts [/bib_ref] [bib_ref] Intellectual impairment in neurofibromatosis 1, Ferner [/bib_ref] [bib_ref] The nature and frequency of cognitive deficits in children with neurofibromatosis type..., Hyman [/bib_ref] [bib_ref] Social and emotional problems in children with neurofibromatosis type 1: Evidence and..., Johnson [/bib_ref] [bib_ref] Language and reading deficits associated with neurofibromatosis type 1: Evidence for a..., Mazzocco [/bib_ref] [bib_ref] Learning difficulties in neurofibromatosis type 1: The significance of MRI abnormalities, North [/bib_ref] [bib_ref] Cognitive function and academic performance in children with neurofibromatosis type 1, North [/bib_ref] [bib_ref] Cognitive deficits in neurofibromatosis 1, North [/bib_ref] [bib_ref] Neurofibromatosis and psychological processes, Varnhagen [/bib_ref] [bib_ref] Neuropsychological deficits in adults with neurofibromatosis type 1, Zoller [/bib_ref].
Several studies have suggested a frequency of attention deficit disorder (ADD) with or without hyperactivity in approximately 30-40% of the NF1 population [bib_ref] MRI and nonverbal cognitive deficits in children with neurofibromatosis 1, Bawden [/bib_ref] [bib_ref] How children with neurofibromatosis type 1 differ from "typical" learning disabled clinic..., Cutting [/bib_ref] [bib_ref] Brain tumors in children with neurofibromatosis: Additional neuropsychological morbidity?, Dewinter [/bib_ref] [bib_ref] The nature and frequency of cognitive deficits in children with neurofibromatosis type..., Hyman [/bib_ref] [bib_ref] Behavioral phenotype of neurofibromatosis, type 1. Mental Retardation and Developmental, Kayl [/bib_ref].
In summary, the cognitive phenotype of NF1 is complex, variable, and unpredictable, and can include a wide range of learning disabilities, other neuropsychological deficits, and less often, mental retardation. Formal neuropsychological evaluation can help elucidate the specific challenges of an individual with NF1 to allow for appropriate intervention. Intervention is based on the presenting cognitive features, and these are managed in the same way as they would be in the non-NF1 population.
## Life expectancy
Individuals with NF1 are predicted to have a lifespan of approximately 15 years less than that seen in the general population [bib_ref] Mortality in neurofibromatosis 1: An analysis using U.S. death certificates, Rasmussen [/bib_ref] [bib_ref] Life expectancy, mortality and prognostic factors in neurofibromatosis type 1: A twelve-year..., Zoller [/bib_ref]. [bib_ref] Factors associated with mortality in neurofibromatosis, type 1, Khosrotehrani [/bib_ref] reviewed data on 703 NF1 patients. The major cause of death in this population was malignancy. The second major cause was tumor-related neurological complications, and less frequent were vascular complications and accidents, suicide or causes of death that were indeterminate. Other reports demonstrate that cardiovascular disease is a frequent cause of premature death in individuals with NF1, and that myocardial infarction and cerebrovascular accidents occur at a younger than expected age among NF1 patients [bib_ref] Life expectancy, mortality and prognostic factors in neurofibromatosis type 1: A twelve-year..., Zoller [/bib_ref]. Complications from surgery also may lead to a decreased life span.
## Molecular basis of disease
The elucidation of the molecular basis of NF1 began in 1990 when the gene, NF1, was identified and the protein product, neurofibromin, were characterized [bib_ref] A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic..., Cawthon [/bib_ref] [bib_ref] Type 1 neurofibromatosis gene: Identification of a large transcript disrupted in three..., Wallace [/bib_ref]. The NF1 gene, located at 17q11.2 is approximately 350 kb in size and contains 60 exons. Within the NF1 gene are three additional genes contained within an intron, which are transcribed in the opposite direction [bib_ref] cDNA sequence and genomic structure of EVI2B, a gene lying within an..., Cawthon [/bib_ref] [bib_ref] Identification and characterization of transcripts from the neurofibromatosis 1 region: The sequence..., Cawthon [/bib_ref] [bib_ref] The oligodendrocyte myelin glycoprotein belongs to a distinct family of proteins and..., Mikol [/bib_ref]. The protein, neurofibromin, contains 2,818 amino acids.
The various functions of neurofibromin are still being investigated. It appears to serve a tumor suppressor function within the Ras signaling pathway [bib_ref] Neurofibomin, a tumor suppressor in the nervous system, Zhu [/bib_ref]. Typically, neurofibromin inactivates Ras by stimulating its conversion from Ras-GTP to Ras-GDP, thus controlling cell proliferation. However, when neurofibromin is abnormal or absent, Ras remains active and promotes cell proliferation and tumor growth. This is thought to be the mechanism responsible for the formation of tumors associated with NF1. It is also thought that abnormalities in this pathway contribute to the occurrence of learning disabilities.
To date, hundreds of mutations in the NF1 gene have been identified, many of which are unique to an individual or family [bib_ref] Independent NF1 mutations in two large families with spinal neurofibromatosis, Messiaen [/bib_ref]. Mutations identified include deletions, insertions, splice site mutations, amino acid substitutions, full gene deletions and chromosomal rearrangements. In the majority of cases, the mutation results in a truncated protein. A majority of molecular studies have not identified a strong genotype-phenotype correlation. [bib_ref] Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1, Rasmussen [/bib_ref]. However, in 2007, Upadhyaya et al. identified 21 patients with an atypical presentation and a 3-bp in-frame deletion in exon 17. All patients lacked cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Other exceptions that demonstrate a possible genotype-phenotype correlation include some of the NF1 variants, including Spinal NF, NF-Noonan syndrome and individuals with deletions of the entire NF1 gene. (See "Variants of NF1").
There appears to be a parent-of-origin effect on the types of de novo mutations that arise in the NF1 gene, with gene deletions being more frequent on the maternally derived chromosome and other types of mutations occurring preferentially on the paternally derived chromosome [bib_ref] Example of somatic mosaicism in a series of de novo neurofibromatosis type..., Ainsworth [/bib_ref] [bib_ref] Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes, Stephens [/bib_ref].
It should be noted that although NF1 is common, no convincing evidence of homozygous NF1 mutations have been reported, suggesting that at least one functional NF1 allele is essential in early fetal development [bib_ref] Epidemiology of neurofibromatosis type 1, Friedman [/bib_ref]. This is further supported by the fact that homozygosity for NF1 mutations in mice leads to abnormal heart development and mid-gestation embryonic lethality [bib_ref] Tumour predisposition in mice heterozygous for a targeting mutation in NF1, Jacks [/bib_ref].
## Differential diagnosis
Individual signs and symptoms of NF1 can be seen in the absence of other clinical findings. Isolated tumors, including optic gliomas and neurofibromas, are well documented, although Lisch nodules are rarely seen outside of the NF1 spectrum. The presence of one or two CALS is fairly common in the general population; however, having multiple (three or more) CALS is noted in less than 1% of children without other features of a genetic condition [bib_ref] Café-au-lait spots: The pediatricians perspectives, Tekin [/bib_ref]. The diagnosis of NF1 is subsequently confirmed in a majority of these patients [bib_ref] Relationship between café-au-lait spots as the only symptom and peripheral neurofibromatosis (NF1):..., Fois [/bib_ref] [bib_ref] Diagnostic outcome in children with multiple caféau-lait spots, Korf [/bib_ref]. Some individuals with red hair, fair skin, and, often, Irish ancestry are referred to clinics to rule out NF1 due to multiple CALS. These CALS are paler and more irregular than typical NF1 CALS. It is unclear whether this is an extremely mild variant of NF1 or a normal pigmentary variation [bib_ref] Abstracts of papers and posters presented at the fifteenth annual education conference..., Schneider [/bib_ref].
Several conditions have features that overlap with NF1. See [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref].
## Variants of nf1
## Segmental neurofibromatosis
Clinical findings of NF1 that are confined to one or more well-circumscribed regions of the body have been described in many individuals. This entity is known as "segmental NF." Typically, these manifestations do not encompass the entire clinical spectrum of NF1 and may include only dermatologic findings and/or neurofibromas. Ophthalmologic findings are seldom observed [bib_ref] Ophthalmological manifestations in segmental neurofibromatosis type 1, Ruggieri [/bib_ref]. Usually, a mild clinical course is anticipated for those patients who present with only pigmentary features. However, studies looking at long-term outcomes of these patients are very limited. Therefore counseling patients about clinical prognosis based on the assumed presence of a mutation in a mosaic state must be undertaken with caution.
It is believed that segmental NF1 is caused by a post-zygotic mutation in the NF1 gene. [bib_ref] Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1..., Tinschert [/bib_ref] reported the first molecular evidence of this phenomenon. The timing of the post-zygotic event is believed to determine the extent of involvement. Mutations arising early in embryologic development may result in a more widespread mosaicism that may appear as classic NF1 [bib_ref] Somatic mosaicism in a patient with neurofibromatosis type 1, Colman [/bib_ref]. A milder phenotype presenting as patchy distribution, smaller segment involvement, or isolated findings, may be the result of mutations arising later in embryologic development.
Providing an accurate risk assessment for the offspring of an individual with segmental NF1 presents a great challenge. There have been reports of individuals with segmental NF1 having children with classic NF1 [bib_ref] Familial segmental neurofibromatosis, Oguzkan [/bib_ref] [bib_ref] Epidemiology of neurofibromatosis type 1 (NF1) in northern Finland, Poyhonen [/bib_ref]. Since individuals with segmental NF1 are presumed to have some proportion of cells that harbor an NF1 gene mutation, they should be counseled that the risk to their offspring for classic NF1 could be as high as 50%, though it is likely to be considerably lower. Lymphocyte molecular testing in segmental NF may not be informative as the sample may not include the affected region or cells. However, for individuals who have had informative molecular confirma-tion in the affected cells, prenatal genetic testing for that mutation could be pursued in future pregnancies.
## Spinal neurofibromatosis
A subset of patients with NF1 has a variant in which their tumors are primarily localized to the spinal nerve roots. These individuals exhibit variable skin manifestations. This variant is referred to as spinal neurofibromatosis (SNF). The hallmark of this condition is multiple bilateral symmetrical enlargement of the nerve root on the spine [bib_ref] NF1 mutations and clinical spectrum in patients with spinal neurofibromas, Kluwe [/bib_ref]. Cord compression is a frequent complication in SNF . In contrast, spinal cord tumors associated with clinical symptoms are uncommon in classic NF1, affecting less than 7% of patients [bib_ref] NF1 mutations and clinical spectrum in patients with spinal neurofibromas, Kluwe [/bib_ref] [bib_ref] Neurofibromatosis type 1: Pathology, clinical features and molecular genetics, Deimling [/bib_ref]. Lisch nodules may or may not be present. The diagnosis of spinal neurofibromatosis by physical examination alone can be difficult, as individuals can be affected and not meet diagnostic criteria for the classic form of NF1. Most patients with SNF will have a variable number of CALS, but even in adults, the dermal neurofibromas may not be present . Spinal neurofibromatosis is also inherited in an autosomal dominant fashion and appears to be associated with mild mutations, such as missense, nonsense, or splicing mutations in the NF1 gene [bib_ref] NF1 mutations and clinical spectrum in patients with spinal neurofibromas, Kluwe [/bib_ref].
## Nf-noonan syndrome
Noonan syndrome is characterized by short stature, characteristic facial features, a webbed neck and congenital heart disease (most commonly pulmonic stenosis). In 1985, Allanson et al. first reported the concurrence of NF1 and Noonan syndrome (NFNS). In subsequent years, controversy has remained as to whether NFNS represents a variable manifestation of either NF1 or Noonan syndrome; a chance occurrence of two common genetic disorders; or a distinctive clinical entity [bib_ref] Is there a "Neurofibromatosis-Noonan syndrome, Carey [/bib_ref] [bib_ref] NF1 gene mutations represent the major molecular event underlying Neurofibromatosis-Noonan syndrome, De Luca [/bib_ref] identified NF1 mutations in 16/17 patients with the NFNS phenoytype. They found an increased prevalence of in-frame mutations involving exons 24 and 25 of the NF1 gene. No mutations in PTPN11, the gene most commonly associated with Noonan syndrome, were observed, suggesting that most cases of NFNS are due to mutations within the NF1 gene.
## Watson syndrome
Watson syndrome is characterized by pulmonic stenosis, multiple café-au-lait spots, and decreased IQ in addition to other various manifestation of NF1 [bib_ref] Watson syndrome: Is it a subtype of type 1 neurofibromatosis, Allanson [/bib_ref] [bib_ref] Evidence of central nervous system involvement in Watson syndrome, Leao [/bib_ref] [bib_ref] Pulmonic stenosis, café-au-lait spots, and dull intelligence, Watson [/bib_ref]. Linkage analysis, as well as identification of a gene deletion in one patient, support the hypothesis that this is an allelic variant of NF1 [bib_ref] Watson syndrome: Is it a subtype of type 1 neurofibromatosis, Allanson [/bib_ref] [bib_ref] Analysis of mutations at the neurofibromatosis (NF1) locus, Upadhyaya [/bib_ref].
## Nf1 gene microdeletion
Approximately 4-5% of NF1 patients have deletions of the entire NF1 gene. [bib_ref] Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene, Kluwe [/bib_ref]. The phenotype in these patients tends to be more severe, with an earlier onset of neurofibomas and the presence of mental deficiency, variable dysmorphic features and other congenital anomalies. [bib_ref] Deletions spanning the neurofibromatosis 1 gene: Identification and phenotype of five patients, Kayes [/bib_ref] [bib_ref] Deletion of the entire NF1 gene detected by FISH: Four deletion patients..., Wu [/bib_ref] [bib_ref] Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1, Rasmussen [/bib_ref]. In addition, some of these individuals appear to have connective tissue abnormalities such as mitral valve prolapse and joint laxity. [bib_ref] Connective tissue dysplasia in five new patients with NF1 microdeletions: Further expansion..., Mensink [/bib_ref]. A study by De Raedt et al. suggested that the risk of MPNSTs is higher in this group of patients than in individuals with other types of mutations [bib_ref] Elevated risk for MPNST in NF1 microdeletion patients, De Raedt [/bib_ref].
## Ongoing research
Research in NF1 is concentrated on the underlying causes of the various symptoms of the condition as well as potential therapies and treatments. Current studies are listed on the Children's Tumor Foundation webpage (http://www. ctf.org), the Neurofibromatosis, Inc. webpage (http://www. nfinc.org), and at http://www.clinicaltrials.gov. Active areas of investigation include genotype-phenotype correlations; the role of modifier genes; etiology of extensive phenotypic variability; neurodevelopmental issues; and treatments for neurofibromas and other tumors.
## Genetic counseling
## Contracting
As with other genetic counseling indications, ascertaining the family's understanding of the reason for the visit as well as their primary questions and concerns, and mutually developing a plan to address these concerns, are key components of establishing rapport in the NF counseling process [bib_ref] The structure of psychosocial genetic counseling, Weil [/bib_ref].
## Medical and developmental history
See [fig_ref] Figure 1: Sample [/fig_ref] at the end of the text for a sample clinic intake form.
## Family history
To identify additional family members who may be affected with NF, obtain at least a three generation, targeted pedigree from the consultand or proband using standardized pedigree symbols [bib_ref] Recommendations for standardized human pedigree nomenclature, Bennett [/bib_ref]. When possible, verify positive or questionable family history with medical records. Suggestions for a targeted family history are listed in [fig_ref] Table V: Suggestions for Targeted Family HistoryBirthmarks or other targeted skin findings Benign growth... [/fig_ref].
## Psychosocial assessment and counseling
Similar to genetic counseling for other conditions, obtaining a thorough psychosocial history and assessment is critical to the NF counseling process. General suggestions for a targeted psychosocial history are listed in [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref].
In addition to topics that are covered during a typical genetic counseling session, individuals with NF1 may have some unique psychosocial concerns may need to be addressed. a. Realize that many individuals have received information about NF1 from other sources , and that this information may be inaccurate, outdated, or only representative of the most severe cases of NF1. b. Recognize that the list of potential complications associated with NF1 is extensive. Appreciate that the information may be overwhelming for some individuals. The genetic counselor should use his or her clinical judgment in gauging the appropriate amount of information discussed during a session and may wish to continue discussions at subsequent appointments. c. Assess perception of the risk for malignancy. The term "tumors" can be especially frightening and it should be stressed that most NF tumors are benign. Malig- Early onset HNPCC-related cancers Hematologic malignancies Autosomal recessive, consanguinity common [bib_ref] Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis..., Bandipalliam [/bib_ref] [bib_ref] HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes..., Raevaara [/bib_ref] [bib_ref] Café-au-lait spots and early onset colorectal neoplasia: A variant of HNPCC?, Trimbath [/bib_ref] nancy risks should be discussed in the context of the general population's cancer risk, which is approximately 41% (http://seer.cancer.gov/csr/1975_2003/ results_merged/topic_lifetime_risk.pdf). d. Address concerns and fears regarding the variable and unpredictable natural history of NF1. Explain that the majority of individuals lead productive lives, meaning that they are able to attend school, be employed and live independently. Providing the family with a list of concerning symptoms (See "Education") can be helpful in giving the family a sense of control when they are experiencing anxiety about the unpredictable nature of NF1. e. Assess perception of the impact of NF1 on the individual's daily life, with a focus on cosmetic and medical concerns. [bib_ref] Quality-of-life impairment in neurofibromatosis type 1: A crosssectional study of 128 cases, Wolkenstein [/bib_ref] found that quality of life in adults with NF1 was negatively correlated with the visibility of the manifestations of NF1. f. Discuss family's concerns regarding labeling and selffulfilling prophecies. Many parents are concerned that the diagnosis of a genetic condition will lower a child's selfexpectations or the expectations of others for the child. g. Assess the family's knowledge and perception of the Elephant Man. Despite the current belief that "The Elephant Man" did not have NF1, older literature and resources often refer to NF1 as the disease of "The Elephant Man." Families of patients with NF1 may still be affected by the association of NF1 with the difficult life of Joseph Merrick [bib_ref] The elephant man' as 'self' and 'other': The psychosocial costs of a..., Ablon [/bib_ref]. h. Elicit the individual's experiences at school, work and other social situations. In addition to the learning disabilities, many NF1 patients have difficulty with social skills. This may also be impacted by the cooccurrence of ADHD. i. Be aware of issues regarding counseling an individual with a learning disability. In familial cases of NF1, a parent may also have a learning disability. This may affect an individual's understanding and perception of the disorder, their ability to recognize or cope with the potential medical issues, and their comprehension of the genetic implications for future offspring. In these families, it is particularly important to determine the level of understanding and adjust the counseling session to reflect the family's comprehension level. It is also important to keep in mind that individuals with learning disabilities may prefer alternate methods of receiving information and may benefit from reinforcement at follow-up visits. j. As indicated, assist the family in navigating the complexities of special education and/or other interventional services. Many individuals with NF1 require additional services in school, and obtaining these services may prove challenging and frustrating.
## Risk assessment
In order to complete an accurate risk assessment, it is crucial to determine whether the disease and/or mutation was inherited or de novo. This can often be accomplished through physical and ophthalmologic examination of the proband's parents. Alternatively, if a DNA mutation has been identified in the patient, molecular genetic testing can be performed.
## If the mutation is de novo
Risk for siblings of proband is low (thought to be less than 1%), but remains increased due to the possibility of germline mosaicism (see "Special Considerations").
## If the mutation is familial
Apply principles of autosomal dominant inheritance to pedigree. All offspring of an affected parent have a 50% risk These targeted questions may also aid in differential diagnosis. to inherit the mutation. As indicated, identify nearest genetics/ NF clinic for affected relatives not living in the area.
## Education
## Clinical features and natural history
Review the main features of the condition, its natural history, and the typical timeline for the development of features. See "Natural History."
Inheritance Pattern and Recurrence Risk NF1 is an autosomal dominant condition. Approximately 50% of NF1 cases are inherited from a parent. The remaining 50% of cases of NF1 are due to a de novo mutation in the proband. This is felt to be due, in part, to the large size of the NF1 gene, which makes it more susceptible to mutation. Penetrance is essentially 100%, but expressivity is variable, even amongst family members. If neither parent of the proband has NF1, the chance of recurrence is low. However, because of the possibility of germline mosaicism, the recurrence risk is likely somewhat higher than the general population risk (see "Special Considerations").
Please see "Variants of NF1" for recurrence risks for segmental NF.
## Prenatal testing and reproductive options
Prenatal molecular genetic testing is available for families in which the mutation has been identified in the proband. Alternatively, if there are multiple affected family members, and linkage has been established within the family, linkage analysis is an option. In these situations, prenatal diagnosis is possible via chorionic villus sampling (CVS) or amniocentesis. In the vast majority of cases, ultrasound is not useful in the prenatal diagnosis of NF1. There are some reports of prenatal identification of NF1-related abnormalities [bib_ref] Prenatal ultrasound abnormalities in a patient with generalized neurofibromatosis type 1, Drouin [/bib_ref] [bib_ref] Congenital oral tumor associated with neurofibromatosis detected by prenatal ultrasound, Hoyme [/bib_ref] [bib_ref] Prenatal diagnosis of neurofibromatosis type 1: Sonographic and MRI findings, Mcewing [/bib_ref]. These abnormalities included cardiac and craniofacial anomalies as well as tumors. However, the abnormalities included in these reports were atypical for NF1, and in only one instance was the diagnosis of NF1 considered before birth [bib_ref] Prenatal diagnosis of neurofibromatosis type 1: Sonographic and MRI findings, Mcewing [/bib_ref].
Given the variability and unpredictable nature of the condition, genetic counseling is critical for a couple considering prenatal testing for NF1. Genetic counseling informs a couple about the signs, course, and genetics of NF1. It also facilitates the discussion of personal, moral, and ethical issues they need to explore in order to make an autonomous decision that meets their needs.
## Alternate risk reduction options
In families where a parent is affected and the risk to offspring is 50%, various options can reduce the risk in a future pregnancy. The use of assisted reproductive technology with a donor gamete from an unaffected individual in place of the gamete from the affected parent can greatly reduce the risk to future children. Alternatively, preimplantation genetic diagnosis (PGD) may be available for couples in which the causative NF1 mutation has been identified or if linkage phase has been established.
## Signs and symptoms that warrant immediate referral and evaluation
Parents and patients often find it helpful to be informed of what types of symptoms warrant an immediate referral and evaluation.
See [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref] for signs and symptoms warranting emergent evaluation.
## Follow-up
## Management
Management recommendations for patients with NF1 vary between centers and must be tailored to the individual. It is not the intention of this manuscript to address specific management recommendations. It should be noted, however, that management of these patients typically requires a multidisciplinary team. Disciplines that may be involved in the care of a patient with NF1 are listed in [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref].
## Documentation
Providers are encouraged to thoroughly document all patient interactions. This may be done via a patient summary letter and/or a physician note. In many centers, these two forms of documentation are combined. Please see [fig_ref] Table I: Significant Milestones in the History of NF1 [/fig_ref] for a list of suggested items to be included.
## Special considerations
## Germline mosaicism
Germline mosaicism is a recognized phenomenon occurring in a number of dominant genetic disorders and has been observed in NF1 [bib_ref] Molecular characterization of the breakpoints of a 12-kb deletion in the NF1..., Lazaro [/bib_ref] [bib_ref] Germ line mosaicism, Zlotogora [/bib_ref]. Therefore, caution must be used when discussing recurrence risks with the parents of a child with an apparently de novo case of NF1, even if parental lymphocyte analysis is negative following mutation identification in the proband. Nevertheless, it is estimated that the risk for recurrence due to germline mosaicism is less than 1%.
## Consent for dna testing
Informed consent for molecular analysis should be obtained from the patient or legal guardian prior to the acquisition of a sample for DNA testing. A consent form from the clinical testing laboratory should be reviewed with the family. Typically, this form describes the limitations and benefits of testing, how results will be reported, and any other potential uses of the specimen.
## Patient resources
It is important to aid the family in identifying additional sources of support, such as advocacy and support groups, and other families. A list of patient resources is listed in [fig_ref] Table X: Patient Resources Children's Tumor Foundation [/fig_ref].
Acknowledgments The authors are grateful to the many reviewers that contributed their time and expertise to this manuscript. Genetic counselor reviewers included Stefanie Dugan, Lynn Holt, Kory Keller, and Barb Pettersen. Drs. Bruce Korf and Jan Friedman also provided invaluable feedback, as did Mr. Robert Miyamoto, a representative of the Children's Tumor Foundation. The authors would also like to thank the Genetics Services committee for their guidance throughout the process. Lacy Miles and Dr. Kenneth Grizzle also provided valuable input on the cognitive section. Above all, the authors are appreciative of the families that are directly impacted by neurofibromatosis. We hope that they will benefit from this manuscript.
[fig] Figure 1: Sample [/fig]
[table] Table I: Significant Milestones in the History of NF1 [/table]
[table] Table V: Suggestions for Targeted Family HistoryBirthmarks or other targeted skin findings Benign growth or tumors Malignant tumor or cancer Significant hearing problem such as hearing loss or ringing of the ears Significant vision problem such as tumor, poor vision or blindness Bone or joint problems (fractures, dislocations, curved spine) Developmental delay, learning disability, ADHD or MR Seizures, epilepsy or other nervous system problems Macrocephaly [/table]
[table] Table X: Patient Resources Children's Tumor Foundation (formerly NNFF): http://www.ctf.org; 800-323-7938 Neurofibromatosis, Inc: http://www.nfinc.org; 800-942-6825 Understanding NF1: http://www.understandingNF1.org British Columbia Neurofibromatosis Program: http://www.bcnf.bc.ca; 800-385-BCNF (2263) National Society of Genetic Counselors: http://www.nsgc.org American College of Medical Genetics: http://www.acmg.net American Society of Human Genetics: http://genetics.faseb.org/ genetics/ashg/ashgmenu.htm Gene Tests: http://www.genetests.org Age at Diagnosis (if applicable): Medical Record #: Referring Physician: Primary Care Physician: Reason for Referral: Chief complaint: Medical History: Work-up to date (neuroimaging, radiographs, EEG, audiogram, DNA testing, etc.): Current review of systems: General Health: Illnesses Itching Medications Café-au-lait spots/Hyperpigmented lesions: Neurofibromas/Dermal tumors: [/table]
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Ratified AVA policies July 2011
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Ratified AVA policies July 2011
## Importing dogs
Position statement Dogs being imported should be considered for behavioural assessment as well as physical examination before they are permitted to enter Australia.
Dogs should not be imported if they exhibit or carry behavioural characteristics that may inappropriately threaten the safety of human beings or other animals.
The establishment and enforcement of behavioural standards for all dogs whose owners apply for their importation into Australia are strongly supported. These standards should also apply to any genetic material imported, with assessment of temperament of donors of semen, ova or embryos.
The Australian Veterinary Association (AVA) calls on the Australian government to change the importation regulations and permit conditions to satisfy the need for effective behavioural assessment of imported dogs.
# Background
Current behavioural restrictions on import requirements for dogs are based on specific breeds. A case-by-case assessment of individual dogs is a more effective means of preventing the importation of aggressive dogs and thereby protecting the community.
## Control of wild rabbits
## Policy
Reducing the adverse impact of wild rabbits is a legitimate and necessary objective for those responsible for managing agricultural land, pastoral land, national parks and other land. Methods employed for the control of rabbits must be as humane as possible. The total eradication of rabbits on the Australian continent is not a realistic goal.
# Background
The European rabbit (Oryctolagus cuniculus) has caused, and continues to cause, very severe damage to agricultural and natural areas in the southern half of Australia. It poses a serious threat to the survival of some native species of plants and animals.
## Guidelines
The following guidelines should be observed for the control for wild rabbits.
- The use of sodium fluoroacetate (1080) and anticoagulants is an acceptable method of poisoning rabbits. Strychnine should not be used in rabbit control. - Methods of applying poisoned baits should minimise the risk to non-target species. - Ripping of warrens alone is effective but should be used in conjunction with other methods so that rabbit numbers are minimal when ripping is carried out. - The AVA rejects the use of explosives alone because the operator has insufficient control to ensure that it is not inhumane. It is a reasonable technique to employ to destroy warrens in rocky ground or inaccessible country after an efficient poisoning program has been carried out. - Fumigation may be necessary, but the AVA urges that more effective, humane and less irritant fumigants be developed. - The use of steel-jawed traps is inhumane and is not an efficient means of controlling rabbits. - Shooting is humane if the bullet passes through the brain, causing instantaneous loss of consciousness. Shooting through the heart may be more practical in some situations. Shooting is generally not an efficient method of controlling rabbits if no other method is used, but it can be useful to reduce the number of rabbits that survive poisoning or warren ripping. - Myxomatosis has been an extremely effective agent in rabbit control. Although this disease causes distress to rabbits, it is a necessary part of any comprehensive rabbit control campaign, given the context of the Australian environment. - The imported calicivirus causes an acute fatal disease in rabbits and has now been released in the field for rabbit control. The AVA believes that this disease causes less suffering than other current methods of control, including 1080 and myxomatosis.
## Other recommendations
The AVA supports ongoing research to find more practical and effective and humane methods of control, particularly research into fertility control (including virus-vectored immunosterilisation and related techniques).
## Other relevant policies and position statements
- 13.1 Control of native and introduced animals causing damage to agriculture and habitat Date of ratification by AVA Board: 8 July 2011
## Distal limb neurectomy
## Policy
Distal limb neurectomy in appropriate and in selected cases is an acceptable and useful treatment option for chronic irreversible heel pain causing lameness in horses.
The use of neurectomised horses in competitive events should be regulated by the sporting authorities and be subject to a specific Code of Practice or Standard of Practice.
The indiscriminate use of distal limb neurectomies is not supported.
# Background
Distal limb neurectomy involves removal of part of the nerve to the hoof of the horse. It is performed in cases of ongoing irreversible heel pain. Opinion is divided on the merits of horses being allowed to compete in strenuous athletic events after distal limb neurectomy.
## Guidelines
The welfare of the horse must be the major consideration before distal limb neurectomy is used as a treatment procedure.
Before performing a distal limb neurectomy, a veterinarian must be satisfied that the owner fully understands:
- all implications of the operation - the possible side effects of the operation - the requirement for continuing care of the horse after the operation - that some sporting authorities prohibit horses from competition after distal limb neurectomy.
Date of ratification by AVA Board: 8 July 2011
## Use of projectile syringe equipment
## Policy
Systems for the remote injection of drugs in livestock, wild animals or companion animals can be used safely and humanely, provided that the people involved in the procedure have the required licensing, skills, competencies and knowledge. Licensing is a necessary legal requirement. Non-veterinarians who need to use projectile syringe equipment must be under the direct supervision of a veterinarian.
# Background
Significant developments have been made in the design and use of systems for the remote injection of immobilising drugs, vaccines and other medications.
Veterinarians and non-veterinarians must have specialised skills and knowledge before any attempt is made to use such equipment on an animal. New South Wales has an accreditation course to ensure that people are appropriately trained. Other states are encouraged to adopt a similar program.
It is recognised that non-veterinarians may be required to use or deploy remote injection devices when veterinarians may lack firearms skills or when a veterinarian may not be readily available in an emergency situation. Human safety issues must also be considered in the use of projectile syringes, particularly when immobilising drugs are being used, including the retrieval of projectile syringes.
Permits must be obtained where appropriate from the relevant authorities before using projectile firearms. All precautions should be taken to minimise risks to human safety or to the animal's welfare when using remote injection devices.
The selection of appropriate immobilising drugs and drug dosages requires careful consideration of a range of variables, including species, the individual animal (age, sex, mental state, health status) and the effect required. The Australian Veterinary Association's special interest group, the Australian Veterinary Conservation Biologists (AVCB), can provide advice and assistance on the selection and use of projectile syringe equipment, and on drugs appropriate for the chemical restraint of a range of species.
Date of ratification by AVA Board: 8 July 2011
## Vaccination of dogs and cats
# Position statement
Vaccination protocols should be determined within a veterinarianclient-patient relationship, based on attributes such as duration of immunity of available vaccines and an individual animal's requirements.
Every animal should be immunised and each individual animal only as frequently as necessary. Current scientific consensus recommends that adult cats and dogs should be vaccinated with core vaccines triennially where applicable.
Informed consent is important.
Core vaccines should be administered to all animals to protect them against severe, life-threatening diseases that have a global distribution.
# Background
Vaccination is one of the most common veterinary procedures undertaken in small animal practice. Vaccination programs have played an important role in preventing diseases and fostering early detection and treatment through regular clinical examinations during the life of the animal [bib_ref] AVMA Council on Biologic and Therapeutic Agents' report on dog and cat..., Klingborg [/bib_ref]. Vaccination recommendations in the past were considered a simple part of animal care, but are now a complex and controversial issue [bib_ref] AVMA Council on Biologic and Therapeutic Agents' report on dog and cat..., Klingborg [/bib_ref]. It is being recognised that veterinarians should aim to reduce the vaccine load on individual animals to minimise the risk of adverse reactions to the products.
Although annual vaccination has long been considered standard practice in Australia, scientific information exists to suggest that the duration of immunity (DOI) delivered by many of the products available is variable and may be significantly longer than 12 months.
## Guidelines
- The Vaccination Guideline Group (VGG) of the World Small Animal Veterinary Association (WSAVA) recommends that vaccines be defined as core, non-core or not recommended.
᭺ Core vaccines should be administered to all animals to protect them against severe, life-threatening diseases that have a global distribution. Dogs: canine distemper virus, canine adenovirus and canine parvovirus. Cats: feline parvovirus, feline calicivirus and feline herpesvirus. ᭺ Non-core vaccines are required by only those animals whose geographic location, local environment or lifestyle places them at risk of contracting specific infections. Dogs: parainfluenza virus, Bordetella bronchiseptica and Leptospira interrogans. Cats: feline leukaemia virus, Chlamydia felis and Bordetella bronchiseptica. Feline immunodeficiency virus vaccines may also be classified in this group. ᭺ Vaccines that have insufficient scientific evidence to justify their use are not recommended. - The Australian Veterinary Association (AVA) believes that in most cases, core vaccines need not be administered any more frequently than triennially and that even less frequent vaccination may be considered appropriate if an individual animal's circumstances warrant it. However, local factors may dictate more frequent vaccination scheduling. These recommendations may be 'off label' for some vaccines. - Individual animals will require assessment by a veterinarian to select the most appropriate vaccine and vaccination protocol. The veterinarian-client-patient relationship is important to fully understand the individual's needs. - Revaccination recommendations should aim to create and maintain clinically relevant immunity while minimising the potential for adverse reactions. - Because of maternally derived antibody and the variability in its level and duration between individuals, vaccines should ideally be administered two to three times to puppies and kittens, with timing of the final dose being variable but not earlier than the age of 16 weeks (the suggested age varies with the manufacturer and the vaccine). If cost is an issue and only one vaccine is possible, it should be at the age of 16 weeks or older. - A booster vaccine should be administered approximately 12 months later. - 'Off label' use of vaccines will require consultation with the pet owner for informed consent. - An 'annual health check' is strongly recommended, even if animals are not to be vaccinated. - Non-core vaccines target diseases that are of limited risk in a geographic region or, based on the lifestyle of the pet, help prevent against diseases that are a less severe health risk to infected animals. - The decision to use non-core vaccines is made for individual pets based upon consultation between the veterinarian and owner. ᭺ Many non-core vaccines require annual vaccination. - Vaccines that the WSAVA VGG considered in their 2007 report should not be recommended at that time included canine coronavirus, Giardia for cats and dogs, feline immunodeficiency virus and feline infectious peritonitis. - At the time of vaccine administration the following information should be recorded in the patient's permanent medical record: ᭺ date of vaccination ᭺ identity of person administering the vaccine ᭺ vaccine name, batch number and expiry date ᭺ site and route of administration. - Adverse vaccine experiences are defined as any side effect, unintended consequence or lack of protection associated with the administration of a vaccine product. This includes any injury, toxicity or hypersensitivity reaction associated with the vaccination, whether or not the event can be attributed directly to the vaccine. Any adverse event should be reported, identifying the product, animal and reaction involved, to the manufacturer and the Australian Pesticides and Veterinary Medicines Authority (APVMA) Adverse Experience Reporting Program. - Recommendations for vaccination protocols should be determined within a veterinarian-client-patient relationship rather than by non-veterinarians such as within boarding facilities.
# Background
Whips are used during horse racing to control or guide the horse and to make the horse perform more competitively; however, there is ongoing research questioning whether whip use will result in improving a horse's placing (Evans and McGreevy 2011).
The whip functions as a training aid by being a tool for negative reinforcement and hence the whip should be used to educate the horse when it responds incorrectly.
Incorrect use of a whip includes the use of the whip on any part of the body other than the hindquarters or the shoulder and any use that results in welts or breaks the horse's skin or causes psychological injury to the horse.
There should be additional research into the use of whips in horse racing.
## References
Evans D, McGreevy P. An investigation of racing performance and whip use by jockeys in Thoroughbred races. PLoS One 2011;6:e15622.
## Other relevant policies and position statements
- 7.6 Equine competitive events - 17.8 The provision of optimum veterinary services to the horse racing industry
Date of ratification by AVA Board: 8 July 2011
## Vaccination of rabbits and ferrets
## Policy
Vaccination of pet rabbits against rabbit caliciviral disease and ferrets against distemper is recommended.
# Background
Rabbit calicivirus disease occurs in wild and domestic European rabbits (Oryctolagus cuniculus) in Australia, causing acute haemorrhage and sudden death. The virus was prematurely released in Australia in 1995. A short time later a vaccine became available for use in pet and farmed rabbits.
Myxomatosis occurs in Australia; however, a vaccine is not available or allowed to be used in Australia because of the risk of the vaccinate strain entering the wild rabbit population and stimulating immunity.
Distemper occurs in ferrets. Distemper is also known to exist in Australia, therefore the ferret population can be considered to be at risk No specific monovalent vaccine for ferrets is available in Australia. Consequently polyvalent canine vaccines are used.
Circus animals include both domestic species (small and large) and non-domestic species. It is difficult to meet the needs of non-domestic animals -for example, for space, socialisation, exercise and natural habitat -within the constraints of circus life. Most animals are weaned early and hand reared to allow imprinting, thus facilitating handling and training.
These animals are different from zoo animals and are likely to be kept under different conditions. For example, animals that normally socialise well may need to be kept as individuals. Circus animals are exercised during training procedures, so the size of their cages may not be as critical as for zoo animals. Positive re-enforcement training is recommended.
Domestic circus animals present fewer welfare problems than nondomestic animals.
Generations of breeding in confinement and socialisation with humans make the husbandry requirements of domestic animals less difficult to maintain than non-domesticated species. They interact with people and can be more easily exercised and trained. Kath was one of the first females to graduate from the University of Sydney in 1938. After graduation, she practiced in both Victoria and New South Wales (NSW) before joining the Australian Army Veterinary Corps in 1943 and being posted to Brisbane and Moreton Island. After the War, she married Thomas Walker and moved to Coolatai Station in Warialda, western NSW, where she promptly set about educating the district on the need for veterinary expertise, while juggling being a veterinarian, mother and housewife (Oh, those burnt dinners!).
## Reference
Having being orphaned by the time she graduated, Kath set up the Farr Prize for Equitation for second year veterinary science students, in memory of her parents. Recipients who also wrote Kath a letter of thanks were granted a holiday/work experience at Coolatai Station. This was where I met Kath for the first time. Kath met me at the railway station dressed in a skirt, shirt and heels, making me doubt that she was a real veterinarian. Kath never wore slacks, but as she said, she 'always made sure she wore a skirt or dress big enough to get over a fence. '
A Life Member of the AVA, Kath, accompanied by Tom, was a regular at AVA conferences where she liked to ask difficult questions of the lecturers. Also a 60 year member of the Australian Red Cross, Kath was awarded the OAM for services to veterinary science in 1999.
Throughout her life, Kath regularly travelled to Sydney to indulge in the ballet and sail on the harbour. She was an avid reader and a talented embroiderer. Kath passed away in 2009 at the age of 92 (Tom passed away in 2010) and is survived by her two sons, six grandchildren and one great-grandchild. To this day, I still miss our weekly phone calls, her acidic comments, laughter and friendship. The Kath Farr Scholarship, worth $1000, will be awarded annually to a final year female veterinary science student from The University of Sydney who wishes to pursue a rural veterinary career.
## Mary rose couper
The AVA is calling for donations to the fund through the Veterinary Science Foundation at The University of Sydney to help support the future careers of female rural veterinarians and commemorate the life of one of Australia's great veterinarians.
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https://europepmc.org/articles/pmc7159501?pdf=render
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Policy Reducing the adverse impact of wild rabbits is a legitimate and necessary objective for those responsible for managing agricultural land, pastoral land, national parks and other land. Methods employed for the control of rabbits must be as humane as possible. The total eradication of rabbits on the Australian continent is not a realistic goal. Background The European rabbit (Oryctolagus cuniculus) has caused, and continues to cause, very severe damage to agricultural and natural areas in the southern half of Australia. It poses a serious threat to the survival of some native species of plants and animals.
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4d9b3467978508d00c7eba2b29bd00f3afa3477d
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pubmed
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Hypopharyngeal cancer: United Kingdom National Multidisciplinary Guidelines
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Hypopharyngeal cancer: United Kingdom National Multidisciplinary Guidelines
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. With an age standardised incidence rate of 0.63 per 100 000 population, hypopharynx cancers account for a small proportion of the head and neck cancer workload in the UK, and thus suffer from the lack of high level evidence. This paper discusses the evidence base pertaining to the management of hypopharyngeal cancer and provides recommendations on management for this group of patients receiving cancer care.Recommendations- Cross-sectional imaging with computed tomography of the head, neck and chest is necessary for all patients; magnetic resonance imaging of the primary site is useful particularly in advanced disease; and computed tomography and positron emission tomography to look for distant disease. (R) - Careful evaluation of the upper and lower extents of the disease is necessary, which may require contrast swallow or computed tomography and positron emission tomography imaging. (R) - Formal rigid endoscopic assessment under general anaesthetic should be performed. (R) - Nutritional status should be proactively managed. (R) - Full and unbiased discussion of treatment options should take place to allow informed patient choice. (G) - Early stage disease can be treated equally effectively with surgery or radiotherapy. (R) - Endoscopic resection can be considered for early well localised lesions. (R) - Bulky advanced tumours require circumferential or non-circumferential resection with wide margins to account for submucosal spread. (R) - Offer primary surgical treatment in the setting of a compromised larynx or significant dysphagia. (R) - Midline lesions require bilateral neck dissections. (R) - Consider management of silent nodal areas usually not addressed for other primary sites. (G) - Reconstruction needs to be individualised to the patients' needs and based on the experience of the unit with different reconstructive techniques. (G) - Consider tumour bulk reduction with induction chemotherapy prior to definitive radiotherapy. (R) - Consider intensity modulated radiation therapy where possible to limit the consequences of wide field irradiation to a large volume. (R) - Use concomitant chemotherapy in patients who are fit enough and consider epidermal growth factor receptor blockers for those who are less fit. (R)
# Introduction
The hypopharynx is subdivided into the piriform sinuses, the posterior pharyngeal wall and the postcricoid area. The majority of cancers arise in the piriform sinuses (65-85 per cent), 10-20 per cent arise from the posterior pharyngeal wall and 5-15 per cent from the post-cricoid area. As is the case at other sites in the head and neck, the overwhelming majority (95 per cent) of cancers are squamous cell carcinomas (SCCs). Five-year survival is poor with overall survival at 30 per cent, although for T1 and T2 tumours the survival is almost 60 per cent. This discrepancy is a reflection of late presentation, as hypopharynx tumours remain relatively asymptomatic until they are quite advanced. Cases of T1N0 account for only 1-2 per cent of all cases seen and 80 per cent of patients are stage III or IV at presentation. Half of all patients present because of cervical nodes and the incidence of distant metastases at presentation are higher than that for any other head and neck cancer.
## Clinical presentation
The cardinal symptoms of hypopharyngeal cancer are:
- Neck mass, with approximately half of patients presenting such, which reflects the fact that late presentation is common - Sore throat, particularly if well localised and associated with referred ear pain on swallowing - Dysphagia, which is progressive and frequently results in significant weight loss and malnutrition - Hoarseness, voice change and/or upper airway obstruction, a late symptom indicating advanced disease.
## Assessment and staging
Clinical examination Assessment of hypopharyngeal cancer requires a full symptomatic history, evaluation of associated medical conditions or comorbidity, determination of weight loss as well as performance status (Karnofsky or World Health Organization). The medical history and performance status are critical in recommending the extent and intention of treatment. Mortality and morbidity rates are much higher in patients with significant weight loss, comorbidity or poor performance indicators.
A full head and neck examination, including nasendoscopy, is necessary in order to assess the size and position of the primary tumour, mobility of the vocal fold and cervical metastases. Clinical examination is also important in assessment of pre-vertebral fascia involvement and can be assessed by examining laryngopharyngeal mobility in the lateral direction. This is then complemented by radiological assessment and staging endoscopy under general anaesthetic.
## Imaging considerations
It is widely agreed that imaging is better performed prior to biopsy, as this can potentially avoid post-operative oedema which may overstage the disease on subsequent imaging. In addition, it allows assessment of any additional abnormalities that have been uncovered by radiological evaluation such as second primary tumours.
Cross-sectional imaging is mandatory in the work up and can take the form of either computed tomography (CT) or magnetic resonance imaging (MRI). In addition to this, the chest should always be imaged due to the increased incidence of lung metastases in advanced hypopharyngeal cancer and to look for synchronous primaries. There is debate about which modality to use. The critical points in imaging are assessing extent of disease (particularly the lower limits of the primary cancer) and the presence of thyroid cartilage invasion. Magnetic resonance imaging gives better soft tissue definition and has greater sensitivity (80 per cent) for cartilage invasion, however, is less specific (74 per cent) than CT, and can therefore potentially overstage disease. The multiplanar capabilities of MR can also help in staging the disease. When compared with histological assessment, CT and MRI produce sensitivities of 66 and 89 per cent, respectively, and specificities of 94 and 84 per cent, respectively. The benefit of CT is that the chest can be imaged at the time of the neck imaging as well as the reduced potential for motion artefact due to the speed of the assessment, whereas, if MRI is used the patient needs additional imaging which may be less convenient for the patient. There is debate whether or not a simple chest X-ray is sufficient or whether CT is necessary. There is evidence to support both arguments, however, as hypopharyngeal cancer usually presents with stage III or IV diseases, it seems reasonable to recommend chest CT, as there is a higher incidence of distant metastatic disease in hypopharyngeal cancer.
Currently, the Royal College of Radiologists 2014 guidelines recommends CT or MRI scanning for imaging the hypopharynx.Computed Tomography should use slice thickness acquired at 0.625-1.25 mm and reformatted at no greater than 2.5 mm for viewing. Scans should be performed during quiet respiration with arms at the side of the patient. Patients should be instructed not to swallow during the evaluation. Magnetic resonance imaging scanning will require a combination of axial, sagittal and coronal T1W and T2W sequences, often with contrast enhancement with spectral fat suppression to assess the extent of soft tissue involvement and cartilage invasion.
Positron emission tomography (PET)-CT is now recommended for assessment of advanced hypopharyngeal primaries, the lower limit of disease in cases not accessible via endoscopy as well as in imaging post-treatment patients to assess for residual and/or recurrent disease.
## Examination under anaesthetic and endoscopy
Endoscopy in theatre serves three functions: first, it allows assessment of the extent of the primary tumour, second, it allows biopsy of the tumour to confirm pathology and finally it allows assessment of other potential primary sites. This last indication was the rationale of the old fashioned triple endoscopy philosophy which incorporated bronchoscopy as well as pharyngolaryngoscopy and oesophagoscopy. It is generally recognised that with the advent of good imaging of the chest the role of formal bronchoscopy has become virtually obsolete.
At the end of all these assessments then a clinical stage can be reached using the tumour-node-metastasis (TNM) classification system [fig_ref] TABLE I T: STAGING FOR HYPOPHARYNGEAL TUMOURS [/fig_ref].
## Recommendations
- Cross-sectional imaging with CT of the head, neck and chest is necessary for all patients; MRI of the primary site is useful particularly in advanced disease; and CT-PET to look for distant disease (R) - Careful evaluation of the upper and lower extents of the disease is necessary, which may require contrast swallow or CT-PET imaging (R) - Formal rigid endoscopic assessment under general anaesthetic should be performed (R)
## Management
High importance should be placed on exploring patient preferences and involving them in treatment decisions. A clear and unbiased discussion of all options will help the patients and the medical team make the most appropriate decisions. Many of these patients present with dysphagia and significant weight loss and can be profoundly malnourished. This needs to be managed proactively soon after diagnosis and may require insertion of nasogastric or gastrostomy feeding tubes prior to any treatment taking place. A full assessment of the patient's performance status should be carried out to determine their ability to undergo major surgery or their ability to lie flat for radiotherapy and attend daily for seven weeks. Although some prospective randomised data exists, several aspects of the decision making for hypopharyngeal SCC remain controversial as no treatment has been shown to be superior in terms of disease control and survival. [bib_ref] Radiotherapy or surgery for head and neck squamous cell cancer: establishing the..., Hall [/bib_ref] This section summarises the principles of surgical and non-surgical treatment for these tumours.
## Recommendations
- Nutritional status should be proactively managed (R) - Full and unbiased discussion of treatment options should take place to allow informed patient choice (G)
## Surgical treatment
Based on the extent of the tumour, transoral and open surgical options exist for hypopharyngeal cancer. [bib_ref] Cancer of the hypopharynx, Bradley [/bib_ref] Transoral approaches have a greater ability to preserve function suitable for smaller tumours where resections can be achieved with clear margins. Radiation therapy is favoured over open partial pharyngeal resections nowadays.
Early stage disease. Early stage (I and II) disease can be treated with equal effectiveness with surgery or radiation. [bib_ref] Surgical treatment for hypopharynx carcinoma: feasibility, mortality, and results, Eckel [/bib_ref] [bib_ref] Organ preserving transoral laser microsurgery for cancer of the hypopharynx, Martin [/bib_ref] Early lesions of the hypopharynx can be treated by transoral resection or open partial laryngopharyngectomy with or without reconstruction. Surgery offers the advantage of providing prognostic information, such as peri-neural or angioinvasion and lymph node status. This allows the use of post-operative irradiation for those patients likely to gain the most benefit, while sparing other patients side effects without a significant survival advantage. Occult nodal disease is present in 30-40 per cent of patients, so any treatment plan should include elective treatment of the cervical nodes.
Late stage disease. Unfortunately, more than 80 per cent are advanced stages III and IV at presentation (with locally advanced disease present in the majority). Submucosal extension is present in more than 60 per cent of surgical specimens and is occult in one-third. [bib_ref] Submucosal tumor extension in hypopharyngeal cancer, Ho [/bib_ref] Local recurrence rates have been reported to occur in equal proportion between patients with negative margins and those with positive margins, underscoring the difficulty in clearing disease. Histological studies have reported submucosal extension ranging from 1 to 2 cm, resulting in the recommendation that minimal resection margins of 1.5 cm superiorly, 3 cm inferiorly and 2 cm laterally are required in patients treated surgically. The incidence and extent of submucosal spread is higher in patients who have undergone previous radiotherapy, with macroscopically undetected submucosal spread present in 80 per cent. Bulky advanced tumours will usually require circumferential or non-circumferential resection with free flap cover.
Recurrent disease. Surgical salvage after failure of irradiation therapy has a lower success rate for Tumour limited to one subsite of the hypopharynx and 2 cm or less in greatest dimension T2
Tumour invades more than one subsite of the hypopharynx or an adjacent site, or measures more than 2 cm but 4 cm or less in greatest diameter without fixation of hemilarynx T3
Tumour measures more than 4 cm in greatest dimension or with fixation of hemilarynx T4a Tumour invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, oesophagus or central compartment soft tissue, which includes pre-laryngeal strap muscles and subcutaneous fat T4b Tumour invades pre-vertebral fascia, encases carotid artery or involves mediastinal structures hypopharyngeal cancer than at any other site in the head and neck, and larynx preservation is rarely possible. [bib_ref] Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery, Godballe [/bib_ref] Patients who have undergone previous irradiation require even greater resection margins.
## Recommendations
- Early stage disease can be treated equally effectively with surgery or radiotherapy (R) - Endoscopic resection can be considered for early well localised lesions (R) - Bulky advanced tumours require circumferential or non-circumferential resection with wide margins to account for submucosal spread (R) - Offer primary surgical treatment in the setting of a compromised larynx or significant dysphagia (R)
Management of the neck. Midline lesions, those involving the posterior pharyngeal wall or post-cricoid area, and lesions of the medial wall of the piriform sinus, require bilateral neck dissection or irradiation, because of a higher incidence of failure in the contralateral neck. In surgically treated patients with a clinically N0 neck, unilateral or bilateral neck dissection is warranted, depending on the site and size of the primary.
In the clinically positive neck, a modified radical neck dissection or a selective neck dissection on one or both sides should be considered. Due attention must be given to nodal involvement of the 'silent nodal areas'retropharynx, parapharynx, paratracheal and mediastinum.
## Recommendations
- Midline lesions require bilateral neck dissections (R) - Consider management of silent nodal areas usually not addressed for other primary sites (G)
Reconstruction. Reconstruction of pharyngeal defects and in particular circumferential defects present major challenges. Modern chemoradiotherapy protocols, medical comorbidity and poor nutritional status increase surgical morbidity. The aims of reconstruction are to restore swallowing and speech, keeping mortality and morbidity, in particular fistula and stricture rates, to a minimum.
Partial pharyngeal defects. Partial pharyngeal defects with more than 3.5 cm of unstretched remaining pharyngeal mucosal width may be closed primarily.
Defects with less than 3.5 cm of pharyngeal mucosal width remaining may be reconstructed using a pedicled flapusually a pectoralis major flap. Free flaps, such as the radial forearm flap and the anterolateral thigh flap may also be used. These reconstructions are also called 'patch' grafts. If the pharyngeal mucosal remnant is very narrow (<1 cm in width), some surgeons would recommend excision of the remnant and undertaking a total circumferential reconstruction. However, many surgeons preserve this remnant and reconstruct around it as it may reduce the stricture rate.
Total circumferential pharyngolaryngectomy defects. Lower anastomosis above the clavicles: Where the lower anastomosis of a total circumferential pharyngolaryngectomy reconstruction would lie above the clavicle, several options exist: jejunal free flap (JFF), gastro-omental free flap (GOFF), tubed radial forearm free flap (RFFF) and a tubed anterolateral thigh free flap (ALT). [bib_ref] Circumferential pharyngeal reconstruction: history, critical analysis of techniques, and current therapeutic recommendations, Patel [/bib_ref] All the above options carry the risk of free flap failure, anastomotic leaks, stricturing, donor site morbidity, failure of voice rehabilitation, swallowing problems and a small peri-operative mortality rate.
Previously untreated cases: jejunal free flaps have been associated with poorer swallowing thought to be due to uncoordinated peristalsis and wet sounding speech. The RFFF is easy to tube but has donor site issues related to the size of the flap required. Recent literature has suggested that in previously untreated cases, ALTs tubed over a salivary bypass tube appear to provide the lowest complication rateswith minimal donor site morbidity, lower leak rates and lower stenosis rates. [bib_ref] Functional outcomes and donor site morbidity following circumferential pharyngoesophageal reconstruction using an..., Murray [/bib_ref] Good swallowing and voice rehabilitation have been reported. However, many authors have not been able to replicate results in the literature and continue to use the JFF. Use of a salivary bypass tube appears to reduce the fistula rates in fasciocutaneous flaps.
Post-chemoradiotherapy (salvage cases): In general, reconstructive surgery using free flap surgery post-chemoradiotherapy carries a higher risk of complications due to the deleterious effects of chemoradiotherapy on tissue vascularity and wound healing. In such cases, limited case series suggest that the use of the GOFF may have an advantage due to the availability and vascularity of the omentum. [bib_ref] Morbidity and functional outcomes following gastro-omental free flap reconstruction of circumferential pharyngeal..., Patel [/bib_ref] The omentum can be wrapped around the anastomotic site to decrease the possibility of leakage and also improve the vascularity of the overlying skin quality. Any of the other options mentioned previously may also be used in the salvage cases. In the patients at high risk of breakdown, a pectoralis major flap may be used to reinforce the anastomotic suture lines in the pharynx.
Lower anastomosis below the clavicles: If the resection extends below the clavicles, a gastric pull through or colonic transposition flap may be used. [bib_ref] Surgical management of carcinoma of the hypopharynx and cervical esophagus: analysis of..., Triboulet [/bib_ref] Both these techniques carry increased morbidity and mortality due to the need to enter multiple visceral cavities. Gastric pull through carries a mortality rate of 5-15 per cent, morbidity of 31-55 per cent and reported fistula rates of 3-23 per cent. Colonic transposition carries similar risks, and appears to be less commonly used. It can however provide a higher cranial reach than gastric pull through, and is therefore useful for tumours that extend up high into the oropharynx.
Swallowing after reconstruction with fasciocutaneous flaps (RFFF and ALT) and GOFF is reported to be superior to that after JFF reconstruction. There is little literature on the outcome of speech rehabilitation following free flap reconstruction of total pharyngeal defects. However, speech rehabilitation is thought to be best when fasciocutaneous flaps are used to reconstruct the pharynx. There is a question as to the advisability of primary tracheoesophageal puncture in these cases. It has been argued that the presence of a puncture site and valve or catheter can increase the chance of infection and flap failure, and for this reason, many surgeons would recommend secondary puncture once the patient has healed and received their post-operative radiotherapy as indicated. Some centres perform a puncture if there is a reasonable distance between the lower anastomosis and the site of the puncture. As there is no evidence to support either position, it is best to decide on an individual case basis and depending on the experience of the team.
## Recommendation
- Reconstruction needs to be individualised to the patients' needs and based on the experience of the unit with different reconstructive techniques (G)
## Non-surgical management
Definitive radiotherapy is a potentially organ-sparing alternative to surgery in the treatment of early SCC of the hypopharynx. In combination with systemic therapy, it also has a role in the curative management of locally advanced cancers, although typically not those in which the cartilage is extensively involved or the function of both vocal cords significantly impaired. Post-operative radiation or chemoradiation improves locoregional disease control and overall survival in the presence of well-established high-risk features such as a positive margin or extra-capsular nodal extension of disease. [bib_ref] Defining risk levels in locally advanced head and neck cancers: a comparative..., Bernier [/bib_ref] There has been no randomised side-by-side comparison of surgery and radiotherapy in T1 and 2 N0 hypopharyngeal cancer. In advanced cancers, prospective trials have shown equivalent rates of local control and survival when surgery and adjuvant treatment was compared with primary non-surgical therapy. [bib_ref] Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results..., Lefebvre [/bib_ref] Given that the risk of local or locoregional failure is greater than that of distant metastases, cancers that prove radiation resistant are sometimes surgically salvageable. The choice of initial therapy is often driven by pragmatic clinical factors such as age, performance status, medical comorbidity and patient wishes as well as more subjective considerations such as tumour accessibility, local expertise or predicted functional outcome after radiotherapy. A multidisciplinary approach involving surgical and radiation oncologists, speech and language therapists and clinical nurse specialists is required.
The lymphatic drainage of the hypopharynx and the resulting significant risk of occult nodal disease at presentation typically mandate extensive irradiation of atrisk nodal groups as well as treatment of the primary tumour site and clinically apparent nodes. Intensity modulated radiation therapy (IMRT) is now well established in UK radiotherapy centres. This technique, in combination with adherence to consensus guidelines regarding target volume delineation and sophisticated imaging of patient position and anatomical changes during radiotherapy, allows much more precise and accurate targeting of tumouricidal radiation dose to the target. Intensity modulated radiation therapy also reduces radiation dose to organs at risk, such as the parotid, resulting in reduced medium term toxicity. There is also some evidence that patients treated with IMRT rather than three-dimensional conformal radiotherapy achieve higher rates of local control and better functional outcomes. Intensity modulated radiation therapy should therefore be considered the standard of care.
The predominantly loco-regional pattern of treatment failure in hypopharyngeal cancer has generated interest in treatment intensification, particularly in the setting of locally advanced disease. Intensity modulated radiation therapy has facilitated attempts at escalation of radiation dose. The addition of concomitant systemic therapy in the form of cisplatin (or cetuximab in patients with contraindications such as impaired renal function) confers a modest improvement overall survival at the expense of increased acute toxicity. All but the least fit patients under the age of 71 with stage III or selected stage IV disease should therefore be considered for combination treatment. Patients aged 71 or more were shown in the meta-analysis of chemotherapy in head and neck cancer to be unlikely to benefit from the addition of systemic therapy. [bib_ref] Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis..., Blanchard [/bib_ref] [bib_ref] Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on..., Pignon [/bib_ref] The optimal use of induction chemotherapy in hypopharyngeal cancer, as in other anatomical subsites, remains a topic of discussion. Two large trials have demonstrated its utility in an organ preservation approach with comparable survival to surgery in laryngeal cancer. Induction therapy reduces the incidence of distant metastases but does not have a consistent effect on overall survival, although individual studies comparing induction schedules with and without a taxane have shown a significant benefit for triple-agent chemotherapy. [bib_ref] Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer, Posner [/bib_ref] One pragmatic approach is to offer induction chemotherapy prior to chemoradiation to fit patients with bulky T3 or early T4 disease, 13 with laryngectomy for those who do not respond to chemotherapy, and to patients at high risk of distant relapse such as those with N2b or c or N3 disease.
## Recommendations
- Consider tumour bulk reduction with induction chemotherapy prior to definitive radiotherapy (R) - Consider IMRT where possible to limit the consequences of wide field irradiation to a large volume (R) - Use concomitant chemotherapy in patients who are fit enough and consider EGFR blockers for those who are less fit (R)
## Palliative care
It has been estimated that up to 25 per cent of patients are not suitable for curative treatment at presentation because of age, the extent of locoregional disease, distant metastases, comorbidity or refusal of surgery. Following treatment, 50-60 per cent of patients develop a recurrence in less than 12 months, and most mortality in the first two years following diagnosis is due to locoregional recurrence. The overall fiveyear disease specific survival rate is approximately 30-35 per cent with five-year survival rates of 14-22 per cent for stage IV disease. Volume of disease and laryngeal involvement adversely impact survival. Combination chemotherapy has been shown to improve overall survival. [bib_ref] Platinum-based chemotherapy plus cetuximab in head and neck cancer, Vermorken [/bib_ref] Patients with hypopharyngeal cancer may suffer from severe symptoms; including pain, swallowing difficulties, aspiration, chest infections, anorexia and weight loss. In many cases, symptoms will have been aggravated by previous treatments; surgery, radiation and chemotherapy (mucositis, hypopharyngeal stenosis, infections, pharyngocutaneous fistula, psychological distress and cachexia). All of these require attention and some may be relieved by surgical interventions such as tracheostomy and the insertion of a gastrostomy to relieve breathing and restore hydration and nutrition. Some patients, with minimal local symptoms are suitable for targeted agents in recurrent local and/or metastatic disease. These are highly selected patients and palliative treatments should be discussed and offered to patients through the multidisciplinary team (MDT). Patients with symptomatic lung metastases are often those who benefit most from palliative chemotherapy. Palliative radiotherapy may be used for patients, unsuitable for curative treatment, who present with bleeding or uncontrolled pain from the hypopharynx and can be excellent for cutaneous metastases, painful lymph nodes or bony disease.
## Key points.
- The majority of cancers arise in the piriform sinuses (65-85 per cent), 10-20 per cent arise from the posterior pharyngeal wall and 5-15 per cent from the post-cricoid area - Patient choice and involvement in treatment decisions is of high importance and a clear and unbiased discussion of their options will help them and their medical team make the most appropriate treatment decisions - Primary non-surgical treatment is recommended for most locally advanced tumours unless the laryngeal function is compromised or significant dysphagia exists - Early stage (I and II) disease can be treated with equal effectiveness with surgery or radiation - Bulky advanced tumours will usually require circumferential or non-circumferential resection with free flap cover - Five-year survival is poor with overall survival at 30 per cent, although for T1 and T2 tumours the survival is almost 60 per cent - Up to 25 per cent of patients are not suitable for curative treatment at presentation because of age, the extent of locoregional disease, distant metastases, comorbidity or refusal of surgery.
[table] TABLE I T: STAGING FOR HYPOPHARYNGEAL TUMOURS [/table]
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https://www.cambridge.org/core/services/aop-cambridge-core/content/view/3AB4267CA8BC22A3E528E4C9093DAC43/S0022215116000529a.pdf/div-class-title-hypopharyngeal-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf
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Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. With an age standardised incidence rate of 0.63 per 100 000 population, hypopharynx cancers account for a small proportion of the head and neck cancer workload in the UK, and thus suffer from the lack of high level evidence. This paper discusses the evidence base pertaining to the management of hypopharyngeal cancer and provides recommendations on management for this group of patients receiving cancer care. Recommendations • Cross-sectional imaging with computed tomography of the head, neck and chest is necessary for all patients; magnetic resonance imaging of the primary site is useful particularly in advanced disease; and computed tomography and positron emission tomography to look for distant disease. (R) • Careful evaluation of the upper and lower extents of the disease is necessary, which may require contrast swallow or computed tomography and positron emission tomography imaging. (R) • Formal rigid endoscopic assessment under general anaesthetic should be performed. (R) • Nutritional status should be proactively managed. (R) • Full and unbiased discussion of treatment options should take place to allow informed patient choice. (G) • Early stage disease can be treated equally effectively with surgery or radiotherapy. (R) • Endoscopic resection can be considered for early well localised lesions. (R) • Bulky advanced tumours require circumferential or non-circumferential resection with wide margins to account for submucosal spread. (R) • Offer primary surgical treatment in the setting of a compromised larynx or significant dysphagia. (R) • Midline lesions require bilateral neck dissections. (R) • Consider management of silent nodal areas usually not addressed for other primary sites. (G) • Reconstruction needs to be individualised to the patients’ needs and based on the experience of the unit with different reconstructive techniques. (G) • Consider tumour bulk reduction with induction chemotherapy prior to definitive radiotherapy. (R) • Consider intensity modulated radiation therapy where possible to limit the consequences of wide field irradiation to a large volume. (R) • Use concomitant chemotherapy in patients who are fit enough and consider epidermal growth factor receptor blockers for those who are less fit. (R)
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2a73a73d2fe5bc25bc66c9ecb4adb48a33e2e20c
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pubmed
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Diagnosis and Management of Group A Streptococcal Pharyngitis: A Practice Guideline
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Diagnosis and Management of Group A Streptococcal Pharyngitis: A Practice Guideline
This is the second in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of these guidelines is to provide assistance to clinicians when making decisions on treating the conditions specified in each guideline. The targeted providers are pediatricians, family practitioners, and internists. The targeted patients and setting for the acute pharyngitis guideline are pediatric, adolescent, and adult outpatients with a complaint of sore throat. Funding was provided by the IDSA. Panel members represented experts in adult and pediatric infectious diseases. The guidelines are evidence-based. A standard ranking system was used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary, algorithms, and tables highlight the major recommendations.
## Most oral antibiotics must be administered in the conventional
Outcomes 10-day course to achieve maximal pharyngeal eradication of group
The desired outcomes are: (1) prevention of acute rheumatic A streptococci, but the use of certain newer agents has been reported fever; [bib_ref] Purpose of quality standards sensitivity with respect to true infections, Gross [/bib_ref] prevention of suppurative complications (e.g., peritonsillar to achieve comparable bacteriologic and clinical cure rates among abscess, cervical lymphadenitis, or mastoiditis); (3) abatement of patients with streptococcal pharyngitis when these agents are given clinical symptoms and signs; (4) a rapid decrease in infectivity so for £5 days. However, definitive results from comprehensive studas to reduce transmission of group A b-hemolytic streptococci to ies are not available; thus, final evaluation of these proposed shorter family members, classmates, and other close contacts and to allow courses of oral antibiotic therapy is not possible, and they cannot the rapid resumption of usual activities; (5) minimization of potenbe recommended at this time. Moreover, these antibiotics have tial adverse effects of inappropriate antimicrobial therapy. much broader spectrums than penicillin, and most, even when administered for short courses, are more expensive.
Except under special circumstances, neither repeated bacteri-Evidence ologic testing (culture or RADT) of patients who have success-We reviewed a large number of clinical trials of diagnostic fully completed a course of antimicrobial therapy nor routine and treatment strategies for group A streptococcal pharyngitis. testing of asymptomatic household contacts of patients with
The reports were examined for indicators of quality. For examgroup A streptococcal pharyngitis is recommended.
ple, studies of treatment were evaluated for randomization, A small percentage of patients will have recurrences of acute blinding, use of streptococcal typing to differentiate treatment pharyngitis that are associated with throat cultures (or RADTs) failures from new infections, duration and timing of follow-up positive for group A streptococci within a short period following examinations, and statistical power [bib_ref] Streptococcal pharyngitis: current therapy and criteria for evalua-27, Peter [/bib_ref] [bib_ref] Purpose of quality standards sensitivity with respect to true infections, Gross [/bib_ref]. completion of a course of antimicrobial therapy. Such episodes may be treated with one of the antimicrobial agents appropriate for treatment of the initial illness. If these episodes were previously Values treated with oral agents and compliance is in question, retreatment
In evaluating diagnostic options, we placed a high value with intramuscular benzathine penicillin G should be considered.
on selecting the diagnostic test that was most accurate for When multiple episodes occur over the course of months or years, differentiating acute pharyngitis due to group A b-hemolytic it may be difficult to differentiate viral infections in a streptococcal streptococci from that due to other agents. For evaluation of carrier from true group A streptococcal infections. Certain antimitreatment, particularly high values were assigned to proven crobial agents, such as clindamycin and amoxicillin/clavulanate, clinical and bacteriologic efficacy, safety, spectrum of antimimay be beneficial because they have been shown to yield high crobial activity, and relative cost. rates of pharyngeal eradication of streptococci under these particular circumstances.
## Benefits and costs
The group A b-hemolytic streptococcus is the most common Definition bacterial cause of acute pharyngitis [bib_ref] immunoassay for rapid detection of group A b-hemolytic streptococci: 97(6pt2)(suppl):949 -54. should..., Bisno [/bib_ref]. Accurate diagnosis, followed by appropriate antimicrobial therapy, is important for Group A streptococcal pharyngitis (pharyngotonsillitis) is an acute infection of the oropharynx and/or nasopharynx with the reasons previously stated (see the section on outcomes). Although acute pharyngitis is one of the most frequent illnesses Streptococcus pyogenes.
for which pediatricians and other primary care physicians are consulted, less than half of patients with this condition are infected by group A streptococci. Moreover, the signs and Objective symptoms of group A streptococcal and nonstreptococcal pharyngitis overlap so broadly that accurate diagnosis on clinical The objective of this practice guideline is to provide recommendations for the accurate diagnosis and optimal treatment grounds alone is usually impossible [bib_ref] Perplexity and precision in the diagnosis of streptococ-29, Wannamaker [/bib_ref].
With the exception of very rare infections by certain of the of group A streptococcal pharyngitis.
other pharyngeal bacterial pathogens listed in table 1 (e.g., Corynebacterium diphtheriae and Neisseria gonorrhoeae), antimicrobial therapy is of no proven benefit in the treatment of acute Options pharyngitis due to bacteria other than the group A streptococcus. It is therefore extremely important for physicians to be able to Physicians caring for patients with acute pharyngitis must formulate differential diagnoses and determine which, if any, exclude the diagnosis of group A streptococcal pharyngitis to prevent inappropriate administration of antimicrobials to large confirmatory tests should be performed. If clinical and laboratory evaluations result in a diagnosis of group A b-hemolytic numbers of patients with pharyngitis. The administration of such therapy unnecessarily exposes patients to the associated expense streptococcal pharyngitis, one of several antimicrobial agents and treatment schedules may be selected. and hazards, and it may also contribute to the emergence of / 9c37$$se43 08-25-97 15:12:42 cidal UC: CID temperate climates, it usually occurs in the winter and early spring. Patients with group A b-hemolytic streptococcal pharyngitis commonly present with sore throats (generally of sudantibiotic-resistant bacteria that is being reported with increasing den onset), pain on swallowing, and fever. Headache, nausea, frequency in the United States and elsewhere.
vomiting, and abdominal pain may also be present, especially If a diagnosis of group A streptococcal pharyngitis is conin children. Physical examination reveals tonsillopharyngeal firmed, the clinician must select the most appropriate antimicroerythema with or without exudates and tender enlarged anterior bial agent known to be effective against the group A streptococcervical lymph nodes (lymphadenitis). Other findings may incus. The cost of an effective course of antimicrobial therapy clude a beefy red swollen uvula, petechiae on the palate, excorimay vary as much as 20-fold, depending on the drug chosen.
ated nares (especially in infants), and a scarlatiniform rash. The regimens recommended herein are judged to be optimal However, none of these findings is specific for group A bin regard to specificity, safety, and cost. hemolytic streptococcal pharyngitis, and they may occur with other upper respiratory infections. Conversely, the absence of Recommendations fever or the presence of clinical features such as conjunctivitis, cough, hoarseness, coryza, anterior stomatitis, discrete ulcera-
## A. diagnosis
tive lesions, viral exanthem, and diarrhea strongly suggests a viral rather than a streptococcal etiology. Differential diagnosis. Viruses are the most common nonbacterial causes of acute pharyngitis (table 1) [bib_ref] immunoassay for rapid detection of group A b-hemolytic streptococci: 97(6pt2)(suppl):949 -54. should..., Bisno [/bib_ref]. Respiratory viruses such as adenovirus, parainfluenza virus, rhinovirus, and Who Should Be Tested for Group A b-Hemolytic Streptococcal respiratory syncytial virus frequently cause acute pharyngitis.
## Pharyngitis?
Other viral agents of acute pharyngitis include coxsackievirus and ECHO viruses as well as herpes simplex virus. Epstein-When attempting to decide whether to perform a laboratory test for a patient who presents with acute pharyngitis, the clini-Barr virus is a frequent cause of acute pharyngitis that is often accompanied by the other clinical features of infectious mono-cal and epidemiological findings mentioned above should be considered before the test is performed. A history of close nucleosis (e.g., generalized lymphadenopathy and splenomegaly). Systemic infections with measles virus, cytomegalovirus, contact with a well-documented case of streptococcal pharyngi-/ 9c37$$se43 08-25-97 15:12:42 cidal UC: CID tis is helpful, as is an awareness of a high prevalence of group A positive throat cultures that would not otherwise be identified. Thus, while initial therapeutic decisions may be made on the b-hemolytic streptococcal infections in the community. Testing usually need not be performed for patients with acute pharyngi-basis of the results of an overnight culture, it is advisable to reexamine plates at 48 hours that are negative at 24 hours [bib_ref] Suitability of throat culture procedures for detection of group streptococcal pharyngitis and..., Kellogg [/bib_ref] tis whose clinical and epidemiological features do not suggest a group A streptococcal etiology. Selective use of diagnostic (category A, grade II).
The clinical significance of the number of group A b-hemostudies for group A b-hemolytic streptococci will result in an increase in both the proportion of positive test results and the lytic streptococcal colonies present on the throat culture plate is problematic. While cultures are more likely to be strongly percentage of patients with positive tests who are truly infected rather than merely streptococcal carriers (category A, grade II).
positive for patients with true acute group A streptococcal pharyngitis than for patients who are streptococcus carriers, Efforts have been made to incorporate clinical and epidemiological features of acute pharyngitis into scoring systems that there is so much overlap that the differentiation cannot be made accurately on the basis of the degree of positivity of the throat attempt to predict the probability that a particular illness is caused by group A b-hemolytic streptococci [bib_ref] A simple scorecard for the tentative diagnosis of streptococcal tococcic infection, Breese [/bib_ref] [bib_ref] Streptococcal pharyngitis: evaluation of clinirheumatic fever by treatment of the preceding streptococcal..., Stillerman [/bib_ref]. How-culture alone [bib_ref] Diagnosis of pharyngitis: methodology of throat cultures, Gerber [/bib_ref] (category A, grade II).
The most widely used test for differentiating group A strepto-ever, at best these clinical scoring systems predict positive results of throat cultures or RADTs only £80% of the time.
cocci from other b-hemolytic streptococci in physicians' offices is probably the bacitracin disk test. This test provides a Therefore, unless the diagnosis of group A streptococcal pharyngitis can be confidently excluded on clinical and epidemio-presumptive identification based on the observation that ú95% of group A streptococci show a zone of inhibition around a logic grounds (see Clinical Diagnosis above), bacteriologic studies should be performed (category A, grade II). disk containing 0.04 units of bacitracin, while 83% -97% of non-group A streptococci do not [bib_ref] extraction method with pronase B for grouping beta-hemolytic strepto-42. World Health Organization...., Ederer [/bib_ref] [bib_ref] Bacitracin differentiazation, 1988. tion of presumptive identification of group A b-hemolytic streptococci:..., Murray [/bib_ref]. An alternative and highly specific method of identifying Throat Cultures streptococcal serogroups is the detection of the group-specific cell-wall carbohydrate antigen directly on isolated bacterial Culture of a throat swab on a sheep blood agar plate remains the standard for the documentation of the presence of group A colonies. Commercial kits containing group-specific antisera are available for this purpose. Such tests are appropriate for streptococci in the upper respiratory tract and for the confirmation of the clinical diagnosis of acute streptococcal pharyngitis use by microbiology laboratory personnel, but most physicians who perform throat cultures would find it difficult to justify [bib_ref] Controlled studies of streptococinfections on clinical grounds, Breese [/bib_ref] (category A, grade II). A single throat swab cultured correctly on a blood agar plate has a sensitivity of 90% -95% in the additional expense for the minimal improvement in accuracy that serogrouping with an antigen detection test would detecting the presence of group A b-hemolytic streptococci in the pharynx [bib_ref] Comparison of throat cultures and rapid strep tests for diagnorate of rheumatic..., Gerber [/bib_ref] (category A, grade II).
provide [bib_ref] Diagnosis of pharyngitis: methodology of throat cultures, Gerber [/bib_ref]. Several variables impact on the accuracy of the throat culture results. For example, the manner in which the swab is obtained
## Rapid antigen detection tests
has an important impact on the yield of streptococci from the throat culture [bib_ref] Streptococcal pharyngitis: optimal site for throat culof rheumatic fever by treatment of..., Brien [/bib_ref] [bib_ref] Cultures of Streptococcus 466 -71. pyogenes from the oropharynx, Gunn [/bib_ref]. Throat swab specimens should be ob-A disadvantage of culturing a throat swab on blood agar plates is the delay (overnight or longer) in obtaining the culture tained from the surface of both tonsils (or tonsillar fossae) and the posterior pharyngeal wall. Other areas of the oropharynx results. RADTs have been developed for the identification of group A b-hemolytic streptococci directly from throat swabs. and mouth are not acceptable sites for sampling, and these sites should not be touched before or after the appropriate areas Although these rapid tests are more expensive than blood agar cultures, the advantage they offer over the traditional procedure have been sampled. In addition, false-negative results may be obtained if the patient has received antibiotics shortly before is the speed with which they can provide results. Rapid identification and treatment of patients with streptococcal pharyngitis or at the time the throat swab specimen is collected.
It has also been reported that the use of anaerobic incubation can reduce the risk of the spread of group A b-hemolytic streptococci, allowing these patients to return to school or work and selective culture media may increase the proportion of positive cultures [bib_ref] Effect of atmosphere of incubation from rheumatic fever: routine administration of benzathine..., Schwartz [/bib_ref] [bib_ref] Effect of atmosphere and duration of fever in children and adolescents. A..., Lauer [/bib_ref]. However, the data on the impact of sooner, and can reduce the acute morbidity associated with this illness (category A, grade II). The use of RADTs the incubation atmosphere and the culture media are conflicting, and, in the absence of a definite benefit, the increased cost vs. throat cultures for certain populations (e.g., patients seen in emergency departments) has been shown to significantly and effort associated with anaerobic incubation and selective culture media are difficult to justify, particularly for physicians increase the number of patients appropriately treated for streptococcal pharyngitis [bib_ref] Clinical evaluation of a latex aggluti-References nation test for streptococcal pharyngitis: performance..., Lieu [/bib_ref]. who process throat cultures in their own offices [bib_ref] Effect of atmosphere of incubation from rheumatic fever: routine administration of benzathine..., Schwartz [/bib_ref] [bib_ref] Ann Intern Comparison of throat culture methods for the recovery of group..., Roddey [/bib_ref] [bib_ref] Diagnosis of pharyngitis: methodology of throat cultures, Gerber [/bib_ref] (category A, grade II).
Most of the RADTs that are currently available have an excellent specificity ( §95%) when compared with blood agar Another variable that can impact on the yield of the throat culture is the duration of incubation. tomatic pharyngitis after the organism's presence in the throat The first RADTs were based on latex agglutination methodis confirmed by microbiological or immunologic means (figure ology, were relatively insensitive, and had unclear endpoints. 1). When there is clinical or epidemiological evidence that Newer tests based on EIA techniques offer more sharply deresults in a high index of suspicion, antimicrobial therapy can fined endpoints as well as increased sensitivity. More recently, be initiated while laboratory confirmation is pending provided RADTs for which optical immunoassay and chemiluminescent such therapy is discontinued if the diagnosis of streptococcal DNA probes are used have become available. Data on these pharyngitis is not confirmed. Early initiation of antimicrobial newer tests suggest that they may be more sensitive than other therapy results in faster resolution of the signs and symptoms RADTs and perhaps even as sensitive as standard throat cul- (category A, grade I) of the infection, but two facts tures on sheep blood agar plates. However, in view of someshould be recalled. First, group A streptococcal pharyngitis is what conflicting data, additional corroborative information usually a self-limited disease; fever and constitutional sympis needed before these tests can be recommended for routine use toms disappear spontaneously within 3 or 4 days of onset, even without confirmatory throat cultures for negative test results.
when antimicrobial therapy is not administered . Second, Titers of antibodies to streptococci reflect past and not presit has been shown that therapy can be safely postponed £9 days ent immunologic events and are of no value in the diagnosis after the onset of symptoms and still prevent the occurrence of of acute pharyngitis. These titers are valuable for confirming the major nonsuppurative sequel, acute rheumatic feverprior streptococcal infections in patients suspected of having (category A, grade I). acute rheumatic fever or acute glomerulonephritis. They also These facts allow the clinician flexibility in initiating therapy are helpful in prospective epidemiological studies that are conduring the evaluation of an individual patient with presumed ducted to separate patients with acute infection from those who group A streptococcal pharyngitis. The results of the initial are carriers.
therapeutic studies were reported nearly 50 years ago; since Guideline: The diagnosis of acute group A streptococcal then numerous antimicrobial agents have been examined in pharyngitis should be suspected on clinical and epidemiological grounds and then supported by the results of a laboratory test. Either a positive throat culture or RADT provides adequate confirmation of the presence of group A b-hemolytic streptococci in the pharynx, but a negative RADT result should be confirmed with a throat culture (category A, grade II).
## Repeated diagnostic testing
Most asymptomatic patients with group A b-hemolytic streptococci present in the upper respiratory tract after a complete course of appropriate therapy are streptococcal carriers [29, 30]. Therefore, follow-up throat cultures are not routinely indicated for asymptomatic patients who have received a complete course of therapy for group A streptococcal pharyngitis (category A, grade II). However, there are special situations when follow-up throat cultures should be performed for asymptomatic patients. Throat CID clinical trials and have been shown to be capable of eradicating been shown to be resistant to erythromycin. Sulfonamides and tetracyclines are not recommended for treatment of group group A streptococci from the upper respiratory tract. However, it must be recognized that the only antimicrobial actually exam-A streptococcal pharyngitis because of the higher rates of resistance to these agents among group A streptococci and the ined in controlled studies and shown to be capable of preventing initial attacks of rheumatic fever has been intramuscular reposi-frequent failure of these agents to eradicate even susceptible organisms from the pharynx. tory penicillin (category A, grade I). These studies were performed with procaine penicillin G in oil containing Antimicrobial therapy. When selecting an antimicrobial for treatment of group A streptococcal pharyngitis, important is-aluminum monostearate , a preparation that has since been supplanted by benzathine penicillin G. (For this reason, sues include efficacy, safety, antimicrobial spectrum (narrow vs. broad), dosing schedules, compliance (or adherence), and no regimens listed in table 2 have been assigned a grade of A1.) There are data, although not definitive, indicating that cost. These factors influence the cost-effectiveness of antimicrobial therapy. benzathine penicillin G is effective in primary prevention of rheumatic fever (prevention of an initial attack of rheumatic A number of antibiotics have been shown to be effective for treating group A streptococcal pharyngitis. These agents in-fever following an episode of group A streptococcal pharyngitis) . Benzathine penicillin G has also been shown clude penicillin and its congeners (such as ampicillin and amoxicillin), as well as numerous cephalosporins, macrolides, and to decrease the occurrence of rheumatic fever cases during epidemics of streptococcal pharyngitis in military recruit camps clindamycin. However, penicillin remains the treatment of choice because of its proven efficacy, safety, narrow spectrum,. Moreover, benzathine penicillin G has been proven effective for preventing rheumatic fever in patients who have had and low cost [31, . Erythromycin is a suitable alternative for patients who are allergic to penicillin. First-or second-a previous attack of the disease (secondary prophylaxis)(category A, grade I). Other antimicrobials can effectively erad-generation cephalosporins are also acceptable for penicillinallergic patients who do not manifest immediate hypersensitiv-icate group A streptococci from the upper respiratory tract, and it is assumed that such eradication is an adequate measure of ity to b-lactam antibiotics.
Most oral antibiotics must be administered for 10 days to effectiveness in the primary prevention of rheumatic fever.
Antimicrobial resistance has not been a significant issue in achieve maximal pharyngeal eradication of group A streptococci, but certain new agents have been administered in shorter the treatment of group A streptococcal pharyngitis in the United States. There has never been a clinical isolate of group A courses. It has been reported that azithromycin , cefuroxime, cefixime [bib_ref] Efficacy of tonsillectomy pharyngitis and/or tonsillitis: comparison with 10-day penicillin for recurrent..., Adam [/bib_ref] , and cefpodoxine [bib_ref] course treatment of acute group A b-hemolytic streptococcal tonsil-Clindamycin treatment of chronic..., Pichichero [/bib_ref] can be used to streptococcus documented to be resistant to penicillin anywhere in the world. Although there have been geographic areas where achieve comparable bacteriologic and clinical cure rates among patients with streptococcal pharyngitis when these drugs are isolates have been highly resistant to macrolide antibiotics (specifically erythromycin), this has not been and currently is not given for £5 days. However, definitive results from comprehensive studies are not available, and thus it is not possible to a clinically significant problem in North America. Less than 5% of group A streptococci isolated in the United States have endorse these proposed shorter courses of oral antibiotic ther- * Amoxicillin is often used in place of oral penicillin V in young children; the efficacy of amoxicillin appears to be equal to that of penicillin V, and this choice is primarily related to acceptance of the taste of the suspension. † See text. ‡ For patients weighing less than 60 lbs (27 kg). § Two milliliters of C-R bicillin(900/300) contains 900,000 units of benzathine penicillin G and 300,000 units of procaine penicillin G; this preparation thus contains less benzathine penicillin G than is conventionally used in the treatment of adolescents or adults.
Available data indicate that orally administered first-and second-generation cephalosporins also are effective in eradicating group A streptococci from the upper respiratory tract; these agents should not be used in patients with immediate hypersensitivity to b-lactam antibiotics.
First-generation cephalosporin A II Second-generation cephalosporin A II. # These are total daily doses (maximum daily dose, 1 g per day).
/ 9c37$$se43 08-25-97 15:12:42 cidal UC: CID apy at this time. Moreover, the spectra of these antibiotics are special circumstances are present (see the section on Repeated Diagnostic Testing). Because routine retesting is no longer much broader than that of penicillin, and, even when they are administered for short courses, they are more expensive.
advised, only those patients whose signs and symptoms of acute pharyngitis return within the succeeding few weeks will Antimicrobials for group A streptococcal upper respiratory tract infections may be given either orally or parenterally. , noncompliance with the pre-group A streptococcal pharyngitis. Intramuscular benzathine penicillin G is preferred for patients who are unlikely to com-scribed antimicrobial regimen [52], or a new infection with a group A streptococcus acquired from family, classroom, or plete a full 10-day course of oral therapy.
Guideline: patients with acute streptococcal pharyngitis community contacts. A second episode of pharyngitis with the original infecting group A streptococcal strain (i.e., treatment should receive therapy with an antimicrobial agent in a dosage and for a duration that is likely to eradicate the infecting organ-failure) cannot be ruled out, but this occurs only rarely. Streptococcal carriers do not ordinarily require further anti-ism from the pharynx. On the basis of penicillin's narrow spectrum of antimicrobial activity, the infrequency with which microbial therapy. These individuals have group A b-hemolytic streptococci present in their throats but have no evidence of it produces adverse reactions, and its modest cost, it is the drug of choice for nonallergic patients.
an immunologic reaction to this organism . During the winter and spring in temperate climates, £20% of asymptom-Management of close contacts and pharyngeal carriers. Approximately 25% of individuals within the household of an index atic school-aged children may be streptococcus carriers. They may be colonized by group A b-hemolytic streptococci for patient may also harbor group A streptococci in their upper respiratory tracts. However, it is usually not necessary to perform several months, and during that period they may have episodes of intercurrent viral pharyngitis. When tested, these patients throat cultures for these contacts or treat them if they are asymptomatic. In those situations in which repeated testing is indicated are found to have group A b-hemolytic streptococci in their pharynges and appear to have acute streptococcal pharyngitis. (see the section on Repeated Diagnostic Testing), performing cultures for asymptomatic family contacts and treating those who Streptococcal carriers are unlikely to spread the organism to their close contacts and are at low risk, if any, for developing are positive are advisable. When a larger group (e.g., schools, day care centers, or domiciliary institutions) is involved in a suppurative complications or nonsuppurative complications (e.g., acute rheumatic fever) . documented outbreak of group A streptococcal upper respiratory infections or scarlet fever, throat cultures should be performed Moreover, it is more difficult to eradicate group A streptococci from the upper respiratory tracts of streptococcal carriers for all patients; however, only those with positive throat cultures should be treated with antimicrobials. The administration of intra- . This has been shown to be true with penicillin therapy and also may be true with some other antimicrobials. In fact, muscular injections of benzathine penicillin G has been shown to be very effective in terminating such outbreaks.
many of the published studies showing relatively high rates of failure to eradicate group A streptococci from the upper Strains of group A streptococci that cause invasive infections may spread to close contacts of the index case. Secondary cases respiratory tract with penicillin therapy were likely ''contaminated'' with carriers. of severe invasive infection have rarely occurred in family and institutional contacts and in health care workers . Data
In practice it is difficult to differentiate a carrier with an intercurrent non-group A streptococcal infection from a patient are as yet too limited to assess with precision the risk of secondary illness or to make a firm recommendation regarding the with acute streptococcal pharyngitis. Helpful clues include the patient's age, season of the year, local epidemiology (e.g., the advisability of routinely performing cultures and treating close contacts of patients with group A streptococcal infections such presence of influenza or enteroviral illnesses), and the precise nature of the presenting signs and symptoms (see the section as necrotizing fasciitis or the toxic shock -like syndrome.
Guideline: It is not necessary to perform throat cultures or on clinical diagnosis above). In many instances, however, the clinician may not be able provide treatment for household contacts of patients with group A streptococcal pharyngitis, except in specific situations in confidently to distinguish persistent carriage from acute infection and will elect to administer another course of antimicrobi-which there is increased risk of frequent infections or of nonsuppurative sequelae (category B, grade III).
als. For single episodes of symptomatic, culture-confirmed or RADT-confirmed group A streptococcal pharyngitis that occur shortly after completion of a course of appropriate antimicro-
## C. management of patients with repeated episodes of acute
bial therapy, any of the agents listed in table 2 is appropriate.
## Pharyngitis and cultures or radts positive for group a
Because patient compliance with oral antimicrobials often is b-Hemolytic Streptococci an issue, a regimen of intramuscular benzathine penicillin G should be considered. For these single repeated episodes, it is Performing routine throat cultures (or rapid antigen testing) for asymptomatic patients after completion of antibiotic therapy not necessary to reculture the throat after the second course of therapy unless the patient remains or becomes symptomatic or for group A streptococcal pharyngitis is not necessary unless / 9c37$$se43 08-25-97 15:12:42 cidal UC: CID unless special circumstances are present (see the section on There have been no definitive controlled studies of therapy for multiple, repeated symptomatic episodes of culture-positive Repeated Diagnostic Testing above).
An even more challenging clinical circumstance is a pa-acute pharyngitis in the same patient; however, the regimens listed in [fig_ref] Table 3: Retreatment of symptomatic patients with multiple repeated culture-positive episodes of pharyngitis [/fig_ref] have been reported to result in low bacteriologi-tient -usually a school-aged child or adolescent -who has multiple episodes of acute pharyngitis and cultures or RADTs cal failure rates [55 -58].
Guideline: A small percentage of patients will have recur-positive for group A streptococci within a period of months to years. It is likely that most patients in this category are rences of acute pharyngitis and throat cultures (or RADTs) positive for group A streptococci within a short period of time streptococcal carriers with nonstreptococcal infections. For patients who have frequent distinct episodes of infection, informa-following completion of a course of antimicrobial therapy. A single such episode may be retreated with the regimens listed tion regarding the clinical response to antibiotic therapy and the presence or absence of group A streptococci in throat cultures in table 2. When multiple episodes occur over the course of months or years, it may be difficult to differentiate viral infec-performed during asymptomatic intervals is helpful in distinguishing persistent carriage from repeated episodes of strepto-tions from true group A streptococcal infections in a streptococcal carrier. Use of certain antimicrobial agents has been shown coccal pharyngitis. Serotyping of repeated streptococcal isolates from an individual patient may also assist in arriving at to yield high rates of streptococcal eradication in the pharynx under these particular circumstances (category A, grade II). this determination, but such studies can be done only in specialized research laboratories.
Suggested regimens with these agents are listed in table 3. When physicians suspect Ping-Pong spread to be associated with multiple repeated episodes of group A streptococcal infections in one family, performing simultaneous cultures for all D. Indicators of Quality family contacts and treating those whose cultures are positive may be helpful (category B, grade III). There is no credible Indicators of quality of care for patients with acute pharyngitis include: (1) performance of throat cultures or RADTs for evidence that family pets are reservoirs for group A streptococci or that they contribute to familial spread.
patients suspected of having group A streptococcal pharyngitis;
(2) performance of throat cultures for patients with negative Continuous antimicrobial prophylaxis for group A streptococcal infection is not recommended because there is insuffi-RADTs; (3) prescription of one of the antimicrobial regimens recommended in table 2 for patients with acute pharyngitis cient evidence to show that it is effective, except for preventing recurrences of acute rheumatic fever. Surgical removal of the and positive tests for group A streptococci; (4) withholding or discontinuing antimicrobial therapy for patients with throat tonsils may be considered for the rare patient whose symptomatic episodes do not diminish in frequency over time and for cultures negative for group A streptococci; (5) omission of routine follow-up cultures for patients who have received an whom no alternative explanation for the recurrent pharyngitis is evident. Tonsillectomy may decrease recurrences of symp-adequate course of antimicrobial therapy; (6) avoidance of routine throat cultures for asymptomatic family contacts of patients tomatic pharyngitis in selected patients, but only for a limited period of time [54] (category A, grade I).
with group A streptococcal pharyngitis; (7) avoidance of con- † Although shorter courses of some newer macrolides and cephalosporins have been reported to be effective for treating group A streptococcal upper respiratory tract infections, the evidence is not yet sufficient to recommend these agents for therapy at this time (this is also true for patients with repeated infections or for those in whom the organism is difficult to eradicate). ‡ Maximum dose, 750 mg of amoxicillin per day. § Benzathine penicillin G is useful for patients whose compliance with previous courses of oral antimicrobials is questionable. Limited data suggest that the addition of rifampin
[fig] Figure 1: Diagnosis and management of acute pharyngitis. This cultures should be performed routinely for patients with histories algorithm applies to uncomplicated cases of acute pharyngitis; addiof rheumatic fever. Such cultures should also be considered for tional diagnostic and therapeutic measures may be necessary for papatients who develop acute pharyngitis during outbreaks of either tients with suppurative complications (e.g., peritonsillar abscess or acute rheumatic fever or poststreptococcal acute glomerulonephricervical lymphadenitis) or when infection with uncommon pharyngeal tis as well as during outbreaks of group A streptococcal pharyngitis bacterial pathogens (e.g., Corynebacterium diphtheriae or Neisseria gonorrhoeae) is suspected. (0 Å if negative; / Å if positive). in closed or semiclosed communities [30, 31]. Follow-up throat [/fig]
[table] Table 1: Microbial etiology of acute pharyngitis. rubella virus, influenza virus, and a number of other viral agents may be associated with acute pharyngitis. Other agents such Microbe Disorder as Mycoplasma pneumoniae and Chlamydia pneumoniae are uncommon causes of acute pharyngitis.Clinical diagnosis. There are certain characteristic epide- [/table]
[table] Table 2: Antimicrobial therapy for group A streptococcal pharyngitis. [/table]
[table] Table 3: Retreatment of symptomatic patients with multiple repeated culture-positive episodes of pharyngitis. * Macrolides (e.g., erythromycin) and cephalosporins are not included in this table, as there are insufficient data to support their efficacy in this specific circumstance. [/table]
[table] 10: mg/kg b.i.d. 1 4 days; maximum dose, 300 mg b.i.d.) to a benzathine penicillin G regimen may be beneficial for eradicating streptococci from the pharynx [58]. [/table]
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https://academic.oup.com/cid/article-pdf/25/3/574/822750/25-3-574.pdf
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Abstract This is the second in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of these guidelines is to provide assistance to clinicians when making decisions on treating the conditions specified in each guideline. The targeted providers are pediatricians, family practitioners, and internists. The targeted patients and setting for the acute pharyngitis guideline are pediatric, adolescent, and adult outpatients with a complaint of sore throat. Funding was provided by the IDSA. Panel members represented experts in adult and pediatric infectious diseases. The guidelines are evidence-based. A standard ranking system was used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary, algorithms, and tables highlight the major recommendations. Indicators of quality will assist in guideline implementation. The guideline will be listed on the IDSA home page at http://www.idsociety.org.
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Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2
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Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2
## General remarks
## Indications for endoscopic resection
Among lesions in which the depth of invasion does not extend beyond the mucosal layer (T1a), those confined within the mucosal EP or the LPM are only extremely rarely associated with lymph-node metastasis; therefore, endoscopic resection is a sufficiently radical treatment for these lesions. Lesions extending up to the muscularis mucosae or slightly infiltrating the submucosa (up to 200 μm) are also amenable to mucosal resection; however, they are associated with an elevated risk of lymph-node metastasis. Therefore, these represent relative indications [bib_ref] Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading..., Katada [/bib_ref] [bib_ref] Long-term outcome after endoscopic mucosal resection in patients with esophageal squamous cell..., Shimizu [/bib_ref]. Furthermore, about 50% of the lesions that show deeper (more than 200 μm) invasion into the submucosa (T1b) are associated with metastasis, and in such cases, even if they are classified as superficial carcinomas, should be treated in the same manner as advanced carcinomas. Mucosal resection covering 3/4 of the entire circumference is likely to be associated with postoperative cicatricial stenosis. Therefore, sufficient explanation should be given to the patient prior to the operation and preventive measures must be taken [bib_ref] Predictive factors for esophageal stenosis after endoscopic submucosal dissection for superficial esophageal..., Mizuta [/bib_ref] [bib_ref] Esophageal stenosis after endoscopic mucosal resection of superficial esophageal lesions, Katada [/bib_ref].
## Diagnosis by histopathology of the resected tissue specimens
There are limitations to all the modes of diagnosis of the depth of tumor invasion prior to treatment. It is also difficult to accurately determine the depth of invasion of extensive lesions. Furthermore, preoperative diagnosis of the histologic type of the invasive tumors or that of vascular invasion is impracticable. Histopathologic examination of the resected tissue specimens is, therefore, important for determining whether an additional treatment is required or not, and diagnosis of tissue specimens obtained by en bloc resection is indispensable.
## Treatment of lesions not amenable to endoscopic resection
Insufficient elevation of the mucosa after submucosal injection may pose difficulty in additional ER of residual marginal lesions after ER, or ER after radiotherapy or chemoradiotherapy. These cases and cases with a bleeding tendency are not suitable for ER, and other treatment options such as PDT [bib_ref] Photodynamic therapy as salvage treatment for local failures after definitive chemoradio therapy..., Yano [/bib_ref] and APC would need to be considered.
## Superiority of en bloc resection
En bloc resection is desirable for histologic diagnosis of the resected specimens. ESD enables en bloc resection of lesions that were formerly subjected to fractional resection. Further development of equipment and spread of improved techniques are anticipated.
## Complications
Various complications, including bleeding (0.2%), esophageal perforation (1.9%), and post-resection cicatricial stenosis (6.0-16.7%), have been reported in association with ER. Sufficient explanation should be provided to the patients, and measures must be taken for prevention/treatment of these complications.
## Cq18: is additional treatment recommended in cases detected to have pt1a-mm lesion following endoscopic treatment for superficial esophageal cancer?
# Recommendation statement
There is strong evidence to recommend an additional treatment in patients identified as having a pT1a-MM lesion with positive vascular invasion after endoscopic treatment (rate of consensus: 85% ; strength of evidence: D).
## Explanatory note
There are no reports of randomized comparative or case-control studies demonstrating the usefulness of additional treatment in patients in whom the resected specimens collected at endoscopic treatment are histopathologically diagnosed as pT1a-MM lesions.
According to the reports based on the results of surgical treatment, the frequency of lymph-node metastasis in resected specimens obtained from patients with pT1a-MM squamous cell carcinoma was 0-27%, and summarization and analysis of data from major reports revealed that it was present in 30/210 cases (14.2%; 95% CI 9.85-19.76) [bib_ref] Clinicopathologic analysis of lymph node metastasis in surgically resected superficial cancer of..., Endo [/bib_ref] [bib_ref] Evaluation of endoscopic mucosal resection for superficial esophageal carcinoma, Noguchi [/bib_ref] [bib_ref] Pathological feature of superficial esophageal squamous cell carcinoma with lymph node and..., Araki [/bib_ref] [bib_ref] Histological criteria for additional treatment after endoscopic mucosal resection for esophageal cancer:..., Eguchi [/bib_ref] [bib_ref] Risk factors of lymph node metastasis in T1 esophageal squamous cell carcinoma, Kim [/bib_ref] [bib_ref] Feasibility of endoscopic resection in superficial esophageal squamous carcinoma, Choi [/bib_ref] [bib_ref] The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a..., Akutsu [/bib_ref] [bib_ref] T1 squamous cell carcinoma of the esophagus: long-term outcomes and prognostic factors..., Tanaka [/bib_ref]. There are few or no reports on the frequency of metastasis in pT1a-MM adenocarcinoma cases, however, that in cases of pT1a adenocarcinomas is reported to be in the range of 0-5%; summarization and analysis of data from major reports revealed that it was presented in 91/1882 cases (4.9%; 95% CI 3.95-5.9) [bib_ref] Risk stratification for early esophageal adenocarcinoma: analysis of lymphatic spread and prognostic..., Barbour [/bib_ref] [bib_ref] The prevalence of lymph node metastasis in patients with T1 esophageal adenocarcinoma...., Leers [/bib_ref] [bib_ref] Treatment trends, risk of lymph node metastasis, and outcomes for localized esophageal..., Merkow [/bib_ref]. Meanwhile, the frequency of recurrent lymph-node metastasis in cases diagnosed from the resected specimens collected at endoscopic treatment as pT1a-MM disease was 0-4.2% for squamous cell carcinoma, with a tallied frequency of 5/223 (2.24%; 95% CI 0. [bib_ref] Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading..., Katada [/bib_ref] [bib_ref] The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a..., Akutsu [/bib_ref] [bib_ref] Long term outcome and metastatic risk after endoscopic resection of superficial esophageal..., Yamashina [/bib_ref] , and 0% for adenocarcinoma [bib_ref] Risk of lymph node metastasis associated with deeper invasion by early adenocarcinoma..., Herrero [/bib_ref]. For squamous cell carcinomas, in particular, the frequency of lymph-node metastasis differed markedly between cases with pT1a-MM disease identified in surgical specimens and that identified in endoscopically resected specimens. This difference in the frequency of lymph-node metastasis is considered to be mainly attributable to the difference in the method of histopathologic diagnosis between surgical specimens and endoscopically resected specimens. As surgical specimens are larger in size as compared to endoscopically resected specimens, the possibility of cases diagnosed as pT1a-MM disease of including pT1b cases cannot be ruled out. As a ground for this presumption, it has been reported that the frequency of lymphatic invasion in pT1a-MM cases substantially differs between cases who have undergone endoscopic resection and those who have undergone surgery (pT1a-MM in endoscopically resected cases: 0-8.1% [bib_ref] Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading..., Katada [/bib_ref] [bib_ref] The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a..., Akutsu [/bib_ref] ; surgically treated cases: 18.2-41.2% [bib_ref] Clinicopathologic analysis of lymph node metastasis in surgically resected superficial cancer of..., Endo [/bib_ref] [bib_ref] Evaluation of endoscopic mucosal resection for superficial esophageal carcinoma, Noguchi [/bib_ref] [bib_ref] Pathological feature of superficial esophageal squamous cell carcinoma with lymph node and..., Araki [/bib_ref] [bib_ref] Histological criteria for additional treatment after endoscopic mucosal resection for esophageal cancer:..., Eguchi [/bib_ref] [bib_ref] The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a..., Akutsu [/bib_ref].
Reports of studies conducted to identify the risk factors for lymph-node metastasis in cases with superficial cancer of the esophagus limited to pT1a-MM cases are scarce. It was from the analysis of the data of 50 pT1a-MM cases in one study, that the frequency of lymph-node metastasis significantly differed between lymphatic invasion-negative cases and lymphatic invasion-positive cases (negative cases: 4/38 (10.5%); positive cases: 5/12 (41.7%) [bib_ref] Histological criteria for additional treatment after endoscopic mucosal resection for esophageal cancer:..., Eguchi [/bib_ref]. Multivariate analysis to identify the risk factors for lymph-node metastasis revealed an odds ratio for positive lymphatic invasion of 3.63-6.11 for T1 cases overall [bib_ref] Risk factors of lymph node metastasis in T1 esophageal squamous cell carcinoma, Kim [/bib_ref] [bib_ref] Feasibility of endoscopic resection in superficial esophageal squamous carcinoma, Choi [/bib_ref] , 3.83 for pT1a-MM/ pT1b-SM1 cases [bib_ref] Histological criteria for additional treatment after endoscopic mucosal resection for esophageal cancer:..., Eguchi [/bib_ref] , and 7.333 when the analysis was limited to pT1a-MM cases [bib_ref] The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a..., Akutsu [/bib_ref]. Assessment of the risk factors for metachronous metastasis in cases treated by endoscopic resection revealed a frequency of lymph-node or distant metastasis of 3.73% (15/402) for the pT1 cases overall, 0.36% (1/280) for pT1a-EP/LPM cases, 4.29% (3/70) for pT1a-MM cases, 11.7% (2/17) for pT1b-SM1 cases, and 25.7% (9/35) for pT1b-SM2 cases; hence, the frequency increased progressively with advancing depth of invasion, and multivariate analysis identified depth of invasion as the sole significant risk factor, with a hazard ratio of 13.1 (95% CI 1.3-133.7, p = 0.03) for pT1a-MM vs. pT1a-EP/LPM [bib_ref] Long term outcome and metastatic risk after endoscopic resection of superficial esophageal..., Yamashina [/bib_ref]. For superficial carcinomas overall, on the other hand, positive lymphatic invasion failed to be identified as a significant risk factor for metachronous metastasis; however, when the analysis was limited to only pT1a cases, the 5-year cumulative incidence of metastasis was significantly higher in the lymphatic metastasis-positive cases as compared to the lymphatic metastasis-negative cases (46.7% vs. 0.7%, p < 0.0001) [bib_ref] Long term outcome and metastatic risk after endoscopic resection of superficial esophageal..., Yamashina [/bib_ref]. Cases diagnosed as having pT1a-MM cases after endoscopic resection had a greater risk of recurrence of metastasis as compared to those diagnosed as having pT1a-EP/LPM disease and positive lymphatic invasion may be cited as a risk factor, although it is difficult to arrive at a conclusion, because all the papers reviewed represented retrospectively accumulated case reports and an additional treatment mainly consisting of chemoradiotherapy was administered to lymphatic invasion-positive cases among the patients treated by endoscopic resection.
Surgical treatment or chemoradiotherapy is considered as a radical additional treatment in patients diagnosed by histopathology of the endoscopically resected specimens as having pT1a-MM disease. Gratifying therapeutic results in surgically treated T1a patients have been reported, with a reported 5-year disease-specific survival rate of 98-100% and overall survival rate 82-100% [bib_ref] The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a..., Akutsu [/bib_ref] [bib_ref] T1 squamous cell carcinoma of the esophagus: long-term outcomes and prognostic factors..., Tanaka [/bib_ref] [bib_ref] The prevalence of lymph node metastasis in patients with T1 esophageal adenocarcinoma...., Leers [/bib_ref]. Meanwhile, the mortality rate from postoperative complications has been reported to be in the range of 0.2-3.6% [bib_ref] Histological criteria for additional treatment after endoscopic mucosal resection for esophageal cancer:..., Eguchi [/bib_ref] [bib_ref] T1 squamous cell carcinoma of the esophagus: long-term outcomes and prognostic factors..., Tanaka [/bib_ref] [bib_ref] Treatment trends, risk of lymph node metastasis, and outcomes for localized esophageal..., Merkow [/bib_ref] [bib_ref] Prediction of lymph node status in superficial esophageal carcinoma, Ancona [/bib_ref]. In regard to the results of chemoradiotherapy for cStage I (cT1N0M0) disease, the reported 4-year overall survival rate was 80.5%, 5-year overall survival rate was 66.4%, and 5-year disease-specific survival rate was 76.8%, despite the inclusion of a significant proportion of cT1b cases (85.2% for cT1a cases) [bib_ref] Treatment results of chemoradiotherapy for clinical stage I (T1N0M0) esophageal carcinoma, Yamada [/bib_ref] [bib_ref] A phase II trial of chemoradiotherapy for stage I esophageal squamous cell..., Kato [/bib_ref]. Esophageal fistula (3.2%), esophagostenosis (3.2%), Grade 3 cardiac ischemia (1%), and respiratory failure (2.8%) were reported as serious late complications, but there has been no report of treatmentrelated death [bib_ref] Treatment results of chemoradiotherapy for clinical stage I (T1N0M0) esophageal carcinoma, Yamada [/bib_ref] [bib_ref] A phase II trial of chemoradiotherapy for stage I esophageal squamous cell..., Kato [/bib_ref]. In patients given additional chemoradiotherapy after endoscopic resection, the 5-year overall survival rate and disease-specific survival time were both 100% among pT1a-MM cases as well as T1b-SM1 cases, and the 3-year survival rate was 92.9% for pT1a-MM cases, although the sample sizes in the studies were small; neither report contained any detailed description on adverse events, although there were no cases of serious adverse events or treatment-related death [bib_ref] Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading..., Katada [/bib_ref] [bib_ref] EMR combined with chemoradiotherapy: a novel treatment for superficial esophageal squamous-cell carcinoma, Shimizu [/bib_ref]. Taking into consideration the benefit-risk balance, the additional treatment may be useful for patients diagnosed by histopathology of the endoscopically resected specimens as having pT1a-MM disease, who are at a high risk of recurrence.
From the above results, the strength of evidence was rated as D, considering that most of the reports cited represented retrospective case accumulations, and no recommendation based on high-level evidence has been made yet. Chemoradiotherapy, which is the mainly adopted modality for additional treatment, is covered by the national health insurance. Taking into account the benefit-risk balance, strength of evidence, and patient preferences, we conclude that there is strong evidence to recommend additional treatment in patients identified as having a pT1a-MM lesion with positive vascular invasion after endoscopic treatment.
## Surgical treatment
## Surgery for cervical esophageal carcinoma
## Summary
In the treatment of cervical esophageal carcinoma, simultaneous laryngectomy is often required; therefore, preoperative chemoradiotherapy or definitive chemoradiotherapy is often undertaken in an attempt to conserve the larynx. Larynx-preserving surgery enables conservation of vocal function, although it is associated with an increased risk of aspiration and pneumonia, necessitating the need for caution while selecting this treatment. Lowering of the QOL due to the loss of vocal function poses a serious problem in patients who have undergone combined laryngectomy. No significant difference in the post-treatment prognosis has been reported so fact between cervical esophageal carcinoma patients treated by surgery and radical chemoradiotherapy. The appropriate treatment in these patients should be selected with due consideration given to the QOL, etc.
## General remarks
Since cervical esophageal carcinoma develops in a region densely packed with important structures such as the trachea, large blood vessels, nerves, and the thyroid, it is frequently associated with malignant invasions of the adjacent organs. Lymph-node metastasis is also frequently encountered; therefore, it is not uncommon for the malignancy to be at an advanced stage at diagnosis. There are a significant number of cases in which surgery is indicated inasmuch as widespread metastasis is uncommon, unlike the case in thoracic esophageal cancer. A major problem in surgery for cervical esophageal cancer is that simultaneous laryngectomy is also indicated in many cases. Under these circumstances, surgery may be performed after tumor shrinkage is obtained by preoperative chemoradiotherapy in an effort to preserve the larynx, or radical chemoradiotherapy may be administered, followed by salvage surgery in the event of detection of residual disease or recurrence.
Larynx-preserving surgery is indicated for patients in whom the tumor has not invaded the pharynx, larynx, or trachea. Conservation of vocal function is the utmost benefit of this option, although it is associated with the risk of aspiration or pneumonia; not uncommonly, primary tracheotomy is required. Therefore, sufficient consideration should be given as to the indication and choice of operative procedure, e.g., an additional aspiration-preventive measure such as laryngeal elevation could be employed.
Combined laryngectomy (laryngopharyngoesophagectomy) is indicated for patients with tumors invading the pharynx, larynx, and trachea. The procedure may even be indicated for patients without direct pharyngeal invasion, in whom sufficient preservation of the esophagus to perform anastomosis with intestinal graft is difficult. Marked lowering of QOL due to loss of vocal function poses a serious problem in patients who have undergone combined laryngectomy.
Reconstruction after surgical resection of cervical esophageal carcinoma is frequently performed using a free jejunal graft [bib_ref] The use of short segment free jejunal transfer as salvage surgery for..., Mayanagi [/bib_ref] or a gastric tube [bib_ref] Pharyngo-laryngoesophagectomy and gastric pull-up for post-cricoid and cervical oesophageal squamous cell carcinoma, Ullah [/bib_ref]. The method of first choice is reconstruction using a free jejunal graft, although reconstruction using a gastric tube is chosen for cases in which the disorder is complicated by thoracic esophageal cancer or in which the cervical esophageal cancer extends caudad to involve the thoracic esophagus.
The frequency of lymph-node metastasis in cases of cervical esophageal cancer is relatively high, although it is confined in most cases to the cervical region and a part of the upper mediastinum; therefore, lymph-node dissection is primarily targeted at lymph nodes in these regions. Nevertheless, reports on the outcomes of lymphadenectomy in patients with cervical esophageal cancer are few as yet, and further investigation is needed. No significant difference in the post-treatment prognosis has been reported until date between cervical esophageal carcinoma patients treated by surgery alone and those treated by radical chemoradiotherapy. Selection among the available treatment options should be made with due consideration given to the post-treatment QOL, etc.
## Surgery for thoracic esophageal carcinoma
## Summary
Thoracic esophageal carcinoma is often accompanied by extensive lymph-node metastasis in the cervical, thoracic, and abdominal regions. Therefore, it is a common practice that, in T1b-SM 2, 3 or more advanced cases regarded as advanced cancer cases, a right thoracotomy with esophagectomy and lymphadenectomy of the cervical, mediastinal, and upper abdominal regions is carried out. According to the revision of the Japanese Classification of Esophageal Cancer, supraclavicular lymph nodes [#104] are classified in Group 2, to ensure 3-fields' lymphadenectomy for D2 resection in the surgical treatment of middle thoracic esophageal carcinoma.
In thoracoscopic surgery, thoracic manipulations are currently also carried out with the patient in the prone position, whilst, previously, thoracic manipulations were predominantly undertaken with the patient in the left-lateral decubitus position. This is still at the stage of clinical research. A randomized comparative study to compare the long-term outcomes of this type of surgery vs. conventional standard surgery with thoracotomy has been started (JCOG1409 Study), and the results are awaited.
## General remarks
Thoracic esophageal carcinoma is frequently associated with extensive lymph-node metastasis in the cervical, mediastinal, and upper abdominal regions. Therefore, it is common practice to perform a right thoracotomy to meet the need for adequate dissection of the mediastinal lymph nodes, along with esophagectomy and lymphadenectomy in lymph-node stations of the cervical, thoracic and abdominal regions to complete the entire extent of resection. Depth of invasion beyond T1a-MM is a predictor of lymph-node metastasis, and stage T1b-SM 2, 3 lesions should be counted as advanced carcinomas [bib_ref] The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a..., Akutsu [/bib_ref] [bib_ref] The Prevalence of Overall and Initial Lymph Node Metastases in Clinical T1N0..., Akutsu [/bib_ref].
The extent of lymph-node dissection should be determined according to individual cases after preoperative evaluation of the location, size, and depth of invasion of the main lesion by imaging modalities such as CT, ultrasonography (US), magnetic resonance imaging (MRI), and PET, because the distribution and incidence of lymph-node metastasis vary with the aforementioned parameters. Based on the analysis of data from a nationwide registry conducted by the Japan Esophageal Society [bib_ref] Registration Committee for Esophageal Cancer of the Japan Esophageal Society. Efficacy of..., Tachimori [/bib_ref] , the supraclavicular lymph nodes [#104] are placed in Group 2, to ensure three fields' lymphnode dissection for D2 dissection in the treatment of middle thoracic esophageal carcinoma in the 11th edition of the Japanese Classification of Esophageal Cancer. It is not feasible to dissect the supraclavicular lymph nodes [#104] via thoracic manipulation, and a cervical approach is necessary for secure lymph-node dissection in this region.
It is common practice that radical surgery for thoracic esophageal carcinoma is usually accomplished using a combination of three approaches: the cervical, thoracic, and abdominal approaches. The mediastinal approach has also been proposed as an alternative to the cervical approach for dissection of the cervical paraesophageal lymph nodes [#101].
Thoracoscopy-assisted esophagectomy with esophageal reconstruction has been reported as promising surgical procedures, in view of its minimal invasiveness, radical curability, and favorable long-term outcomes, although studies are ongoing. Various procedures such as endoscopy/laparoscopy-assisted esophagectomy with esophageal reconstruction and mediastinoscopy-or laparoscopy-assisted transhiatal esophagectomy (blunt resection of the esophagus) have been reported, and analysis of the reported cases during the 2011-2013 period in the National Clinical Database (NCD) revealed that 37.6% of the patients underwent endoscopy/laparoscopy-assisted surgery, which was reported as a safe approach with a mortality rate of 2.44%, against an overall mortality rate of 3.03%. The indications for this approach vary among institutions; it has been adopted even for cT3 cases at some institutions, and in patients who have received preoperative chemoradiotherapy at other institutions.
Some techniques have been introduced for ensuring safe endoscopic surgery with a reduced operation time and improved accuracy of lymph-node dissection, including direct manipulations through a small incision via a minor thoracotomy, video-assisted thoracoscopic surgery (VATS) with minor thoracotomy, and hand-assisted laparoscopic surgery (HALS) involving manipulation with one hand inserted into the abdomen. While thoracic manipulations have been predominantly carried out with the patient in the left-lateral decubitus position, complete endoscopic thoracic manipulations have been increasingly performed with the patient placed in the prone position in recent years. Mediastinal lymph-node dissection using a mediastinoscope inserted via a cervical incision and laparoscopic transhiatal lymphnode dissection are some of the other procedures described. Reports have suggested that endoscopy/laparoscopy-assisted surgery enables conservation of the vasculature and nerves while confirming the microanatomy, and also increases the accuracy of lymph-node dissection, as it allows higher power visualization. A randomized comparative study to assess the long-term outcomes of this type of surgery as compared to the conventional standard surgery with a thoracotomy has been initiated (JCOG1409 Study), and the results are awaited [bib_ref] Japan Esophageal Oncology Group/Japan Clinical Oncology Group. A randomized Phase III trial..., Kataoka [/bib_ref].
## Surgery for carcinoma of the esophagogastric junction (abdominal esophageal carcinoma)
## Summary
There is no unanimity of opinions as to treatment policy and surgical procedures for carcinoma of the esophagogastric junction, particularly adenocarcinoma according to Nishi's classification or Siewert type II carcinoma. Based on a retrospective analysis, the Japanese Gastric Cancer Association-Japan Esophageal Society Joint Working Group proposed the optimal extent of lymph-node resection for esophagogastric junction carcinomas measuring ≤4 cm in diameter. Prospective clinical studies to determine the optimal extent of lymph-node resection for more advanced tumors are currently in progress.
## General remarks
For definition of carcinoma of the esophagogastric junction, Siewert's classification is used overseas, whereas, in Japan, Nishi's classification is adopted by both the Japanese Gastric Cancer Association and the Japan Esophageal Society. In Siewert's classification, type I lesions are often handled as carcinomas of the thoracic esophagus and type III lesions as cardiac carcinomas. Squamous cell carcinomas in Nishi's classification, on the other hand, are often treated as thoracic esophageal cancers. Opinions are still divided as to treatment policy and surgical procedures for adenocarcinomas in Nishi's classification and Siewert type II carcinoma.
Carcinoma of the esophagogastric junction may be associated with extremely extensive lymph-node metastasis involving the cervical region, mediastinum, upper abdomen, and areas circumjacent to the abdominal aorta, and no unified view has been reached in regard to the appropriate extent of lymph-node dissection. The Japanese Gastric Cancer Association-Japan Esophageal Society Joint Working Group has laid down recommendations in respect of the extent of lymphadenectomy on the grounds of the dissection effect index (rate of metastasis × 5-year survival rate of patients with metastasis) derived from retrospective analysis of data from surgically treated cases. The efficacy of lymphadenectomy in accordance with this scheme is expected to be verified by future accumulation of cases. Nevertheless, the problems with retrospective analysis of tumors is that the patients are confined to those with tumors measuring ≤4 cm in diameter and that the subject population includes only a small number of cases with dissection of the lymph nodes in the upper and middle mediastinal regions and areas circumjacent to the abdominal aorta. A prospective clinical study to evaluate the outcomes depending on the extent of lymphadenectomy for more advanced tumors is currently in progress.
The Japanese Gastric Cancer Association-Japan Esophageal Society Joint Working Group has proposed a definition of the esophagogastric junction based on endoscopic findings. In the algorithm used as a guide for the extent of lymph-node dissection, as well, lesions are defined according to the principal location of the center of the tumor, i.e., whether it is located proximal or distal to the junction. In the clinical practice setting, however, the junction can scarcely be identified by endoscopy in cases of advanced carcinoma, and that frequent, concurrent hiatal herniation interferes with positional estimation of the junction even by fluoroscopic exploration or CT. Thus, it may be said that only but an obscure judgment about the location of the junction can be obtained in the clinical setting. The extent of resection of the esophagus and stomach is determined in accordance with the extent of lymph-node dissection, and the range of operative procedures available extend from total esophagogastrectomy to lower third esophagectomy plus proximal gastrectomy. In surgery for carcinoma of the esophagogastric junction, the surgical invasiveness is affected not only by the extent of resection, but also by the surgical approach; therefore, the treatment selection must be approached by taking into consideration the balance between the surgical invasiveness and curability of the adopted procedure.
## Perioperative management and clinical path
## Summary
Various improvements have been made to the clinical path system for esophageal cancer at facilities overseas and in Japan, in an effort to implement safe perioperative management with a reduced incidence of complications; however, convincing evidence is still to be presented. The clinical significance of the new concept of perioperative management introduced in recent years; namely, Enhanced Recovery after Surgery (ERAS) or fast-track surgery in surgical resection of the esophagus has drawn increasing attention.
## General remarks
A clinical path is a standard medical practice plan containing information on the patient's condition, goals of medical practice, and relevant evaluations and records, and represents a procedure for improving the quality of medical care through analysis of deviations from the standard. With the introduction of the Diagnosis-Related Group/Prospective Payment System (DRG/PPS) in the 1980s, clinical paths aimed primarily at shortening the length of hospitalization and reducing the medical fees were introduced [bib_ref] Standardized clinical care pathways for major thoracic cases reduce hospital costs, Zehr [/bib_ref]. In Japan, introduction of clinical paths for many disorders began in the 1990s concurrently with the introduction of the Diagnosis Procedure Combination (DPC) system. Clinical paths are generally thought to be important for promoting patient-centered collaborative (team) medical care, including perfection of informed consent as well as for improving the quality of medical care and education of personnel.
Various improvements have been made in the clinical path system for esophageal cancer at facilities overseas and in Japan, in an effort to implement safe perioperative management, with a reduced incidence of complications. It has generally been recognized that preparation of a simple clinical path for esophageal cancer entails greater difficulty as compared to that for carcinomas of other digestive organs, because of the diversity and interinstitutional inequity of procedures and perioperative management techniques, and because of individual differences in the reaction to invasiveness. An increasing number of facilities have been introducing a clinical path for esophageal cancer for safe perioperative management, in parallel with the introduction of minimally invasive operations including endoscopy-aided surgery; however, convincing evidence demonstrating its clinical usefulness is still awaited [bib_ref] Esophagectomy-it's not just about mortality anymore: standardized perioperative clinical pathways improve outcomes..., Low [/bib_ref] [bib_ref] Effectiveness of a written clinical pathway for enhanced recovery after transthoracic (Ivor..., Munitiz [/bib_ref].
In recent years, the new concept of Enhanced Recovery after Surgery (ERAS) or fast-track surgery has been introduced for perioperative management in Europe and the United States. The ERAS Group organized in 2001 under the European Society for Clinical Nutrition and Metabolism (ESPEN) published an ERAS protocol for colectomy in 2004 [bib_ref] Enhanced recovery after surgery: a consensus review of clinical care for patients..., Fearon [/bib_ref] , which has since been applied to perioperative management for various surgeries. Fast-track surgery is a multimodal rehabilitation program with integrated introduction of evidence-based procedures as an approach to patient care to expedite recovery after surgery. Currently, this term is essentially synonymous with ERAS. The Clinical significance of ERAS and fast-track surgery in cases of esophagectomy has recently been investigated, with the results indicating reductions in the incidence of complications, duration of hospitalization, and mortality rate, even though the level of evidence is still not high at present [bib_ref] The effect of formalizing enhanced recovery after esophagectomy with a protocol, Findlay [/bib_ref] [bib_ref] Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines, Findlay [/bib_ref] [bib_ref] Enhanced recovery pathways lead to an improvement in postoperative outcomes following esophagectomy:..., Markar [/bib_ref] [bib_ref] University of Texas MD Anderson Esophageal Cancer Collaborative Group: impact of a..., Shewale [/bib_ref].
Perioperative management of patients with esophageal cancer has, heretofore, been assessed by comparative evaluation of the usefulness of clinical paths established at individual facilities from their independent standpoints. From now on, however, the clinical significance of ERAS/fast-track surgery as perioperative management procedures needs to be verified.
## Chemotherapy for unresectable advanced/ recurrent esophageal cancer
## Summary
Chemotherapy is used as the only systemic therapy modality under various settings in the treatment of esophageal cancer. Chemoradiotherapy and preoperative chemotherapy are used for cStage I-Stage IV local esophageal cancer, and chemotherapy is also used for unresectable advanced/recurrent esophageal cancer. Combination therapy with cisplatin + 5-FU is used for unresectable advanced/recurrent esophageal cancer, although there is no clear evidence of its ability to prolong the survival. Taxanes and other drugs are used as the second-line therapy in patients who become refractory to the first-line therapies, but these have only been reported in phase II studies involving a small number of patients, and should be used carefully.
## General remarks
Systemic chemotherapy is used as the standard therapy for unresectable advanced/recurrent esophageal cancer. Although no comparative study with untreated controls has clearly demonstrated the ability of chemotherapy alone to prolong the survival, both the efficacy of monotherapy and combination therapy has been reported, and chemotherapy is used as standard therapy.
## Drugs and drug combinations that have been shown to be effective as the first-line therapy
Monotherapy with 5-FU, platinum drugs, taxanes, vinca alkaloids, etc., has been reported to be associated with a response rate of 15-40% and a median survival duration of approximately 3-10 months. Combination therapy has been shown to be associated with even higher response rates (20-60%) than monotherapy [fig_ref] Table 1: Reports of the first-line therapy for unresectable advanced/recurrent esophageal cancer [/fig_ref] [bib_ref] Randomised phase II study of cisplatin and 5-fluorouracil (5-FU) versus cisplatin alone..., Bleiberg [/bib_ref] [bib_ref] Phase II evaluation of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma..., Iizuka [/bib_ref] [bib_ref] A phase II study of nedaplatin and 5-fluorouracil in metastatic squamous cell..., Kato [/bib_ref]. Many studies have reported the efficacies of combination therapy with 2 or 3 drugs, whereas only one study has compared the efficacy of combination therapy versus monotherapy. Most of these studies were phase II studies involving a small number of patients. As two-drug combination therapies, the combination of cisplatin and 5-FU, which are expected to have a synergistic effect, and the combination of nedaplatin and 5-FU are used. Combined therapy with cisplatin + 5-FU is considered to be the standard therapy for patients with unresectable advanced/recurrent esophageal cancer. A three-drug combination therapy, a taxane given in combination with cisplatin + 5-FU, has been shown to be highly effective, with a reported response rate of 60% [bib_ref] Doxorubicin, cisplatin, and fluorouracil combination therapy for metastatic esophageal squamous cell carcinoma, Honda [/bib_ref] [bib_ref] Japan Esophageal Oncology Group/Japan Clinical Oncology Group. Phase I/II trial of 2-weekly..., Hironaka [/bib_ref] , but it is unknown whether this therapy can prolong the survival. Therefore, at present, it is considered desirable to use this three-drug combination therapy in clinical studies. A comparative study of combined cisplatin + 5-FU therapy and 2-weekly docetaxel combined with cisplatin + 5-FU is currently ongoing (JCOG1314 Study), and the results of the study are awaited.
## Drugs and combination therapies shown to be effective as the second-line therapy
In regard to the second-line therapy for patients who become refractory to cisplatin + 5-FU, no drugs have been clearly shown to prolong the survival. Drugs that are likely to show efficacy other than fluoropyrimidines and platinum drugs should be used, but the benefit-harm (toxicity) balance should be carefully considered [fig_ref] Table 2: Reports of second-or subsequent-line therapy for unresectable advanced/recurrent esophageal cancer SCC squamous... [/fig_ref]. Monotherapy with taxanes, such as docetaxel and paclitaxel, is often used [bib_ref] A phase II study of singleagent docetaxel in patients with metastatic esophageal..., Muro [/bib_ref] [bib_ref] A phase II study of paclitaxel by weekly 1-h infusion for advanced..., Kato [/bib_ref]. The significance of readministration of drugs used in the first-line therapy and combination therapy [bib_ref] Second-line combination chemotherapy with docetaxel and nedaplatin for Cisplatin-pretreated refractory metastatic/recurrent esophageal..., Jin [/bib_ref] for these patients has not been established.
Although there have been a few reports on moleculartargeted drugs, epidermal growth factor receptor (EGFR) inhibitors have been reported to be associated with response rates in the range of 10-20%. A comparative study of an EGFR inhibitor gefitinib and placebo in patients receiving the second-line therapy for esophageal cancer, including adenocarcinoma, failed to demonstrate any usefulness of gefitinib [bib_ref] Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre,..., Dutton [/bib_ref]. In the future, development of biomarkers, etc., may allow the usefulness of EGFR inhibitors to be demonstrated in particular subsets of subjects, but, at present, their usefulness in the treatment of esophageal cancer remains unknown.
## Drugs and combination therapies shown to be effective as the third-line therapy
For patients who become refractory or intolerant to the first-and second-line therapies, no drugs have been demonstrated to be effective, and palliative symptomatic treatment is recommended. A phase II study reported the efficacy of nivolumab, an immune checkpoint inhibitor with a new mechanism of action [bib_ref] Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial, Kudo [/bib_ref] , but a phase III comparative study is required to validate its applicability in clinical practice.
## Radiotherapy
## Summary
For definitive radiotherapy, concurrent chemoradiotherapy is recommended. The potential usefulness of preoperative chemoradiotherapy for resectable advanced cancer is being investigated in an ongoing clinical study. Chemoradiotherapy or radiotherapy alone is indicated for unresectable patients according to the PS. Palliative radiotherapy is considered for cStage IVb esophageal cancer patients presenting with obstruction. A total dose of 60 or 50.4 Gy is often prescribed for chemoradiotherapy, and it is considered that unnecessary prolongation of the treatment duration should be avoided.
## General remarks
Randomized comparative studies and their meta-analyses have demonstrated that concurrent chemoradiotherapy is more effective than radiotherapy alone for definitive treatment of esophageal cancer [bib_ref] Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer..., Herskovic [/bib_ref] [bib_ref] Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized..., Wong [/bib_ref]. Therefore, concurrent chemoradiotherapy is considered preferable, unless its use is precluded by factors such as advanced age, presence of complications, or any other reasons.
Radiotherapy is indicated for patients with residual lesions in the local or regional lymph nodes. An additional (chemo-) radiotherapy is considered when there is residual cancer after endoscopic treatment for T1a or T1b cancer, or when the patient is suspected to have lymph-node metastasis.
Preoperative chemotherapy is the standard treatments for resectable advanced cancer in Japan. Patients who are not suitable for surgery or who do not wish to undergo surgery are given definitive chemoradiotherapy. In addition, preoperative chemoradiotherapy for these patients is being investigated in an ongoing clinical study. Chemoradiotherapy is indicated for unresectable cancer patients with a good PS, and subsequently, surgery may be considered. Radiotherapy alone may be considered for patients with a poor PS. Palliative radiotherapy may be considered for cStage IVb esophageal cancer patients presenting with obstruction. Radiotherapy may be used not only in patients with postoperative residual lesions and untreated patients, but also in those with postoperative recurrence without distant metastasis. At present, in most facilities, CT-based three-dimensional treatment planning is performed, which allows optimization of the doses to the tumor and risk organs, enabling highly accurate treatment. When radiotherapy alone is performed, since the local control rate may decrease due to accelerated repopulation of the tumor cells, it is considered that unnecessary prolongation of the treatment duration should be avoided [bib_ref] Esophageal cancer treated with radiotherapy: impact of total treatment time and fractionation, Nishimura [/bib_ref]. In regard to the optimal total dose for definitive treatment, a randomized comparative study of chemoradiotherapy at a total dose of 50.4 Gy versus 64.8 Gy, conducted mainly by the US Radiation Therapy Oncology Group (RTOG), failed to demonstrate the superiority of the higher dose [bib_ref] INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combinedmodality..., Minsky [/bib_ref]. In Japan, chemoradiotherapy mainly using 60 Gy has been reported, but clinical studies using 50.4 Gy have also been reported, expecting reduction of the late toxicities of chemoradiotherapy and salvage surgery after definitive radiation. In clinical practice, the dose should be determined considering the several factors such as the patient's general condition, tumor volume, irradiation area, and doses to the risk organs. When radiotherapy alone is performed, a total dose of 60-70 Gy is commonly prescribed.
## Multidisciplinary treatment
## Preoperative/postoperative adjuvant therapy
## Summary
At present, the standard treatment for cStage II and III thoracic esophageal cancer in Japan is preoperative chemotherapy with cisplatin + 5-FU, followed by surgery. On the other hand, in Europe and North America, the standard treatment is preoperative chemoradiotherapy followed by surgery. A randomized comparative study to confirm the superiority of preoperative docetaxel + cisplatin + 5-FU (DCF) therapy and that of preoperative chemoradiotherapy (cisplatin + 5-FU, radiotherapy at 41.4 Gy) over the currently used preoperative regimen of cisplatin + 5-FU (JCOG1109 Study) is ongoing.
## General remarks
In recent years, multidisciplinary treatment, including chemotherapy, radiotherapy, and surgery, has been used for esophageal cancer. The JCOG9204 Study conducted in Japan compared the outcomes of surgery alone with those of surgery plus postoperative chemotherapy with cisplatin and 5-FU [bib_ref] Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma..., Ando [/bib_ref]. While no significant difference in the overall survival were observed between the two groups, the 5-year diseasefree survival (DFS) was significantly better in the surgery plus postoperative chemotherapy group (55%) than in the surgery alone group (45%); furthermore, this improved prognosis was particularly evident in the pathological lymph-node metastasis-positive cases. As a result, surgery plus postoperative chemotherapy became the standard treatment in Japan for patients with histopathologically diagnosed lymph-node metastasis after surgical resection. Subsequently, the JCOG9907 Study investigated the optimal timing, in relation to surgery, of adjuvant chemotherapy with cisplatin + 5-FU, and showed that 5-year overall survival was significantly better in the preoperative chemotherapy plus surgery group (55%) than in the surgery plus postoperative chemotherapy group (43%) [bib_ref] A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus..., Ando [/bib_ref]. Thereafter, preoperative adjuvant chemotherapy with cisplatin + 5-FU followed by radical surgery came to be adopted as the standard of care for cStage II and III thoracic esophageal cancer patients in Japan.
On the other hand, in Europe and North America, preoperative chemoradiotherapy followed by radical surgery is used as the standard treatment. Preoperative chemoradiotherapy yields a higher local control rate than preoperative chemotherapy alone, but may also increase the risk of perioperative complications and surgery-related mortality. So far, in Japan, local control is achieved by accurate lymph-node dissection during surgery, and preoperative radiotherapy has been thought to be unnecessary. In Europe and North America, several randomized comparative studies investigating the usefulness of preoperative chemoradiotherapy have been reported [bib_ref] Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated..., Sjoquist [/bib_ref] , because adequate local control has not yet been achieved by surgery. The CROSS trial, which is a large-scale randomized comparative study conducted in the Netherlands, showed that the overall survival was significantly longer in the preoperative chemoradiotherapy + surgery group than in the surgery alone group (median overall survival, 49.4 vs. 24.0 months) [bib_ref] Preoperative chemoradiotherapy for esophageal or junctional cancer, Van Hagen [/bib_ref]. On the other hand, there were no significant differences in the incidence of postoperative complications between the two groups.
The results of a subgroup analysis in the JCOG9907 Study suggested that the additive effect of the currently used preoperative chemotherapy with cisplatin + 5-FU may be insufficient for improving the prognosis in patients with cStage III thoracic esophageal cancer, and that either preoperative chemotherapy with a more intensive regimen or preoperative chemoradiotherapy may need to be attempted in the future, aimed at better local control. Taxane antitumor agents (paclitaxel/docetaxel) are thought to be effective in patients with esophageal cancer. Recently, DCF therapy, in which docetaxel is added to cisplatin + 5-FU therapy has attracted attention. The JCOG1109 Study, which was started in 2012, is a randomized comparative study performed to confirm the superiority of preoperative DCF therapy and that of preoperative chemoradiotherapy (cisplatin + 5-FU, radiotherapy at 41.4 Gy) over the currently used preoperative regimen of cisplatin + 5-FU, and the results of the study are awaited, so that the standard treatment for cStage II and III thoracic esophageal cancer can be established in Japan [bib_ref] Three-arm phase III trial comparing cisplatin plus 5-FU versus docetaxel, cisplatin plus..., Nakamura [/bib_ref].
## 3
Chemoradiotherapy Summary Chemoradiotherapy has been demonstrated to yield a greater prolongation of the survival than radiotherapy alone in patients with locally advanced esophageal cancer. It is considered as the standard of care in non-surgical treatment, and chemoradiotherapy aimed at complete cure is indicated for cStage 0 to IVa cancer. Although a study comparing chemoradiotherapy and surgery alone in resectable cases reported that chemoradiotherapy can be expected to have equivalent efficacy to surgery, no studies have directly compared the two, and it is speculated that the standard treatment, namely, preoperative chemotherapy + surgical treatment, would yield better results in patients with cStage II and III cancer. Therefore, chemoradiotherapy is considered as one of the options in patients who are intolerant to surgery or refuse surgery. It is important to select the appropriate radiation dose, irradiation area, and chemotherapy regimen while considering a treatment strategy, and also consider the salvage treatments for residual and recurrent lesions after chemoradiotherapy [fig_ref] Table 3: Summary of prospective clinical studies of chemoradiotherapy SCC squamous cell carcinoma, AC... [/fig_ref].
## General remarks
## Chemoradiotherapy for cstage 0 and i disease
Chemoradiotherapy is indicated for lesions covering ≥ 3/4th of the circumference, which are difficult to treat endoscopically, and those invading up to the submucosa or deeper. The JCOG9708 Study showed good results, with a complete response rate of 87.5% and a 4-year survival rate of 80.5% [bib_ref] A phase II trial of chemoradiotherapy for stage I esophageal squamous cell..., Kato [/bib_ref]. Although 9 patients (12.5%) had residual cancer and 30 (41%) developed recurrence after treatment, many of these lesions could be completely cured by endoscopic treatment or surgical resection, and only 9 patients had lesions that could not be radically resected at recurrence. cStage I patients are known to frequently develop recurrent or metachronous multiple lesions in the esophagus after complete response [bib_ref] Comparison between radical esophagectomy and definitive chemoradiotherapy in patients with clinical T1bN0M0..., Motoori [/bib_ref] , and it is important to perform CT and endoscopy every 3-4 months for at least 2 years after complete response is obtained, and subsequently every 6 months, for detecting recurrent or metachronous multiple lesions at a sufficiently early stage as to allow the lesions to be treated endoscopically.
In addition, it has been reported that 10-50% of patients with obvious submucosal invasion or intramucosal lesions with vascular invasion after endoscopic treatment develops lymph-node metastasis, and these patients were likely to have non-curative resection [bib_ref] Clinicopathologic characteristics and survival of patients with clinical Stage I squamous cell..., Igaki [/bib_ref]. For additional treatment of these patients, radical surgery with lymph-node dissection is currently used as the standard of care, while one report has suggested the usefulness of prophylactic chemoradiotherapy in combination with cisplatin + 5-FU for regional lymph nodes [bib_ref] The effectiveness of endoscopic submucosal dissection followed by chemoradiotherapy for superficial esophageal..., Kawaguchi [/bib_ref]. In the JCOG0508 Study, cT1bN0 esophageal cancer with a limited depth of invasion (up to SM2), which was estimated to be treatable endoscopically, was treated endoscopically, and patients with pathologically confirmed complete resection who had pT1a with positive vascular invasion or pT1b received prophylactic chemoradiotherapy. With such treatment, these patients showed a 3-year survival rate (primary endpoint of the study) of 90.7% (90% CI 84.0-94.7). On the other hand, 3 (20%) of the 15 patients who had positive surgical margins after endoscopic treatment and received definitive chemoradiotherapy died of the disease. It should be carefully investigated as to which subpopulation of patients with cT1bN0 disease would be suitable candidates for this treatment. The clinical study was presented at the Annual Meeting of the American Society of Clinical Oncology in June 2016, and its publication is awaited.
## Chemoradiotherapy for cstage ii and iii disease
According to one report, chemoradiotherapy was equivalent to surgery alone for cStage II and III cancer [bib_ref] Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T(2-3)..., Hironaka [/bib_ref]. However, according to the JCOG9906 study, chemoradiotherapy was associated with a complete response rate of 62.2%, 3-year survival rate of 44.7%, and 5-year survival rate of 36.8%, which were considered to be inferior results to those of preoperative chemotherapy + surgery in the same subject population (5-year survival rate of 55%, JCOG9907 Study), although no direct comparison can be made. Therefore, chemoradiotherapy is recommended for patients who refuse surgery or are intolerant to surgery, as a treatment with which complete cure can be expected. The RTOG9405/ INT0123 study conducted by the US RTOG compared cisplatin (75 mg/m 2 on days 1 and 29) + 5-FU (1000 mg/m 2 on days 1-4 and 29-32) chemotherapy with radiotherapy at a radiation dose of 50.4 Gy, and the same chemotherapy with radiotherapy at a radiation dose of 64.8 Gy, and revealed that, while the survival was not prolonged any further, higher toxicity was obtained in the 64.8 Gy group [bib_ref] INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combinedmodality..., Minsky [/bib_ref]. Based on this, chemotherapy with cisplatin (75 mg/m 2 on days 1 and 29) + 5-FU (1000 mg/m 2 on days 1-4 and 29-32) combined with radiotherapy at a radiation dose of 50.4 Gy (RTOG regimen) is considered as one of the standard chemoradiotherapy treatment regimens. A phase II study of a modified RTOG (mRTOG) regimen in Japan reported that addition of prophylactic irradiation of the regional lymph nodes to the original RTOG regimen yielded good results, with a complete response rate of 70.6% and 3-year survival rate of 63.8% [bib_ref] Phase II study of concurrent chemoradiotherapy at the dose of 50.4 Gy..., Kato [/bib_ref]. Late toxicity was reduced in the mRTOG regimen when the radiation dose of 50.4 Gy was used, as compared with that in the JCOG9906 study, in which the radiation dose used was 60 Gy. However, attention should be paid to the development of myelosuppression, mucositis, and gastrointestinal symptoms associated with the increased doses of the chemotherapeutic agents. In addition, active salvage treatment, described below, also contributed to the improved treatment outcomes, and it is necessary to consider treatment strategies including salvage treatments after chemoradiotherapy. Criteria for indications of the mRTOG regimen combined with salvage treatment and the safety of salvage treatment are under investigation in the JCOG0909 Study.
## Chemoradiotherapy for cstage iva esophageal cancer
When a lesion that is not amenable to surgical resection is limited to the irradiation area, chemoradiotherapy is used as a standard treatment. A single-center phase II study of cisplatin + 5-FU in combination with radiotherapy at a radiation dose of 60 Gy reported a complete response rate of 33% and a 3-year survival rate of 23%, and a multicenter study, the JCOG9516 Study, reported a complete response rate of 15% and a 2-year survival rate of 31.5% [bib_ref] Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of..., Ohtsu [/bib_ref] [bib_ref] Phase II study of cisplatin and 5-fluorouracil with concurrent radiotherapy in advanced..., Ishida [/bib_ref]. As a result, chemoradiotherapy with cisplatin + 5-FU has come to be used as a standard treatment. Two randomized studies comparing standard chemotherapy with 5-FU (700 mg/m 2 on days 1-4 and 29-32) + cisplatin (70 mg/m 2 on days 1 and 29) and low-dose chemotherapy with 5-FU (200 mg/m 2 ) + cisplatin (4 mg/m 2 ) on days combined with radiation at the dose of 60 Gy, failed to find any clear advantage of the low-dose chemotherapy [bib_ref] Randomized study of lowdose versus standard-dose chemoradiotherapy for unresectable esophageal squamous cell..., Shinoda [/bib_ref]. A clinical study of DCF therapy, in which docetaxel is added to cisplatin + 5-FU, in combination with radiotherapy reported good results with a complete response rate of 42.1%; however, Grade 3-4 esophagitis or febrile neutropenia occurred in ≥ 30% of the subjects. Therefore, adoption of this treatment needs to be carefully considered. Multidisciplinary treatment in which surgery or chemoradiotherapy is performed after intensive induction chemotherapy has been shown to yield good short-term results with a 1-year survival rate of 67.9% [bib_ref] Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction..., Yokota [/bib_ref] , and a comparative study (JCOG1510) is planned.
## Radiation dose and chemotherapy regimens used in chemoradiotherapy
The RTOG8501 study recommended chemoradiotherapy as a standard treatment, because comparison of radiotherapy (64 Gy) alone and concurrent chemoradiotherapy (cisplatin + 5-FU + 50 Gy) for esophageal cancer revealed significantly superior treatment outcomes of chemoradiotherapy [bib_ref] Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized..., Cooper [/bib_ref]. In addition, a meta-analysis of studies of chemotherapy and radiotherapy reported that concurrent chemotherapy and radiotherapy yielded a significantly greater prolongation of the survival than sequential chemotherapy and radiotherapy [bib_ref] Cancer Care Ontario Practice Guidelines Initiative Gastrointestinal Cancer Disease Site Group. Combined..., Wong [/bib_ref]. Furthermore, the above-mentioned RTOG9405/ INT0123 study revealed no superior outcomes in terms of the survival or local control rate in the high-dose group, concluding that a radiation dose of 50.4 Gy should be used in combination with cisplatin (75 mg/m 2 on days 1 and 29) + 5-FU (1000 mg/m 2 on days 1-4 and 29-32) chemotherapy. Many studies in Japan have used a radiation dose of 60 Gy in combination with lower doses of the antitumor agents, such as cisplatin (70 mg/m 2 on days 1 and 29) and 5-FU (700 mg/m 2 on days 1-4 and 29-32) [bib_ref] Clinical practice and outcome of radiotherapy for esophageal cancer between 1999 and..., Nishimura [/bib_ref] [bib_ref] Long-term results of chemoradiotherapy for stage II-III thoracic esophageal cancer in a..., Umezawa [/bib_ref]. For multidisciplinary treatment including salvage treatment, the mRTOG regimen has also been increasingly used, and its usefulness is now under investigation in the JCOG0909 Study.
## Adverse effects of radical chemoradiotherapy
Adverse effects of chemoradiotherapy are mainly classified into acute and late toxicity. Acute toxicity occurs mainly during concurrent chemotherapy and radiotherapy, within 1-2 months after the start of treatment. Late toxicity is often associated with radiation and occurs a few months to a few years after completion of treatment. Symptoms of acute toxicity include gastrointestinal toxicity, nausea, vomiting, renal impairment, leukopenia, esophagitis, and dysphagia, and should be treated according to guidelines such as the "Guidelines for Proper Use of Antiemetics" and "Practical Guideline of Febrile Neutropenia (FN)". Symptoms of late toxicity include radiation pneumonitis, pleural effusion, pericardial effusion, pericarditis constrictive, and hypothyroidism, which interfere with daily life in approximately 10% of patients [bib_ref] Long-term toxicity after definitive chemoradiotherapy for squamous cell carcinoma of the thoracic..., Ishikura [/bib_ref] [bib_ref] Late toxicity after definitive concurrent chemoradiotherapy for thoracic esophageal carcinoma, Morota [/bib_ref] [bib_ref] Analysis of dose-volume histogram parameters for radiation pneumonitis after definitive concurrent chemoradiotherapy..., Asakura [/bib_ref]. Since late toxicity may be lethal, regular follow-up, medical interviews to obtain information on subjective symptoms such as dyspnea, and early treatment are important.
## Salvage treatment for local residual/recurrent lesions after radical chemoradiotherapy
When there is a local residual or recurrent lesion after chemoradiotherapy for esophageal cancer, salvage surgery or endoscopic treatment may allow long-term survival. It has been reported that, in salvage surgery, R0 resection allows long-term survival, but, at the same time, increases the incidence of postoperative complications and in-hospital mortality [bib_ref] Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carcinoma, Tachimori [/bib_ref] [bib_ref] Salvage esophagectomy for recurrent tumors after definitive chemotherapy and radiotherapy, Swisher [/bib_ref] [bib_ref] Salvage esophagectomy after unsuccessful curative chemoradiotherapy for squamous cell cancer of the..., Meunier [/bib_ref] [bib_ref] Salvage esophagectomy after definitive chemotherapy and radiotherapy for advanced esophageal cancer, Nakamura [/bib_ref] [bib_ref] Factors influencing the long-term survival in patients with esophageal cancer who underwent..., Takeuchi [/bib_ref]. When a residual lesion remains confined in the mucosa, salvage endoscopic treatment can be performed safely [bib_ref] Long-term results of salvage endoscopic mucosal resection in patients with local failure..., Yano [/bib_ref] [bib_ref] Feasibility of endoscopic mucosal resection as salvage treatment for patients with local..., Makazu [/bib_ref]. Photodynamic therapy (PDT) has been reported to yield good results even in cases with suspected invasion of the submucosa or muscularis propria, and PDT is considered as one of the potentially useful treatment options [bib_ref] Local efficacy and survival outcome of salvage endoscopic therapy for local recurrent..., Hatogai [/bib_ref].
## Follow-up after treatment of esophageal cancer
## Summary
The purpose of follow-up after treatment of esophageal cancer is (1) to detect and treat recurrence early, and (2) to detect and treat multiple/double cancers early. Furthermore, follow-up is also important from the standpoint of systemic management and knowing the QOL of the patients after treatment.
Methods of follow-up after treatment of esophageal cancer vary depending on the type of initial treatment and on the stage of cancer progression at the time of the initial treatment. During follow-up, it is important to keep in mind that the early detection/treatment may allow long-term survival and to pay attention to the occurrence of metachronous multiple esophageal cancers and metachronous double cancers in other organs, mainly high-incidence cancers, i.e., gastric cancer and head and neck cancer. Establishment of a consensus-based follow-up system and verification of its effectiveness are required.
## General remarks
## Follow-up after endoscopic resection
No certain method of follow-up after endoscopic resection has been established. Local recurrence often occurs within 1 year after the initial treatment, although it, sometimes, takes up to 2-3 years after the initial treatment, and longterm-follow-up is required [bib_ref] Local recurrence of squamous-cell carcinoma of the esophagus after EMR, Katada [/bib_ref] [bib_ref] Risk factors for local recurrence of superficial esophageal cancer after treatment by..., Esaki [/bib_ref]. Esophagoscopy with iodine staining is mainly used to screen for local recurrence, and many studies have reported that screening for local recurrence is performed every 3 or 6 months for 1 year after resection [bib_ref] Comparison of EMR and endoscopic submucosal dissection for en bloc resection of..., Ishihara [/bib_ref] [bib_ref] Endoscopic submucosal dissection is superior to conventional endoscopic resection as a curative..., Takahashi [/bib_ref] [bib_ref] Local recurrence of squamous-cell carcinoma of the esophagus after EMR, Katada [/bib_ref] [bib_ref] Risk factors for local recurrence of superficial esophageal cancer after treatment by..., Esaki [/bib_ref] [bib_ref] 1,635 Endoscopic submucosal dissection cases in the esophagus, stomach, and colorectum: complication..., Toyonaga [/bib_ref]. Patients with piecemeal resection and those with multiple iodine-unstained areas have a high risk of local recurrence, requiring a more strict esophagoscopy protocol [bib_ref] Comparison of EMR and endoscopic submucosal dissection for en bloc resection of..., Ishihara [/bib_ref] [bib_ref] Endoscopic submucosal dissection is superior to conventional endoscopic resection as a curative..., Takahashi [/bib_ref] [bib_ref] Local recurrence of squamous-cell carcinoma of the esophagus after EMR, Katada [/bib_ref] [bib_ref] Risk factors for local recurrence of superficial esophageal cancer after treatment by..., Esaki [/bib_ref] [bib_ref] Metachronous multiple esophageal squamous cell carcinomas and Lugol-voiding lesions after endoscopic mucosal..., Urabe [/bib_ref]. Lymph-node recurrence/ organ recurrence may be detected 2-3 years later, and regular, long-term follow-up is required [bib_ref] Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading..., Katada [/bib_ref] [bib_ref] Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms, Ono [/bib_ref].
In regard to the methods of examination, follow-up is usually performed every 6-12 months using several equipments such as contrast-enhanced thoracoabdominal CT and EUS [bib_ref] Surveillance after endoscopic mucosal resection or endoscopic submucosal dissection for esophageal squamous..., Katada [/bib_ref]. For example, in the JCOG0508 Study "Single-arm confirmatory study on efficacy of combined treatment of endoscopic mucosal resection and chemoradiotherapy for clinical stage I esophageal carcinoma," medical examinations and contrast-enhanced neck to abdominal CT and measurement of squamous cell carcinoma (SCC) antigen, a tumor marker, are to be performed every 4 months for 3 years after EMR.
## Follow-up after radical surgery
Recurrence after radical surgery occurs in 29-43% of cases in Japan. Although, in approximately 85% of cases, the recurrences occur early, often within 2 years after surgery, in some cases, they occur much later, and this should be borne in mind [bib_ref] Follow-up and recurrence after a curative esophagectomy for patients with esophageal cancer:..., Toh [/bib_ref] [bib_ref] Surgical outcomes in esophageal cancer patients with tumor recurrence after curative esophagectomy, Kunisaki [/bib_ref] [bib_ref] Patterns and time of recurrence after complete resection of esophageal cancer, Sugiyama [/bib_ref]. The patterns of recurrence include lymph-node recurrence, local recurrence, organ recurrence and disseminated recurrence, and mixed type of recurrence [bib_ref] Patterns and time of recurrence after complete resection of esophageal cancer, Sugiyama [/bib_ref].
The actual method of follow-up after radical resection of esophageal cancer is currently determined by each institution, and no studies have clarified the usefulness of regular follow-up or an effective method of follow-up. A nationwide survey conducted by the Guideline Committee [bib_ref] A nation-wide survey of follow-up strategies for esophageal cancer patients after a..., Toh [/bib_ref] revealed that many institutions perform follow-up with tumor markers and diagnostic imaging, mainly CT, ≥ 4 times a year during the first 2 years after resection and at least twice a year from the third year until the fifth year, and that some institutions perform follow-up for up to 10 years. Mainly contrast-enhanced thoracoabdominal CT and upper gastrointestinal endoscopy are performed as follow-up examinations, and neck/abdominal US, bone scintigraphy and PET-CT are performed as necessary. CT is performed every 3-6 months in many institutions, and the frequency of CT often varies depending on the stage of cancer progression and on the number of years after surgery.
## Follow-up after radical chemoradiotherapy
CT, esophagoscopy, and other examinations are usually used for follow-up after radical chemoradiotherapy, but there are no reports clarifying the optimal frequency of these examinations or the optimal follow-up period. According to a nationwide survey [bib_ref] A nation-wide survey of follow-up strategies for esophageal cancer patients after a..., Toh [/bib_ref] , follow-up is performed every 3 months during the first year after chemoradiotherapy at most institutions. For patients with cStage II or more advanced cancers, follow-up similar to that in the first year is performed up to the third year at many institutions, and follow-up is continued for at least 5 years after treatment at all the institutions surveyed. Primary esophageal lesions and lymph-node metastasis are commonly encountered as residual/recurrent lesions after chemoradiotherapy, and in most of these cases, these are detected within 1 to 2 years after the start of treatment.
After definitive chemoradiotherapy for esophageal cancer, not only screening for detecting recurrence, but also follow-up for the early identification of the late effects of radiotherapy such as radiation pneumonitis, pleural effusion, and pericardial effusion is necessary [bib_ref] Long-term toxicity after definitive chemoradiotherapy for squamous cell carcinoma of the thoracic..., Ishikura [/bib_ref]. These late effects may greatly impair the patients' QOL, and patients could die of the late effects.
## Points to consider in patients with metachronous multiple esophageal cancers and double cancers in other organs
Esophageal cancer is characterized by relatively frequent occurrence, metachronously, of multiple cancers in the esophagus. In addition, development of metachronous cancer in other organs, such as gastric cancer and head and neck cancer, is also not rare [bib_ref] Risk of second primary cancer among esophageal cancer patients: a pooled analysis..., Chuang [/bib_ref] [bib_ref] Surgical strategies for esophageal cancer associated with head and neck cancer, Morita [/bib_ref]. Bearing this in mind, upper gastrointestinal endoscopy needs to be regularly performed to carefully observe the pharynx, entire esophagus (remnant esophagus in surgical cases), and stomach. Particular attention needs to be paid to the development of metachronous head and neck cancer in patients with multiple iodineunstained areas and those with head and neck cancer [bib_ref] Surgical strategies for esophageal cancer associated with head and neck cancer, Morita [/bib_ref] [bib_ref] Lugol-voiding lesions are an important risk factor for a second primary squamous..., Hori [/bib_ref]. Magnifying endoscopy with narrow-band imaging (NBI) is useful for detecting superficial head and neck cancer [bib_ref] Narrow band imaging for detecting superficial squamous cell carcinoma of the head..., Katada [/bib_ref]. Furthermore, attention also needs to be paid to the development of colorectal and other cancers.
## Treatment of recurrent esophageal cancer
## Summary
Since there are a variety of initial treatments for esophageal cancer, such as endoscopic treatment, radical surgery, and definitive chemoradiotherapy, treatment for recurrent esophageal cancer needs to be considered individually according to the type of initial treatment. Furthermore, treatment varies depending on whether the pattern of recurrence is lymphnode recurrence, local recurrence, distant organ recurrence, or mixed recurrence, and the general condition of the patient at the time of recurrence also affects the choice of treatment. It is difficult to conduct large-scale clinical studies on the treatment of recurrent esophageal cancer, and there is currently little evidence of the usefulness of any type of treatment used. While cure may be achieved depending on the type of recurrence, for example, by salvage therapy after radical chemoradiotherapy, treatment for suppressing tumor exacerbation or improving QOL is also often used.
## General remarks
## Treatment of recurrence after endoscopic resection
Local recurrence after endoscopic mucosal resection often develops within 1 year after the initial treatment, but may sometimes take until 2 to 3 years after the initial treatment. Recently, indications for endoscopic resection have been expanded in clinical studies. There are no certain indications for, or evidence for the type of additional treatment after endoscopic resection, and some patients receive follow-up alone (see Chapter "Endoscopic treatment").
## Treatment of recurrence after radical surgery
Recurrence after radical surgery for esophageal cancer has been reported to occur in 28-47% of cases in Japan [bib_ref] Follow-up and recurrence after a curative esophagectomy for patients with esophageal cancer:..., Toh [/bib_ref] [bib_ref] Survival factors in patients with recurrence after curative resection of esophageal squamous..., Miyata [/bib_ref] , while the reported recurrence rates of ≥ 50% are not rare in reports from Europe and North America [bib_ref] Classification of recurrent esophageal cancer after radical esophagectomy with two-or three-field lymphadenectomy, Kato [/bib_ref] [bib_ref] Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing, Abate [/bib_ref]. In regard to the patterns of recurrence, 22-68% of cases show lymph node/local recurrence, 12-51% show distant organ metastasis, and 7-27% show a mixture of both types of recurrence. Recurrence in the neck/superior mediastinum is common in cases of lymph-node recurrence, while, in cases of distant organ metastasis, the lung is the most common site of recurrence, followed in frequency by the liver, bone, and brain. Even metastases to the small intestine and colon have been reported.
Patients with recurrence after radical resection for esophageal cancer have extremely poor survival rates, with a median survival duration of 5-10 months after diagnosis. On the other hand, cases of long-term survival and those of complete cure have also been reported, and active treatment for recurrent lesions should be considered [bib_ref] Follow-up and recurrence after a curative esophagectomy for patients with esophageal cancer:..., Toh [/bib_ref] [bib_ref] Survival factors in patients with recurrence after curative resection of esophageal squamous..., Miyata [/bib_ref] [bib_ref] Classification of recurrent esophageal cancer after radical esophagectomy with two-or three-field lymphadenectomy, Kato [/bib_ref] [bib_ref] Recurrence after esophagectomy for adenocarcinoma: defining optimal follow-up intervals and testing, Abate [/bib_ref] [bib_ref] Results of radiation therapy combined with nedaplatin (cis-diammine-glycoplatinum) and 5-fluorouracil for postoperative..., Jingu [/bib_ref] [bib_ref] Outcomes of lymphadenectomy for lymph node recurrence after esophagectomy or definitive chemoradiotherapy..., Watanabe [/bib_ref] [bib_ref] Salvage lymphadenectomy for cervical lymph node recurrence after esophagectomy for squamous cell..., Watanabe [/bib_ref] [bib_ref] Multimodal treatment for lymph node recurrence of esophageal carcinoma after curative resection, Nakamura [/bib_ref] [bib_ref] Concurrent chemoradiotherapy using low-dose continuous infusion of 5-fluorouracil for postoperative regional lymph..., Tsuchida [/bib_ref] [bib_ref] A retrospective evaluation of radiotherapy for the treatment of local esophageal squamous..., Zhu [/bib_ref] [bib_ref] Salvage definitive chemo-radiotherapy for locally recurrent oesophageal carcinoma after primary surgery: retrospective..., Baxi [/bib_ref] [bib_ref] Radiation therapy for recurrent esophageal cancer after surgery: clinical results and prognostic..., Shioyama [/bib_ref] [bib_ref] Salvage radiotherapy for postoperative loco-regional recurrence of esophageal cancer, Yamashita [/bib_ref] [bib_ref] Pattern of postoperative recurrence and hepatic and/or pulmonary resection for liver and/..., Ichida [/bib_ref].
Treatment of recurrence after radical resection for esophageal cancer is selected according to the site, pattern, and extent of recurrence. Treatment varies depending on the condition in each individual, such as the general condition of the patient at the time of recurrence, whether recurrence is in the surgical area, and whether irradiation was given preoperatively or postoperatively. Therefore, there have been a few reports of large-scale studies of the treatment outcomes according to various pathological conditions.
## Treatment of recurrence developing after complete response to definitive chemoradiotherapy
In recent years, definitive chemoradiotherapy has been increasingly chosen as the initial treatment, not only for unresectable esophageal cancer, but also for cases with esophageal cancer that is judged as being resectable. Although complete response has been achieved in many cases, recurrences, including local recurrence, are often encountered. The treatment of recurrence varies depending on the pathology and general condition of the patient, and no consensus has been reached. However, when the recurrence is localized, salvage treatment such as surgery and endoscopic resection may be adopted [bib_ref] Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carcinoma, Tachimori [/bib_ref] [bib_ref] Long-term results of salvage endoscopic mucosal resection in patients with local failure..., Yano [/bib_ref] [bib_ref] Feasibility of endoscopic mucosal resection as salvage treatment for patients with local..., Makazu [/bib_ref] [bib_ref] Outcomes of lymphadenectomy for lymph node recurrence after esophagectomy or definitive chemoradiotherapy..., Watanabe [/bib_ref] [bib_ref] Prognostic analysis of salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous cell..., Wang [/bib_ref] [bib_ref] Comparison of salvage chemoradiation versus salvage surgery for recurrent esophageal squamous cell..., Chen [/bib_ref] [bib_ref] Salvage endoscopic submucosal dissection in patients with local failure after chemoradiotherapy for..., Takeuchi [/bib_ref] [bib_ref] Salvage lymphadenectomy without esophagectomy is an option for recurrent or residual lymph..., Matono [/bib_ref] (see chapter "Multidisciplinary treatment", Chemoradiotherapy).
## Palliative care
## Summary
While palliative care should be commonly provided for cancers at any site, in esophageal cancer patients, dysphagia, malnutrition, cough due to fistula formation with the airways, and other symptoms often decrease the QOL, and provision of treatment for relieving these symptoms and maintaining/improving the QOL of the patients should be considered from even the early stages of treatment. However, the method of palliation adopted is determined by the prevailing practice at individual institutions, and further evaluation is required. All medical professionals need to master the knowledge and skills needed in palliative care.
## General remarks
The World Health Organization (WHO) (2002) defines palliative care as "an approach that improves the quality of life of patients and their families facing problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual." The Second Basic Plan to Promote Cancer Control Programs in fiscal year 2012 states that "promotion of palliative care from the time of cancer diagnosis" is an issue that needs to be focused on. The above-mentioned palliative care is common to all cancer patients and provided in daily practice, not only the attending physicians and nurses, but also palliative care specialists, psycho-oncologists, clinical psychologists, dentists, pharmacists, certified social workers, physical therapists, and other professionals need to engage and provide team care. Methods based on the "Guidelines for Pharmacotherapy of Cancer Pain" established by the Japanese Society for Palliative Medicine are recommended for cancer pain.
Patients with esophageal cancer often suffer from dysphagia and malnutrition due to esophageal obstruction, cough due to aspiration/fistula, and chest pain due to the tumor, resulting in a lowered QOL already at the time of diagnosis. Even while providing treatment for cure, it is important, from the early stage, to provide treatment for the relief of symptoms and for maintaining/improving the QOL of the patients [bib_ref] Palliative therapy for patients with unresectable esophageal carcinoma, Freeman [/bib_ref].
In palliative care for patients with terminal esophageal cancer, problems that need to be handled are, in particular, dysphagia due to esophageal obstruction and malnutrition caused by dysphagia, symptoms caused by airway obstruction or fistula formation with the airway, cachexia, and other symptoms due to distant metastases and hypercalcemia. To improve the symptoms of esophageal obstruction and airway obstruction and those caused by fistula, palliative radiotherapy, chemoradiotherapy, esophageal stenting, airway stenting, esophageal bypass surgery, and/or other treatments may be used [bib_ref] Oesophageal cancer-an overview, Schweigert [/bib_ref] [bib_ref] Patient-reported outcomes evaluating palliative radiotherapy and chemotherapy in patients with oesophageal cancer:..., Amdal [/bib_ref] (see Chapter "Radiotherapy"; Chapter "Multidisciplinary Treatment", Chemoradiotherapy).
For improving dysphagia in unresectable esophageal cancer, a Cochrane Database Systematic Review in 2014 showed that self-expandable esophageal metallic stents are more effective and faster-acting than plastic stents and other methods [bib_ref] Interventions for dysphagia in oesophageal cancer, Dai [/bib_ref]. However, it should be kept in mind that stenting may also cause complications, causing pain and further decreasing the QOL, and the treatment(s) should be undertaken after providing adequate explanation to the patient and obtaining informed consent. In addition to esophageal stenting, intracavitary irradiation, laser irradiation, hyperthermia, ethanol injection, etc., have been reported as treatments for providing relief from esophageal obstruction. While intracavitary irradiation may act more slowly in providing relief from esophageal obstruction than esophageal stenting, it could be a useful alternative treatment to esophageal stenting, as it is associated with a lower incidence of complications, provides more sustained relief from esophageal obstruction, and may be expected to prolong the survival and improve the QOL [bib_ref] Interventions for dysphagia in oesophageal cancer, Dai [/bib_ref]. However, intracavitary irradiation alone is scarcely adopted as a treatment option in Japan (see Chapter "Radiotherapy").
Patients with tracheoesophageal fistula formation have a reduced QOL due to repeated episodes of aspiration and pneumonia, but placement of a covered self-expandable esophageal stent, and in some cases, placement of an airway stent in addition to the esophageal stent, have been reported to be effective [bib_ref] Treatment of malignant tracheoesophageal fistula, Hürtgen [/bib_ref].
In patients with severe obstruction who have already undergone definitive chemoradiotherapy or radiotherapy and in whom radical resection cannot be expected, if it is considered that esophageal stenting would be difficult or dangerous, a nutritional fistula may be created to allow the patient to be switched to home care. Percutaneous endoscopic gastrostomy, which can usually be performed using an endoscope, is effective, and may be performed even before the start of the multidisciplinary treatments in patients with severe obstruction [bib_ref] Percutaneous endoscopic gastrostomy before multimodality therapy in patients with esophageal cancer, Margolis [/bib_ref]. In cases in which percutaneous endoscopic gastrostomy is difficult due to severe obstruction, such that even a small-diameter endoscope is difficult to negotiate through, or in patients with a history of abdominal surgery, open gastrostomy or jejunostomy may be performed.
In addition, medical professionals involved in the treatment of esophageal cancer often encounter potentially fatal complications, such as sudden respiratory arrest due to airway obstruction and massive hematemesis due to aortic perforation. Since it is difficult to save the lives in most of these cases, it is important to provide a thorough explanation in advance, particularly to the patients' families. Patients and their families are thus often forced to live in fear of sudden change/death, and psychological support and mental care for them are indispensable.
## Diagnosis and treatment of barrett's esophagus and barrett's carcinoma
## Summary
An esophagus lined with Barrett's mucosa is called Barrett's esophagus [bib_ref] Columnar-lined lower esophagus: an acquired lesion with malignant predisposition, Naef [/bib_ref]. Barrett's mucosa is endoscopically recognizable columnar epithelium extending from the stomach to the esophagus and does not require histological confirmation of specific columnar epithelial metaplasia [bib_ref] Review article: towards consistency in the endoscopic diagnosis of Barrett's oesophagus and..., Armstrong [/bib_ref] [bib_ref] The development and validation of an endoscopic grading system for Barrett's esophagus:..., Sharma [/bib_ref] [bib_ref] History, molecular mechanisms, and endoscopic treatment of Barrett's esophagus, Spechler [/bib_ref] [bib_ref] Differences in the definitions used for esophageal and gastric diseases in different..., Takubo [/bib_ref] [bib_ref] Definition of Barrett's esophagus: time for a rethink-is intestinal metaplasia dead?, Riddell [/bib_ref]. Identification of the esophagogastric junction is required for the diagnosis of Barrett's mucosa, and the endoscopically identifiable distal end of the lower esophageal palisade vessels is defined, in principle, as the esophagogastric junction. Barrett's mucosa is characterized by at least one of the following histological findings: (1) esophageal gland ducts in the mucosa beneath the columnar epithelium or esophageal glands proper in the submucosa; (2) squamous islands within the columnar epithelium; (3) double muscularis mucosae beneath the columnar epithelium. Barrett's carcinoma is defined as adenocarcinoma arising from Barrett's mucosa. Early, superficial, and advanced cancer are defined in the same manner as for the case of esophageal squamous cell carcinoma, in general, but the deep muscularis mucosae is handled as the genuine muscularis mucosae. Barrett's carcinoma is treated in accordance with the treatment principles for esophageal squamous cell carcinoma at the cancer site. Endoscopic resection is currently indicated for lesions extending in depth down to the lamina propria (EP: remaining in the epithelium, non-invasive lesion; SMM [superficial muscularis mucosae]: remaining in the superficial muscularis mucosae; LPM [lamina propria mucosae]: not reaching the deep muscularis mucosae); however, accumulation of cases is necessary for establishing the optimal treatment.
## Compliance with ethical standards
Ethical Statement All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later versions. This article does not contain any studies with human or animal subjects performed by any author(s).
## Conflict of interest
Funds to support the development of these guidelines were provided by the Japan Esophageal Society. All authors declare that they have no conflict of interest. Members of the Guideline Review Committee and Guideline Steering Committee personally reported their conflicts of interests in conformity with the regulations of the Japan Esophageal Society. The Ethics Committee and the Board of Directors of the Japan Esophageal Society confirmed the personally reported conflict-of-interest situations.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
[table] Table 1: Reports of the first-line therapy for unresectable advanced/recurrent esophageal cancer [/table]
[table] Table 2: Reports of second-or subsequent-line therapy for unresectable advanced/recurrent esophageal cancer SCC squamous cell carcinoma, AC adenocarcinoma a Including 14 patients with the initial treatment [/table]
[table] Table 3: Summary of prospective clinical studies of chemoradiotherapy SCC squamous cell carcinoma, AC adenocarcinoma, 5-FU 5-fluorouracil, NA not available [/table]
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Digital breast tomosynthesis (DBT): recommendations from the Italian College of Breast Radiologists (ICBR) by the Italian Society of Medical Radiology (SIRM) and the Italian Group for Mammography Screening (GISMa)
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Digital breast tomosynthesis (DBT): recommendations from the Italian College of Breast Radiologists (ICBR) by the Italian Society of Medical Radiology (SIRM) and the Italian Group for Mammography Screening (GISMa)
DBT protocols has been solved by the introduction of synthetic mammograms (sDM) reconstructed from DBT datasets. Thus, whenever possible, sDM/DBT should be preferred to DM/DBT. However, before introducing DBT as a routine screening tool for average-risk women, we should wait for the results of randomized controlled trials and for a statistically significant and clinically relevant reduction in the interval cancer rate, hopefully associated with a reduction in the advanced cancer rate. Otherwise, a potential for overdiagnosis and overtreatment cannot be Abstract This position paper, issued by ICBR/SIRM and GISMa, summarizes the evidence on DBT and provides recommendations for its use. In the screening setting, DBT in adjunct to digital mammography (DM) increased detection rate by 0.5-2.7‰ and decreased false positives by 0.8-3.6% compared to DM alone in observational and double-testing experimental studies. The reduction in recall rate could be less prominent in those screening programs which already have low recall rates with DM. excluded. Studies exploring this issue are ongoing. Screening of women at intermediate risk should follow the same recommendations, with particular protocols for women with previous BC history. In high-risk women, if mammography is performed as an adjunct to MRI or in the case of MRI contraindications, sDM/DBT protocols are suggested. Evidence exists in favor of DBT usage in women with clinical symptoms/signs and asymptomatic women with screen-detected findings recalled for work-up. The possibility to perform needle biopsy or localization under DBT guidance should be offered when DBT-only findings need characterization or surgery.
# Introduction
In the last years, many reports have appeared about digital breast tomosynthesis (DBT) in both the diagnostic and screening setting. In fact, thanks to a pseudo-threedimensional reconstruction, DBT allows for overcoming some limitations of standard two-dimensional (2D) digital mammography (DM) caused by structural overlapping and resulting into false-negative and false-positive findings. The X-ray tube moves along an angular direction and generates multiple low-dose variably angled projections of the compressed breast. The reconstruction of multiple images of thin slices of the compressed breast is obtained by specialized software [bib_ref] Breast tomosynthesis: state-of-the-art and review of the literature, Baker [/bib_ref]. The technical solutions proposed by vendors differ for tube movement (continuous/discontinuous), width of oscillation angle, number of projections, type of detector, and other characteristics, although no substantial effects on diagnostic performance related to these differences have been reported so far.
This position paper, issued by the Italian College of Breast Radiologists by the Italian Society of Medical Radiology (SIRM) and the Italian Group for Mammography Screening (GISMa), summarizes the available evidence on DBT and provides practical recommendations for its use. For the levels of evidence (LoE) reported here, we refer to the definitions given by the Centre for Evidence-Based Medicine, Oxford, United Kingdom.
## Dbt for first-level screening
Several studies have evaluated the potential of DBT in first-level screening [bib_ref] Overview of the evidence on digital breast tomosynthesis in breast cancer detection, Houssami [/bib_ref] [bib_ref] Comparison of digital mammography alone and digital mammography plus tomosynthesis in a..., Skaane [/bib_ref] [bib_ref] Prospective trial comparing full-field digital mammography (FFDM) versus combined FFDM and tomosynthesis..., Skaane [/bib_ref] [bib_ref] Integration of 3D digital mammography with tomosynthesis for population breastcancer screening (STORM):..., Ciatto [/bib_ref] [bib_ref] Performance of one-view breast tomosynthesis as a stand-alone breast cancer screening modality:..., Lang [/bib_ref] [bib_ref] Breast cancer screening using tomosynthesis in combination with digital mammography, Friedewald [/bib_ref] [bib_ref] Comparison of tomosynthesis plus digital mammography and digital mammography alone for breast..., Haas [/bib_ref] [bib_ref] Screening outcomes following implementation of digital breast tomosynthesis in a general-population screening..., Mccarthy [/bib_ref] [bib_ref] Clinical performance metrics of 3D digital breast tomosynthesis compared with 2D digital..., Greenberg [/bib_ref] [bib_ref] Early clinical experience with digital breast tomosynthesis for screening mammography, Durand [/bib_ref]. In particular, three European prospective trials conducted in the context of organized population-based screening programs [bib_ref] Comparison of digital mammography alone and digital mammography plus tomosynthesis in a..., Skaane [/bib_ref] [bib_ref] Prospective trial comparing full-field digital mammography (FFDM) versus combined FFDM and tomosynthesis..., Skaane [/bib_ref] [bib_ref] Integration of 3D digital mammography with tomosynthesis for population breastcancer screening (STORM):..., Ciatto [/bib_ref] [bib_ref] Performance of one-view breast tomosynthesis as a stand-alone breast cancer screening modality:..., Lang [/bib_ref] and five retrospective studies from spontaneous screening settings [bib_ref] Breast cancer screening using tomosynthesis in combination with digital mammography, Friedewald [/bib_ref] [bib_ref] Comparison of tomosynthesis plus digital mammography and digital mammography alone for breast..., Haas [/bib_ref] [bib_ref] Screening outcomes following implementation of digital breast tomosynthesis in a general-population screening..., Mccarthy [/bib_ref] [bib_ref] Clinical performance metrics of 3D digital breast tomosynthesis compared with 2D digital..., Greenberg [/bib_ref] [bib_ref] Early clinical experience with digital breast tomosynthesis for screening mammography, Durand [/bib_ref] have shown that DBT combined with DM (or as a stand-alone approach [bib_ref] Performance of one-view breast tomosynthesis as a stand-alone breast cancer screening modality:..., Lang [/bib_ref] allows for a better diagnostic performance than DM alone.
Results of DBT differ according to the study design, the screening interval, and the type of screening setting (organized versus spontaneous). A review [bib_ref] Digital breast tomosynthesis (3D-mammography) screening: data and implications for population screening, Houssami [/bib_ref] reported that DBT provides an increase in cancer detection rate from 0.5 to 2.7 per thousand screened women and a reduction in false-positive recall rate from 0.8 to 3.6 per 100 screened women. The possibility of using only the mediolateral oblique DBT projection, supported by one study [bib_ref] Performance of one-view breast tomosynthesis as a stand-alone breast cancer screening modality:..., Lang [/bib_ref] , has the rationale of dose reduction. However, although many experiences have shown the superior diagnostic performance of two-view DBT compared with one-view DBT [bib_ref] The diagnostic accuracy of dual-view digital mammography, single-view breast tomosynthesis and a..., Svahn [/bib_ref] [bib_ref] Two-view and singleview tomosynthesis versus full-field digital mammography: detecting and characterizing invasive..., Wallis [/bib_ref] , the availability of synthetic 2D mammograms generated from the DBT dataset (see below) has substantially overcome the problem of dose. A reduction in recall rate of greatly varying magnitude (from 6 to 82%, median 31%) has been found . Notably, this variability depends on the baseline recall rate with standard DM because the higher the baseline DM recall rate, the higher the absolute and relative reduction obtained with DBT. Thus, the advantage of reducing the recall rate could be less prominent in those screening programs which already have low recall rates with standard DM.
If both DM and DBT are acquired (separately or with the so-called "combo" modality), the average glandular dose is approximately doubled. In fact, the DBT dose is similar to that of DM . However, considering the dose reduction obtained through the introduction of DM as an alternative to film-screen mammography, the dose of these DM/DBT protocols too remains below the upper limit defined by the "European guidelines for quality assurance in breast cancer screening and diagnosis" published in 2006 .
Of note, radiation exposure would be an issue to take into consideration for a generalized adoption of DM/DBT protocols for population-based mass screening. The solution has come from the synthetic digital mammography (sDM) obtained through specialized algorithms summing and filtering the DBT datasets. Principles and methods have similarities with those generating maximum intensity projections in computed tomography and magnetic resonance imaging (MRI). These sDMs are virtual 2D mammograms obtained from DBT, paying no tradeoff in terms of radiation exposure .
Several authors have compared sDM/DBT protocols with DM/DBT protocols demonstrating a similar diagnostic performance . Therefore, unless additional radiation exposure is specifically justified (as in the work-up of suspicious findings detected at DM), a diagnostic mammography examination can be performed using the sDM/ DBT approach.
Notably, two studies have reported that 54-57% of additional cancers detected by additional ultrasonography screening after negative DM were detected by DBT. This is a relevant argument in favor of DBT, considering the practical hurdles for a generalized mass screening with ultrasonography in adjunct to DM.
However, in the context of organized population-based screening programs, a simple increase in sensitivity and overall diagnostic performance of a new tool, even if statistically significant and clinically relevant, is not enough, per se, for its generalized adoption. According to the European Council Recommendation on cancer screening [31], evidence from randomized controlled trials is needed before introducing new screening tools. In particular, considering the pre-existing evidence in favor of screening mammography (recently confirmed by the International Agency for Research on Cancer [32]), caution is urged due to the possibility that a substantial part of the additional cancers detected by DBT could be overdiagnosed lesions, i.e. indolent malignant lesions that would never surface clinically during the woman's life . Importantly, the consequence would be an increase in overtreatment, i.e. unnecessary surgery, radiation, and/or medical therapy.
It is worth to note that most of the additional cancers detected with DBT have been reported to be invasive [bib_ref] Comparison of digital mammography alone and digital mammography plus tomosynthesis in a..., Skaane [/bib_ref] [bib_ref] Prospective trial comparing full-field digital mammography (FFDM) versus combined FFDM and tomosynthesis..., Skaane [/bib_ref] [bib_ref] Integration of 3D digital mammography with tomosynthesis for population breastcancer screening (STORM):..., Ciatto [/bib_ref] [bib_ref] Performance of one-view breast tomosynthesis as a stand-alone breast cancer screening modality:..., Lang [/bib_ref] [bib_ref] Breast cancer screening using tomosynthesis in combination with digital mammography, Friedewald [/bib_ref] [bib_ref] Comparison of tomosynthesis plus digital mammography and digital mammography alone for breast..., Haas [/bib_ref] [bib_ref] Screening outcomes following implementation of digital breast tomosynthesis in a general-population screening..., Mccarthy [/bib_ref] [bib_ref] Clinical performance metrics of 3D digital breast tomosynthesis compared with 2D digital..., Greenberg [/bib_ref] [bib_ref] Early clinical experience with digital breast tomosynthesis for screening mammography, Durand [/bib_ref]. A large study from the United States [bib_ref] Breast cancer screening using tomosynthesis in combination with digital mammography, Friedewald [/bib_ref] has compared DM/DBT in approximately 174,000 women with DM alone in approximately 281,000 women. The DM/DBT approach was associated with a 29% increase in detection rate and a 15% reduction in recall rate. All the increase in cancer detection was due to invasive cancers (+41%). No increase in the detection of ductal carcinoma in situ, deemed more probably overdiagnosed, was observed. However, we should consider that also invasive cancers can be indolent and overdiagnosed. Thus, no definitive conclusions can be drawn.
Several other issues cannot be ignored when discussing the potential introduction of DBT for screening. They include at least sufficient availability of DBT equipments, management of suspicious findings at DBT alone, and increased reading time [34-36], which implies the need for more breast radiologists involved as screening readers.
Thus, before introducing DBT as a first-level screening tool, we should wait for the results of randomized controlled trials (some of which are already ongoing in Italy) comparing a population sample having DM/DBT or sDM/ DBT at the first round and DM alone at the subsequent round with a population sample having DM alone at both rounds [37]. This will enable us to determine:
1. whether the expected increase in cancer detection at first round with DBT is associated or not associated with a reduction in interval cancer incidence; 2. whether the total incidence of advanced cancers (stage ≥T2) in the whole study period (i.e. considering all cancers detected in the first or second round as well as interval cancers) is lower in the DBT group compared with the control group; and 3. whether the total incidence of breast cancer in the DBT group exceeds that of the control group.
The attention paid to interval cancer rate is explained by the possibility to use this measure as a proxy of effectiveness in mortality reduction [bib_ref] Digital breast tomosynthesis (3D-mammography) screening: data and implications for population screening, Houssami [/bib_ref]. To our knowledge, only two articles [38, 39] have reported results concerning the interval cancer rate of DBT screening. The study design was a single-center retrospective analysis [38] and a multicenter [39] prospective cohort study. Comparing DM alone with DM/DBT screening, a reduction in interval cancer rate was observed in both studies, from 0.7 to 0.5 per thousand screened women [38] and from 0.6 to 0.46 per thousand screened women [39], respectively. These variations were not statistically significant. However, it should be noted that neither study was designed and powered for interval cancer analysis, and that both were conducted in a spontaneous screening setting. These heavy limitations prevent us to draw any conclusion to be extrapolated to European organized biennial screening programs.
## Dbt for work-up of screen-detected suspicious findings, as a first-line diagnostic examination in symptomatic women, for preoperative staging, and targeted evaluation after mri
Several studies have shown that DBT is at least equivalent to additional DM views (magnification, spot compression, 90° views, etc.), also reducing radiation exposure in both the diagnostic and screening setting. In symptomatic women, diagnostic accuracy is improved by DBT, reducing the number of suspicious findings and of unnecessary biopsies . In the presence of palpable lesions, DBT has been reported to be never worse, and often better, than DM for estimating tumor size . The better diagnostic performance of DBT is confirmed also in the case of invasive lobular cancers, as shown by a recent study . In the preoperative setting, the combination of DM, DBT, and ultrasonography could provide the same information as MRI [bib_ref] Accuracy of mammography, digital breast tomosynthesis, ultrasound and MR imaging in preoperative..., Mariscotti [/bib_ref]. Finally, DBT allows for identifying some findings additionally found on preoperative MRI also when they are not visible at targeted ultrasonography, permitting a reduction in the number of MR-guided biopsies [bib_ref] Additional findings at preoperative breast MRI: the value of second look digital..., Clauser [/bib_ref].
Studies evaluating inter-reader variability for DM/DBT versus DM alone have reported for each reader an increase in the detection rate and a reduction in the recall rate with an overall increase in the diagnostic performance [bib_ref] Effect of integrating 3D-mammography (digital breast tomosynthesis) with 2D-mammography on radiologists' true-positive..., Bernardi [/bib_ref] [bib_ref] Incremental effect from integrating 3D-ammography (tomosynthesis) with 2D-mammography: increased breast cancer detection..., Caumo [/bib_ref] [bib_ref] A reader study comparing prospective tomosynthesis interpretations with retrospective readings of the..., Rose [/bib_ref] [bib_ref] Effect of the availability of prior full-field digital mammography and digital breast..., Hakim [/bib_ref].
In the particular context of spontaneous screening, DBT has also been found to reduce the number of short-time repeat examinations [bib_ref] A reader study comparing prospective tomosynthesis interpretations with retrospective readings of the..., Rose [/bib_ref].
All these results allow for recommending DBT for symptomatic women and for work-up of screen-detected suspicious findings.
## Recommendations
Recommendations are presented here for five categories of women:
1. asymptomatic women at average risk (first level of organized or spontaneous screening); 2. asymptomatic women at intermediate risk, including women with a previous breast cancer; 3. symptomatic women and women needing work-up of screen-detected suspicious findings; 4. asymptomatic women at hereditary/familial high risk; 5. asymptomatic women at high risk due to previous chest radiotherapy.
A sixth, final recommendation concerns needle biopsy under DBT guidance.
1. Asymptomatic women at average risk (first level of organized or spontaneous screening)
These women should undergo DM starting not before the age of 40, with a screening interval that may vary according to local health authority's decision. As recently stated by the European Society of Breast Imaging [bib_ref] Position paper on screening for breast cancer by the European Society of..., Sardanelli [/bib_ref] [bib_ref] European Society of Breast Imaging (EUSOBI), with language review by Europa Donna-The..., Sardanelli [/bib_ref] , direct DM should be preferred to film-screen mammography due to a reduced radiation exposure [bib_ref] Dose comparison between screen/film and full-field digital mammography, Gennaro [/bib_ref] and an at least equivalent diagnostic performance [bib_ref] Digital Mammographic Imaging Screening Trial (DMIST) Investigators Group et al (2006) Diagnostic..., Pisano [/bib_ref] (LoE A). The preference is also in favor of DM when compared with indirect digital phosphor storage plate (socalled computer radiography) [bib_ref] A comparative study of computed radiography-based mammography using digital phosphor storage plate..., Chelliah [/bib_ref].
DBT can be used as a first-level screening tool in women at average risk: a) in the context of studies approved by an Ethical Committee, with enrollment after informed consent signature by the woman (for randomized controlled trials, refer to the scheme proposed by the Osservatorio Nazionale Screening [37]); b) in the well-defined context of centers being part of public population-based screening programs, with previous experience with ethically approved studies concerning at least feasibility of screening DBT, demonstrated through articles published in peerreviewed journals.
In both cases, the sDM/DBT approach should be preferred (Loe A). In both cases, centers are requested to provide data regarding the screening process, service, and impact, including the women's compliance. Considering the data management needs, the necessary interactions with information technology services, and the impact of DBT on the whole multidisciplinary team, studies should be performed under umbrella of breast units. Moreover, usual monitoring data should be collected, in particular absolute and/or proportional incidence of interval cancer and of screen-detected cancers of stage T2 or higher [37,. Attention should be paid to avoid that the implementation of DBT studies causes a reduction in screening coverage, compliance, or quality indicators.
## Asymptomatic women at intermediate risk, including those with a previous breast cancer
Up to now, no substantial evidence has been produced in favor or against the use of DBT for screening women at intermediate risk of breast cancer, i.e. those with a lifetime risk from 15 to 19%, estimated using multifactorial models. All these women should undergo screening DM with the same protocols recommended for asymptomatic women at average risk.
For asymptomatic women with a previous history of breast cancer (included in this general category of women at intermediate risk), we refer to the recommendations provided by the GISMa and the Italian College of Breast Radiologists by SIRM [bib_ref] Recommendations for breast imaging follow-up of women with a previous history of..., Bucchi [/bib_ref]. The recent observation of a reduction in indeterminate findings in surveillance after breast cancer treatment [bib_ref] A prospective study comparing digital breast tomosynthesis with digital mammography in surveillance..., Sia [/bib_ref] plays in favor of DBT usage (LoE D) in this setting, with a preference for sDM/DBT protocols.
DBT can be used as a screening tool in women at intermediate risk:
a) in the context of studies approved by an Ethical Committee, with enrollment after informed consent signature by the woman; b) in the well-defined context of centers having previous experience with ethically approved studies concerning DBT, demonstrated through articles published in peerreviewed journals.
Usual performance indicators should be collected, in particular absolute and/or proportional incidence of interval cancer and of screen-detected cancers of stage T2 or higher [36, 61, 62].
## Symptomatic women and women needing work-up of screen-detected suspicious findings
We include in this category both women with suspicious clinical symptoms or signs (asking for a mammogram usually ordered by a general practitioner or a specialist) and asymptomatic women with screen-detected suspicious findings recalled for work-up in the context of spontaneous or organized screening. Women with previous history of breast cancer, if having suspicious clinical symptoms/signs or after a suspicious finding on an imaging study, are also included in this category.
In these women, if an indication to mammography exists and DBT is available, DBT should be performed (LoE A), preferably with a sDM/DBT protocol (LoE B). If sDM mammograms are not available, DBT can be performed after DM (LoE B).
## Asymptomatic women at hereditary/familial high risk
Women at hereditary/familial high risk should be screened in the context of dedicated pathways [bib_ref] Indications for breast magnetic resonance imaging. Consensus document "Attualità in senologia, Sardanelli [/bib_ref] [bib_ref] Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group, Sardanelli [/bib_ref] [bib_ref] High Breast Cancer Risk Italian 1 (HIBCRIT-1) Study. Multicenter surveillance of women..., Sardanelli [/bib_ref] [bib_ref] MRI screening of women with hereditary predisposition to breast cancer: diagnostic performance..., Santoro [/bib_ref] [bib_ref] Triple-negative versus non-triple-negative breast cancers in high-risk women: phenotype features and survival..., Podo [/bib_ref] [bib_ref] European Society of Breast Imaging (EUSOBI), with language review by Europa Donna-The..., Mann [/bib_ref]. Considering the higher radiosensitivity of their breast tissue and the high sensitivity of MRI for breast cancer, mammography can be avoided at least up to 35 years of age, in particular in BRCA1 mutation carriers. If mammography is performed as an adjunct to MRI or in the case of MRI contraindications, a sDM/DBT protocol is suggested (LoE D). In all cases of mammographic work-up, DBT should be preferred to additional DM projections (LoE D).
## Asymptomatic women at high risk due to previous chest radiotherapy
Recommendations regarding breast cancer screening for these women (mainly lymphoma survivors) were recently provided by the Italian College of Breast Radiologists by SIRM [bib_ref] Mammography and MRI for screening women who underwent chest radiation therapy (lymphoma..., Mariscotti [/bib_ref]. Both DM and contrast-enhanced MRI should be performed annually due to the suboptimal sensitivity of each of the two techniques [bib_ref] Prospective study of the efficacy of breast magnetic resonance imaging and mammographic..., Ng [/bib_ref] [bib_ref] Breast cancer detection among young survivors of pediatric Hodgkin lymphoma with screening..., Tieu [/bib_ref] [bib_ref] Screening breast MR imaging in women with a history of chest irradiation, Sung [/bib_ref] [bib_ref] Added cancer yield of breast magnetic resonance imaging screening in women with..., Freitas [/bib_ref]. A sDM/DBT protocol could be preferred to DM alone (LoE D).
## Needle biopsy under dbt guidance
DBT can show doubtful/suspicious findings without any clinical correlate and even undetectable on DM, sDM, or ultrasonography [bib_ref] Overview of the evidence on digital breast tomosynthesis in breast cancer detection, Houssami [/bib_ref] [bib_ref] Comparison of digital mammography alone and digital mammography plus tomosynthesis in a..., Skaane [/bib_ref] [bib_ref] Prospective trial comparing full-field digital mammography (FFDM) versus combined FFDM and tomosynthesis..., Skaane [/bib_ref] [bib_ref] Integration of 3D digital mammography with tomosynthesis for population breastcancer screening (STORM):..., Ciatto [/bib_ref]. This may occur in both the screening and diagnostic settings. In those cases, when the DBT finding is neither detectable at targeted ultrasonography nor at DM review, a needle biopsy (and, when necessary, also presurgical localization) should be performed under DBT guidance. Importantly, DBT guidance offers important advantages in terms of shorter procedure duration and reduced radiation exposure [bib_ref] Stereotactic vacuumassisted biopsies on a digital breast 3D-tomosynthesis system, Viala [/bib_ref] [bib_ref] Digital breast tomosynthesis-guided vacuum-assisted breast biopsy: initial experiences and comparison with prone..., Schrading [/bib_ref].
As a consequence, centers offering DBT should also offer DBT-guided interventions for DBT findings not otherwise identifiable. These interventions can be performed at the same center where DBT was done or at another center functionally connected with the first one. At present, in fact, few centers are equipped with the device for DBTguided interventions.
# Conclusions
Evidence available for DBT allows to recommend its usage for all cases of symptomatic women and women needing work-up of screen-detected suspicious findings (considering both spontaneous and organized screening). In these settings, when available, sDM/DBT protocols should be preferred for symptomatic women.
Breast cancer screening using the current mammography technology has been demonstrated to be effective in reducing mortality from the disease. From this perspective, completing the shift from analog film-screen mammography and computed radiography systems, that are still in use, to direct digital mammography systems ranks first in the order of priorities.
A generalized adoption of DBT as a first-level screening tool should wait for a specific evidence, in particular for a statistically significant and clinically relevant reduction in interval cancer rate (hopefully associated with a reduction in advanced cancer rates). When this evidence will be available, both asymptomatic women at average and intermediate risk (including those with a previous breast cancer history) will be allowed to be screened with DBT on a routine basis. Accurate data collection will be necessary for many years in order to assess the overall impact of DBT technology in terms of mortality reduction and other efficacy/effectiveness indicators. For high-risk women, when a mammogram is indicated, a sDM/DBT protocol should be preferred.
The already existing evidence, which has been built with a non-negligible contribution of Italian breast radiologists, plays in favor of DBT. A trend for making DBT the mammography of the next future can be outlined. However, even in the United States, where FDA approved the use of some DBT devices in some cases for screening, the use of DBT is still quite limited. A recent survey [bib_ref] Digital breast tomosynthesis utilization in the United States: a survey of physician..., Hardesty [/bib_ref] among the members of the Society of Breast Imaging reported that of 670 responders, only 200 (30%) use DBT although 62% of non-users have planned to equip themselves with DBT.
Studies and researches are still needed for a deeper evaluation of DBT, a relevant innovation in breast imaging. In particular, the risk of an increased overdiagnosis and also several organizational issues (including increased reading time) suggest to wait for a more conclusive evidence before adopting DBT in population-based screening, a position shared with other experts and medical or health authority bodies worldwide [bib_ref] Digital breast tomosynthesis (3D-mammography) screening: data and implications for population screening, Houssami [/bib_ref] [bib_ref] Position paper on screening for breast cancer by the European Society of..., Sardanelli [/bib_ref] [bib_ref] European Society of Breast Imaging (EUSOBI), with language review by Europa Donna-The..., Sardanelli [/bib_ref] [bib_ref] Digital breast tomosynthesis (DBT): a review of the evidence for use as..., Gilbert [/bib_ref] [bib_ref] Screening for breast cancer with digital breast tomosynthesis, Melnikow [/bib_ref].
## Compliance with ethical standards
Conflict of interest The authors declare no funding and no conflict of interest for this article.
Ethical standards This article does not contain any studies with human participants or animals performed by any of the authors.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
high resolution X-ray imaging observer study.
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Saudi guidelines for testing and treatment of latent tuberculosis infection
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Saudi guidelines for testing and treatment of latent tuberculosis infection
[bib_ref] The epidemiology of tuberculosis among foreign-born persons in the United States, Mckenna [/bib_ref] [bib_ref] Tuberculin skin testing. The state of the art, Reichman [/bib_ref] [bib_ref] Tuberculin skin testing. Can it contain the impending tuberculosis epidemic? Postgrad, Amin [/bib_ref] [bib_ref] Of postulates and peccadilloes: Robert Koch and vaccine (tuberculin) therapy for tuberculosis, Burke [/bib_ref] [bib_ref] Prevalence of tuberculosis infection in the United States population: the national health..., Bennett [/bib_ref] [bib_ref] LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A..., Mack [/bib_ref]
## Prevalence of ltbi in saudi arabia
The total number of reported tuberculosis cases in the year 2008 was 3 918 cases in a population of approximately 24 807 273. TB not Tuberculosis in Saudi Arabia affects mainly young and middle-aged individuals; most of them aged between 15 and 44 years old. The incidence of all cases was estimated at 15.8/100 000; the incidence of smear-positive tuberculosis was 8.2/100 000. However, WHO 2007 estimation of the incidence of TB new cases was 46/100 000 population/year, the incidence of new smear positive cases was 21/100 000 population/year and the estimated prevalence of all forms of TB cases was 65/100 000 population/year.Al Kassimi et al in 1993 [bib_ref] Nationwide community survey of tuberculosis epidemiology in Saudi Arabia, Al-Kassimi [/bib_ref] conducted the first comprehensive and nationwide tuberculin survey in the Saudi Arabian general population with urban/rural stratification. Using a definition of a positive tuberculin test of 10 mm or more, 33% of the subjects had a positive TST, and 56% were aged 45 years and older. Given that false positive reactions can occur in almost all populations, the most important determinant of the utility of a TST is the expected prevalence of true latent TB infection. The incidence of smear-positive cases of pulmonary tuberculosis varies widely between countries. Based on the observation by Styblo 9 of the relationship between the incidence of smear-positive pulmonary TB and the annual risk of TB infection (ARI), one can calculate the ARI based on the expected prevalence of latent TB infection in persons of a given age. In Saudi Arabia, the estimated incidence of active TB (all forms) is 46 per 100 000 and the incidence of smear-positive TB is 21 cases per 100 000, which gives an annual risk of infection of 0.35%.Using the Stabylo 9 calculation, the prevalence of LTBI at 10 and 20 years is 3.4% and 6.7% respectively, placing Saudi Arabia in the intermediate prevalence (2%-14%) category. 11
Administrative technique for the TST The administration of TST requires proper technique by trained professionals. A standard tuberculin syringe with a 27-gauge needle should be used to inject five tuberculin units of purified protein derivative (PPD) or two tuberculin units of RT-23 intradermally. Usually, the volar or inner surface of the forearm is used. The area of the skin selected for testing should be free of any cutaneous or subcutaneous lesion that could interfere with any interpretation. The injection should be intradermal, and neither too deep nor too shallow. A small wheal measuring approximately 5 mm in diameter should be elicited at the time of injection. If incorrect administration is suspected, a second test dose can be given immediately at a site that is at least 5 cm away from the first one.As a result of its tendency to be adsorbed by glass and plastics, tuberculin materials should never be transferred to secondary containers. It should be administered as soon as feasible after filling the syringe, ideally within 20 minutes. Long-term storage of prefilled syringes is not recommended. Tuberculin material should be kept refrigerated but not frozen, and most importantly, kept protected from light.
## Reading the tst
The tuberculin reaction is a classic, delayed type, hypersensitivity immune reaction. This means that the reaction begins within 24 hours, is maximal between 48 and 72 hours after injection, and then wanes over the next few days. Reading is done between 48 and 72 hours after administration.
The transverse diameter of the induration, but not erythema, is demarcated using the ball-point technique. The induration is measured and recorded in millimeters. If there is no reaction, the size should be recorded as 0 mm and not simply as "negative". Similarly readings of "doubtful" or "positive" are discouraged, particularly in individuals in whom repeated testing is done (see below).Adverse reactions to tuberculin skin testing are uncommon. Local allergic reactions to tuberculin or its components can occur in 2% to 3% of those tested usually in the form of a rash on the arm. Generalized rash has also been observed. These reactions begin shortly after injection and disappear within 24 hours. Severe blistering is possible, for which topical steroids are frequently given, although there is no evidence of their efficacy. The blistered area should be covered with a dry dressing and the patient advised to keep it clean and not to scratch it. 4
## Interpretation of the tst
## False-negative tst
Many factors can cause false-negative tests including viral, bacterial, or fungal infections. The most important GUIDELINES FOR LTBI guidelines cause of a false-negative TST is HIV infection. In HIVinfected persons, the likelihood of a false-negative TST is inversely proportional to the CD4 count: it is uncommon at CD4 counts above 500/mL, and almost universal when the CD4 count is less than 200/mL. Saudi Arabia has a low prevalence of HIV infection of less than 0.01%. [bib_ref] Human immunodeficiency virus and tuberculosis co-infection in Saudi Arabia. Eastern Mediterranean health..., Alrajhi [/bib_ref] [bib_ref] Epidemiology of the human immunodeficiency virus in Saudi Arabia; 18-year surveillance results..., Madani [/bib_ref] HIV infection is therefore not an important cause of a false-negative TST in Saudi Arabia.
It is important to note that patients with active TB can have false-negative tests at the time of diagnosis, particularly those with more advanced disease.Anergy testing with control antigens to which most normal adolescents and adults should react, such as mumps and Candida, have been used to determine whether people can have true-or false-negative tuberculin reactions. However, anergy testing is not routinely recommended in persons who are HIV-infected or otherwise immunocompromised because of the evidence that this testing is unreliable.Other causes of false-negative TSTs are presented in [fig_ref] Table 1: Causes of false-negative tuberculin skin testing Technical factors [/fig_ref].
## False-positive tst
BCG vaccination was started in 1964 in Saudi Arabia and a 95.9% coverage rate was achieved by 2007.The BCG vaccine is given at birth without any booster doses. A case-control study in Saudi Arabia determined the protective effect of the BCG vaccine using the same BCG strain (freeze-dried glutamate BCG, Japan laboratory Tokyo). [bib_ref] Efficacy of BCG vaccine in the prevention of tuberculosis: Meta-analysis of the..., Colditz [/bib_ref] This study demonstrated an 82% protective effect in the 5-14-year-old age group, but no protective effect 25 years after vaccination. [bib_ref] Efficacy of BCG vaccine in the prevention of tuberculosis: Meta-analysis of the..., Colditz [/bib_ref] In several other studies following BCG vaccination in infancy, tuberculin reactivity was seen to wane rapidly so that there was little discernible effect by the age of five years. However, those vaccinated at a later age have larger TST reactions that wane more slowly, with 15% to 25% of the reactions persisting beyond ten years. [bib_ref] Correlation between tuberculin sensitivity after 2 months and 5 years among BCG..., Horwitz [/bib_ref] [bib_ref] BCG vaccination and interpretation of PPD test results, Li [/bib_ref] [bib_ref] Interpretation of the tuberculin skin test in Mycobacterium bovis BCG-vaccinated Singaporean schoolchildren, Chee [/bib_ref] [bib_ref] Tuberculin response of Sri Lankan children after BCG vaccination at birth, Karalliedde [/bib_ref] [bib_ref] Tuberculin skin test survey in a pediatric population with high BCG vaccination..., Menzies [/bib_ref] [bib_ref] False-positive tuberculin skin tests: What is the absolute effect of BCG and..., Farhat [/bib_ref] A meta-analysis including more than 24 studies found that only 1% of patients who received BCG during infancy were TST positive if tested more than ten years after BCG vaccination. However, there was a greater and more long-lasting effect on TST if BCG was given later in life, such as during the primary or secondary school-going years. [bib_ref] Protective effect of BCG against tuberculosis meningitis and miliary tuberculosis: A meta-analysis, Rodrigues [/bib_ref] Most of the international guidelines recommend ignoring BCG' s effect on the interpretation of TST in persons at increased risk of developing active TB. 4
## Nontuberculous mycobacteria
Nontuberculous mycobacteria (NTM) are another major cause of false-positive TST. [bib_ref] Tuberculin skin test survey in a pediatric population with high BCG vaccination..., Menzies [/bib_ref] [bib_ref] Latent tuberculosis infection, Jasmer [/bib_ref] The prevalence of NTM varies considerably between regions, countries, and even within countries. There are few studies of the prevalence of NTM in the Middle East. Two recent hospital-based studies in Kuwait and Saudi Arabia identified NTM in 18 of 325 (5.9%) and 70 of 286 (24.5%) specimens, respectively. [bib_ref] Species spectrum of nontuberculous mycobacteria isolated from clinical specimens in Kuwait, Mokaddas [/bib_ref] [bib_ref] Comparison of clinico-radiological features of patients with positive cultures of nontuberculous mycobacteria..., Bahammam [/bib_ref] An earlier similar study from Saudi Arabia gave an intermediate figure of 9%. [bib_ref] Tuberculosis in Saudi Arabia: Epidemiology and incidence of Mycobacterium tuberculosis and other..., Zaman [/bib_ref] A nationwide population-based survey, however, revealed a much lower figure of 0.004%. [bib_ref] Nationwide community survey of tuberculosis epidemiology in Saudi Arabia, Al-Kassimi [/bib_ref] A recent meta-analysis involving more than 18 studies found that NTM is not a clinically important cause of false-positive TST, particularly in areas of high TB prevalence. 28
## Serial tuberculin testing (conversion or boosting)
When repeated tuberculin testing has been performed, a substantial number of individuals may manifest an increased tuberculin reaction on their second test in the absence of any obvious exposure. It is now realized that this reflects an anamnestic response representing the restimulation of previously acquired immunity from earlier exposure. [bib_ref] Interpretation of repeated tuberculin tests: Boosting, conversion, and reversion, Menzies [/bib_ref] This phenomenon, termed "boosting", results from a previous mycobacterial exposure, including remote BCG vaccination, nontuberculous mycobacterial exposure, or remote infection with MTB. [bib_ref] Interpretation of repeated tuberculin tests: Boosting, conversion, and reversion, Menzies [/bib_ref] It is important to distinguish boosting from the phenomenon of tuberculin conversion which occurs after an initial tuberculin infection. This is because the risk of developing active tuberculosis in persons who manifest the "boosting" phenomenon is actually lower than those -Defective antigens because of improper storage (exposure to light or heat) or manufacturing -Contamination, improper dilution -Injection of too little tuberculin, or too superficial, or too deeply (should be intradermal) -Prolonged storage within the syringe before administration (more than 20 minutes) -Inexperienced or biased reader -Error in recording Biological factors: -Viral, bacterial, or fungal infections -HIV (especially if CD4 count <200) -Live virus vaccination within the past two months -Metabolic derangement, protein depletion, chronic renal failure, severe malnutrition, stress (surgery, burns) -Concurrent use of immunosuppressive drugs: (corticosteroids, TNF inhibitors, and others) -Very young <6 months or elder -Diseases of lymphoid organs: (lymphoma, chronic lymphocytic leukemia, sarcoidosis)
## Guidelines for ltbi
guidelines with an initial positive TST, and much lower than in persons with tuberculin conversion. [bib_ref] Interpretation of repeated tuberculin tests: Boosting, conversion, and reversion, Menzies [/bib_ref] In persons with conversion, the risk of disease is between 5% and 20% over the next two years alone. It is difficult to distinguish the phenomena of boosting and conversion simply on the basis of size, although if the second reaction is >15 mm, it is most likely to be conversion. If the second TST is performed soon (within two weeks) after the first and there is no intervening exposure, then boosting is most likely the cause for a positive TST. If the second test is performed months to years after the first, and there has been exposure to MTB (such as contacts of active cases), then the cause for a positive TST is considered to be recent TST conversion, indicating TB infection. [bib_ref] Interpretation of repeated tuberculin tests: Boosting, conversion, and reversion, Menzies [/bib_ref] In some clinical situations, it may be necessary to repeat the TST on a periodic basis. An initial two-step testing protocol is recommended in this situation. The most common situation is when persons enter an environment where there might be a risk of exposure to TB (e.g., persons entering professions or facilities with an increased risk of occupational exposure such as health care or prisons). [bib_ref] Interpretation of repeated tuberculin tests: Boosting, conversion, and reversion, Menzies [/bib_ref] If the initial TST is negative (<10 mm), then a second test should be performed 1 to 4 weeks later to elicit the booster phenomenon.Boosting can be seen after intervals as long as two years, but this phenomenon is maximal if the two tests are between one and four weeks apart, and a shorter interval is always more practical. If the second tuberculin test is negative (<10 mm), the individual can be considered to be truly negative. If on subsequent retesting, the tuberculin test is positive, this can be considered as a true conversion. This is strong evidence of new infection and should therefore be treated. [bib_ref] Interpretation of repeated tuberculin tests: Boosting, conversion, and reversion, Menzies [/bib_ref] A TST conversion is defined as a TST reaction of 10 mm or more plus as an increase of 6 mm or more of induration from the previous TST results within a twoyear period, regardless of age. [bib_ref] Interpretation of repeated tuberculin tests: Boosting, conversion, and reversion, Menzies [/bib_ref] [bib_ref] Booster effect of two-step tuberculin skin testing among hospital employees from areas..., Mazrou [/bib_ref] The ATS/CDC/ IDSA definition of conversion requires an increase of 10 mm or more from the previous TST result.This more stringent criteria will be more specific but less sensitive to detect conversion.
## Indications for tst and who should be treated
Routine screening of asymptomatic subjects is not recommended. [bib_ref] Latent tuberculosis infection, Nuermberger [/bib_ref] The risk-benefit ratio for treating LTBI depends principally on whether the individual is truly infected and is at substantial risk of developing active TB disease. Therefore, TST screening for LTBI should be reserved for those groups with a high risk of recent infection, or who are at high risk of progression from LTBI to TB disease as outlined in .
Normal healthy individuals with LTBI have an annual risk of 0.1% (1 per 1000) of developing active TB. [bib_ref] How much isoniazid is needed for prevention of tuberculosis in immunocompetent adults, Comstock [/bib_ref] Depending on the individual' s clinical condition, the annual risk of disease, if infected, can range from more than 10% for HIV patients to 1 to 2% for patients on hemodialysis. [bib_ref] Risk factors for tuberculosis in HIV-infected persons: A prospective cohort study: The..., Antonucci [/bib_ref] [bib_ref] Risk of tuberculosis in dialysis patients: Association of tuberculin and 2,4-dinitrochlorobenzene reactivity..., Christopoulos [/bib_ref] [bib_ref] Tuberculosis in dialyzed patients, Pradhan [/bib_ref] High-risk individuals are those whose risk for reactivation is at least six times higher than for normal, healthy individuals. [bib_ref] Risk factors for tuberculosis in HIV-infected persons: A prospective cohort study: The..., Antonucci [/bib_ref] [bib_ref] A prospective study of the risk of tuberculosis among HIV-infected patients, Guelar [/bib_ref] [bib_ref] A prospective study of the risk of tuberculosis among intravenous drug users..., Selwyn [/bib_ref] [bib_ref] Tuberculosis in maintenance haemodialysis patients. Study from an endemic area, Malhotra [/bib_ref] [bib_ref] The epidemiology of tuberculosis in gold miners with silicosis, Cowie [/bib_ref] [bib_ref] Risk factors for developing tuberculosis in HIV-1-infected adults from communities with a..., Wood [/bib_ref] [bib_ref] Recent studies in the epidemiology of tuberculosis, based on the risk of..., Sutherland [/bib_ref] [bib_ref] Controlled chemoprophylaxis trials in tuberculosis: A general review, Ferebee [/bib_ref] [bib_ref] Tuberculosis risk in persons with "fibrotic" x-ray lesions, Steinbrück [/bib_ref] Moderate-risk individuals are those whose risk for reactivation is 3 to 6 times higher than for normal, healthy individuals. [bib_ref] Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent, Keane [/bib_ref] [bib_ref] Antirheumatic drugs and the risk of tuberculosis, Brassard [/bib_ref] [bib_ref] Glucocorticoid use, other associated factors, and the risk of tuberculosis, Jick [/bib_ref] [bib_ref] The role of diabetes mellitus in the higher prevalence of tuberculosis among..., Pablos-Méndez [/bib_ref] [bib_ref] Incidence and coincidence of diabetes mellitus and pulmonary tuberculosis in a Swedish..., Silwer [/bib_ref] [bib_ref] Diabetes mellitus and pulmonary tuberculosis, Boucot [/bib_ref] [bib_ref] Incidence of pulmonary tuberculosis among diabetics, Kim [/bib_ref] [bib_ref] The prognosis of a positive tuberculin reaction in childhood and adolescence, Comstock [/bib_ref] Low-risk individuals are those at slightly increased risk for reactivation and whose risk is 1.5 to 3 times higher than for normal, healthy individuals. [bib_ref] Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body..., Palmer [/bib_ref] [bib_ref] Smoking and tuberculosis: An association overlooked, Maurya [/bib_ref] [bib_ref] Smoking and mortality from tuberculosis and other REFERENCES GUIDELINES FOR LTBI guidelines..., Gajalakshmi [/bib_ref] [fig_ref] Table 4: Relative risk for developing active tuberculosis by selected clinical conditions We recommend... [/fig_ref] shows the estimated risks for TB relative to healthy individuals in various conditions. Defining a positive tuberculin reaction is dependent on the size of the TST: ≥5 mm is considered positive in high-risk individuals whereas ≥10 mm is considered positive in moderate-risk individuals. For persons at low risk for TB and with high risk of exposure to NTM (for whom tuberculin testing is not generally indicated), ≥15 mm of induration is considered positive. Treatment for LTBI is contraindicated in patients with active TB disease and in patients with severe liver disease. 4
The principle indications and precautions in latent tuberculosis testing and treatment 1. The goal of testing for latent tuberculosis infection is to identify individuals who are at risk of new infection, and to identify individuals at increased risk of reactivation due to the biological factors listed in [fig_ref] Table 1: Causes of false-negative tuberculin skin testing Technical factors [/fig_ref] 5.1 If the radiograph is normal and the patient has no symptoms or physical findings consistent with TB, treatment of LTBI may be indicated. 5.2 If the radiograph is normal but the patient has a clinical presentation consistent with TB, further workup is indicated and treatment of LTBI should be delayed until active TB has been ruled out.
## If the radiograph is abnormal and consistent
with TB, specimens of sputum (using sputum induction if necessary) should be obtained. Starting treatment pending the culture results or waiting for culture results before starting therapy, is a clinical judgment dependent on benefit-risk considerations. 5.4 If a radiograph is abnormal but was taken more than three months prior to evaluation, a new radiograph should be performed at the time of evaluation. 5.5 If the abnormality on the chest radiograph is of questionable significance, consultation with an expert is recommended.
## Aims of and recommended regimens for ltbi treatment
The term, 'treatment of LTBI' has been adopted to highlight the fact that the patient is considered to be infected with live (although dormant) bacilli, which could cause active TB disease in the future, and that there is effective treatment available for this infection.
## Aim of treatment
Treatment of LTBI is intended to prevent the development of active TB disease. In the past, this has been referred to as ' chemoprophylaxis' or 'preventive therapy' . Latent tuberculosis infection is associated with a low burden of organisms; therefore, treatment of latent infection requires fewer drugs than active disease to decrease the risk of developing active tuberculosis without creating drug resistance. In most of the cases, use of a single antituberculosis agent is sufficient for the treatment of latent infection, but not for active disease. This regimen should be reserved for those individuals who cannot tolerate INH or for persons exposed to cases with resistance to INH, but susceptible to RIF.
- Rifampin (RIF) alone for four months is generally recommended for adults. - Rifampin alone for six months is generally recommended for children. [bib_ref] Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children..., Pediatrics [/bib_ref] - Rifabutin (RFB) may be substituted for rifampin in the above regimens in situations where rifampin cannot be given, such as in HIV-infected persons taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors. 4
## D. rifampin and pyrazinamide for two months-not recommended
This regimen is not recommended due to fatal hepatotoxicity. Therefore, it should generally NOT be offered as initial therapy to persons with LTBI for either HIVnegative or HIV-infected persons.
## Monitoring of treatment
- Education about adverse effects associated with the treatment of LTBI, with advice to stop treatment and promptly seek medical evaluation if serious adverse effects occur. - Follow-up evaluation at least monthly, including careful questioning and a brief physical examination to assess for evidence of hepatitis or other adverse effects, symptoms of TB disease, and adherence to the regimen. - All persons receiving treatment for LTBI should be monitored clinically for symptoms and signs of adverse drug reactions, beginning at the first initial aminase concentrations exceed three times the upper limit of the normal range when accompanied by symptoms, or five times the upper limit of the normal range in asymptomatic patients.
## Treatment of latent tuberculosis in special situations
## Pregnancy/lactation
Pregnancy has minimal influence on the pathogenesis of TB and there is no evidence to suggest a greater risk of progression of LTBI to active disease during pregnancy.The treatment of LTBI during pregnancy remains controversial. However, under ordinary circumstances, physicians should delay treatment until two to three months after delivery.However, for pregnant women who are HIV-positive or at high risk of progression to active disease and to prevent its consequences on the RIF + PZA: Generally should not be offered for treatment of LTBI.
mother and the fetus, initiation of therapy should not be delayed on the basis of pregnancy alone, even during the first trimester.INH can be given to pregnant women and is not toxic to the unborn child, even during the first four months of gestation. 4,7,61-66 Pregnant women taking INH should receive vitamin B6. Breastfeeding is not contraindicated when the mother is being treated for LTBI. 4
## Treatment of hiv-infected persons
Recommendations for HIV-infected adults are in general similar those for HIV-negative adults, although the quality of evidence and strengths of the recommendations vary. [bib_ref] Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine..., Vernon [/bib_ref] [bib_ref] Identification and management of tuberculosis, Jerant [/bib_ref] [bib_ref] Preventive therapy for tuberculosis in HIV-infected persons: International recommendations, research, and practice, De Cock [/bib_ref] If isoniazid is chosen for treatment of LTBI in persons with HIV infection, nine months of therapy is recommended rather than six months. In addition, rifampin should generally be avoided in persons who are taking protease inhibitors (PIs) or NNRTIs.However, the management of persons co-infected with HIV and LTBI can be highly complex. Our recommendation is that management should be attempted in consultation with physicians who are experts in the treatment of TB and HIV.
## Persons with fibrotic lesions/suspected disease
Patients who have a chest radiograph demonstrating upper lobe fibronodular changes or scarring compatible with previous TB and a positive TST (>5 mm) without evidence of active disease and no history of treatment for TB, are considered at high risk of reactivation and should receive treatment. [bib_ref] Tuberculosis risk in persons with "fibrotic" x-ray lesions, Steinbrück [/bib_ref] [bib_ref] Tuberculosis in a cohort of Southeast Asian Refugees: A five-year surveillance study, Nolan [/bib_ref] Persons with evidence suggestive of healed, primary TB (i.e., calcified solitary pulmonary nodules, calcified hilar lymph nodes, and apical pleural capping) have only slightly increased risk for TB (about double that of the healthy). Their risk for TB and need for treatment of LTBI should be determined by considering other risk factors. 4
## Renal failure
Patients with chronic renal failure are at a high risk of reactivation (relative risk, 10.0-25.3) and all patients with positive reaction are recommended for therapy. [bib_ref] Tuberculosis in maintenance haemodialysis patients. Study from an endemic area, Malhotra [/bib_ref] However, anergic reaction is common among patients requiring hemodialysis, even in patients resident in endemic areas, so that TST may not be very sensitive to detect LTBI. In the absence of randomized trials that are specific for this population, nine months of isonizid (INH) is recommended. 4
## Children and adolescents
Infants and young children (i.e., those younger than five years of age) with LTBI are at high risk of progression to active TB. If untreated, they have up to 40% likelihood of developing active TB. [bib_ref] The prognosis of a positive tuberculin reaction in childhood and adolescence, Comstock [/bib_ref] [bib_ref] Preventive effects of isoniazid in the treatment of primary tuberculosis in children, Mount [/bib_ref] In particular, young children in contact with adults with active TB (i.e., household contacts) are at high risk for developing TB disease and should therefore be targeted for LTBI therapy (after ruling out active TB). The risk of progression decreases gradually through childhood. Infants and young children are more likely than older children and adults to develop life-threatening forms of TB, especially meningeal and disseminated disease. INH therapy for LTBI is more effective for children than adults, with risk reduction of 70-90%. Infants, children, and adolescents generally tolerate INH better than adults. [bib_ref] Preventive effects of isoniazid in the treatment of primary tuberculosis in children, Mount [/bib_ref] The only recommended regimen for the treatment of LTBI in HIV-negative children is a nine-month course of INH as self-administered daily therapy or by DOT twice weekly.Routine administration of pyridoxine is not recommended for children taking INH, but should be given to (1) breastfeeding infants, (2) children and adolescents with diets likely to be deficient in pyridoxine, and (3) children who experience paresthesias while taking INH. RIF alone has been used for the treatment of LTBI in infants, children, and adolescents when INH could not be tolerated, or when the child has had contact with a patient infected with an INH-resistant but RIF-susceptible organism. If RIF alone is used, then a six-month treatment regimen is recommended. [bib_ref] Preventive effects of isoniazid in the treatment of primary tuberculosis in children, Mount [/bib_ref] Liver disease Patients with chronic liver disease with LTBI pose a special problem, as all available regimens are potentially hepatotoxic. Four months of RIF may be safer although the efficacy of such a regimen has not been established. [bib_ref] Safety of treatment of latent tuberculosis infection in compensated cirrhotic patients during..., Jahng [/bib_ref] [bib_ref] Safety and efficacy of isoniazid chemoprophylaxis administered during liver transplant candidacy for..., Singh [/bib_ref] However, frequent clinical and laboratory monitoring for drug side effects is prudent.
## Solid organ transplantation
Solid organ transplantation is associated with a very high risk of LTBI reactivation to active TB. The incidence of infection among such patients is estimated to be 20-74 times that for the general population. [bib_ref] The high incidence of tuberculosis among renal transplant recipients in India, Sakhuja [/bib_ref] [bib_ref] Mycobacterium tuberculosis in lung transplant recipients, Miller [/bib_ref] [bib_ref] Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant..., Aguado [/bib_ref] [bib_ref] Rifampin preventive therapy for tuberculosis in Boston's homeless, Meyers [/bib_ref] They should be treated for LTBI if their TSTs are positive. Safety of INH remains a concern, especially in liver transplant recipients, but is generally safe as long as pretreatment liver transaminase levels are normal. Common strategies include INH for nine months or RIF for four months. Patients should be treated during the pretransplant period, if possible.
## Contacts of patients with drug-susceptible tuberculosis index case
Persons who are contacts of patients with drug-susceptible TB and who have positive tuberculin skintest reactions should be treated with one of the recommended regimens listed above.In addition, some tuberculin-negative close contacts who are at high risk to develop severe active disease (e.g., children younger than five years of age) should be treated and another skin test performed a few weeks after contact has ended. If the repeat skin test is negative, the treatment should be discontinued. [bib_ref] Latent tuberculosis infection, Nuermberger [/bib_ref] Immunosuppressed persons, including those with HIV infection, who are close contacts of persons with active TB, should also receive treatment, even if repeat skin testing remains negative. 4,31
## Contacts of index cases with isoniazid-resistant tuberculosis
For TST-positive contacts of index or source cases with INH-resistant TB, we recommend treatment with four months of RIF; this appeared to be effective for tuberculin converters in two outbreaks of INH-resistant TB. 80, [bib_ref] Rifampin preventive therapy for tuberculosis infection: experience with 157 adolescents, Villarino [/bib_ref] In situations in which RIF cannot be used, rifabutin can be substituted.
## Contacts of patients with a multidrug-resistant tuberculosis index case
Treatment of LTBI after possible exposure to multidrug-resistant TB has not been evaluated in a randomized trial. For those who are at high risk of progression to active TB, preventive therapy with two drugs to which the organism is expected to be susceptible is recommended. Ideally, the selection of drugs should be guided by in vitro susceptibility test results from the isolate to which the patient was exposed and is presumed to be infected.
For persons who are likely to be infected with MDR-TB and are at high risk of developing TB, treatment should be with at least two active agents. Pyrazinamide (PZA) and ethambutol (EMB) or PZA and fluoroquinolones (FQN) have been recommended for 6 to 12 months. 82 However, the latter regimen is very poorly tolerated; 83 hence, we recommend an FQN (levaquin or moxifloxacin) and EMB as the preferred regimen for adults. PZA and EMB are recommended for 9 to 12 months for children because FQN use is contraindicated in pediatric patients. [bib_ref] Latent tuberculosis infection, Nuermberger [/bib_ref] All persons with suspected latent MDR-TB infection should be followed for at least two years, regardless of the treatment regimen. When FQN and EMB can-not be used, experts recommend using a combination of two other drugs to which the infecting organism is likely to be susceptible.
## Use of interferon release assays
A major advance in recent times has been the development of T-cell-based interferon-gamma release assays (IGRAs). [bib_ref] Metaanalysis: new tests for the diagnosis of latent tuberculosis infection: Areas of..., Menzies [/bib_ref] [bib_ref] Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: An..., Pai [/bib_ref] IGRAs are in vitro tests that are based on interferon-gamma (IFN-γ) release after stimulation by antigens (such as early secreted antigenic target 6 [ESAT-6] and culture filtrate protein 10 [CFP-10]) which are more specific to MTB than the purified protein derivative (PPD). Two IGRAs are currently available as commercial kits that are US Food and Drug Administration (FDA)-approved, and marked for use in Europe: the QuantiFERON-TB Gold® In-Tube (QFT) assay (Cellestis Ltd., Carnegie, Australia) and the T-SPOT.TB® assay (Oxford Immunotec, Abingdon, UK). Of the two commercial tests, the QFT assay is simple and easy to use because of its ELISA format, and less expensive.
There are many potential advantages of these new tests. They are standardized and quality-controlled laboratory tests that provide results in a single patient visit. They do not have a 'booster' effect, and can be repeated without the need for two-step testing. They have excellent specificity and are unaffected by BCG and NTM (estimated specificity >98%). [bib_ref] Metaanalysis: new tests for the diagnosis of latent tuberculosis infection: Areas of..., Menzies [/bib_ref] [bib_ref] Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: An..., Pai [/bib_ref] The high specificity of IGRAs is likely to be useful in BCG-vaccinated individuals, particularly in countries where TST specificity is compromised by BCG vaccination after infancy or by multiple BCG vaccinations.
Sensitivity of IGRAs and TST is not consistent across tests and populations, but IGRAs appear to be at least as sensitive as the TST (estimated with active TB as the surrogate reference standard). [bib_ref] Metaanalysis: new tests for the diagnosis of latent tuberculosis infection: Areas of..., Menzies [/bib_ref] [bib_ref] Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: An..., Pai [/bib_ref] However, IGRAs should not be used to diagnose active TB because they cannot distinguish between LTBI and active disease.
IGRAs have some disadvantages, including higher material cost, the need for an equipped laboratory, and a requirement to draw peripheral blood. Evidence is still limited on the prognostic (predictive) value of these tests, and their added value in TB diagnosis and control. Furthermore, the interpretation of IGRA conversions and reversions is unclear, and evidence is rather limited in children and immunocompromised populations. Many studies on IGRA are ongoing in this area to properly define the role of IGRA in day-to-day clinical practice. [bib_ref] T-cell assays for the diagnosis of latent tuberculosis infection: Moving the research..., Pai [/bib_ref]
## Use of igra for the diagnosis of latent tb infection
The use of IGRAs is steadily increasing in low or intermediate incidence countries. More than a dozen countries (e.g., USA, UK, Canada, Germany, France, Switzerland, Japan, Netherlands) now have at least one guideline or statement on the use of IGRAs. There is considerable diversity in how various countries currently recommend and use IGRAs. For example, the CDC guidelines for the USA recommend using either TST or IGRA for LTBI testing. In contrast, many countries (e.g., UK, Canada, Spain, Italy) recommend a two-step approach where TST is done first, followed by IGRA. Globally, the two-step approach seems to be the most popular and possibly a very cost-effective strategy. However, because of the potential boosting effect of TST on IGRA results, [bib_ref] A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients..., Van Zyl-Smit [/bib_ref] it may be best to collect blood for IGRA at the time the TST is read (i.e., within three days of placing PPD).
## Recommendations
1. IGRAs should not be used to diagnose active TB in adults. In children, they may be used as an adjunct test, in combination with TST, chest x-ray, and microbiological investigations. A negative IGRA alone should not be used to rule out active TB. 2. In BCG-vaccinated individuals (adults and children), IGRAs may be used to confirm a positive TST result (i.e., to check if the TST result is a false positive). If a positive TST result is confirmed by a positive IGRA result, LTBI treatment should be initiated after ruling out active TB. 3. In immunocompromised patients, if a false-negative TST result is suspected, IGRAs may be used to rule out LTBI.
# Conclusions
Saudi Arabia is a country of medium prevalence for TB infection. The TST remains a useful tool in the identification of subjects with latent TB infection. NTM infection and BCG vaccination (routinely given in infancy) do not interfere with the interpretation of the test in adolescents and adults. Patients at high risk of developing active TB should be treated with the standard regimens advocated in this statement after due care is taken in excluding active TB disease.
[table] Table 1: Causes of false-negative tuberculin skin testing Technical factors: (potentially correctable) [/table]
[table] Table 2 Table 3: Indications for tuberculin skin testing.A. Individuals with increased risk for new infection: (all patients should be tested regardless of age) -Close contacts of persons with active pulmonary TB -Persons whose tuberculin skin tests have converted to positive (≥10 mm induration and >6 mm increase) within the past two years -Persons who live or work in clinical or institutional settings where TB exposure may Children four years of age 3. Low risk: test not indicated Target for tuberculin skin testing and who should be considered for treatment. Completion of therapy is based on the total number of doses administered, not the duration of therapy alone. iii. Treatment interruptions of more than two months require another evaluation to exclude active TB before restarting therapy. INH for nine months has not been compared directly with daily administration but is considered to be an acceptable alternative, provided all doses of therapy are directly observed. 4b. Six months INH alone-acceptable alternative:• INH may be given for six months if there are any concerns about side effects or adherence. [/table]
[table] Table 4: Relative risk for developing active tuberculosis by selected clinical conditions We recommend withholding INH if serum trans- [/table]
[table] Table 5: Recommended drug regimens for the treatment of LTBI. [/table]
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Pulmonary tuberculosis is a common disease in Saudi Arabia. As most cases of tuberculosis are due to reactivation of latent infection, identification of individuals with latent tuberculosis infection (LTBI) who are at increased risk of progression to active disease, is a key element of tuberculosis control programs. Whereas general screening of individuals for LTBI is not cost-effective, targeted testing of individuals at high risk of disease progression is the right approach. Treatment of those patients with LTBI can diminish the risk of progression to active tuberculosis disease in the majority of treated patients. This statement is the first Saudi guideline for testing and treatment of LTBI and is a result of the cooperative efforts of four local Saudi scientific societies. This Guideline is intended to provide physicians and allied health workers in Saudi Arabia with the standard of care for testing and treatment of LTBI.
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5777bbdc1a56e057ab80441eb69b2e1f07bd1e9c
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pubmed
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Follow-up after treatment for head and neck cancer: United Kingdom National Multidisciplinary Guidelines
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Follow-up after treatment for head and neck cancer: United Kingdom National Multidisciplinary Guidelines
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. In the absence of high-level evidence base for follow-up practices, the duration and frequency are often at the discretion of local centres. By reviewing the existing literature and collating experience from varying practices across the UK, this paper provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition.Recommendations- Patients should be followed up to a minimum of five years with a prolonged follow-up for selected patients. (G) - Patients should be followed up at least two monthly in the first two years and three to six monthly in the subsequent years. (G) - Patients should be seen in dedicated multidisciplinary head and neck oncology clinics. (G) - Patients should be followed up by dedicated multidisciplinary clinical teams. (G) - The multidisciplinary follow-up team should include clinical nurse specialists, speech and language therapists, dietitians and other allied health professionals in the role of key workers. (G) - Clinical assessment should include adequate clinical examination including fibre-optic rigid or flexible nasopharyngolaryngoscopy. (R) - Magnetic resonance imaging and positron emission tomography combined with computed tomography imaging should be used when recurrence is suspected. (R) - Narrow band imaging can be used in the follow-up in selected sites. (R) - Second primary tumours should be part of rationale of follow-up and therefore adequate screening strategies should be used to detect them. (G) - Patients should be educated with regard to the appearance and detection of recurrences. (G) - Patients with persistent pain should be investigated to exclude recurrent disease. (R) - Patients should be offered support with tobacco and alcohol cessation services. (R)
# Introduction
It is accepted that the follow-up of patients who had treatment for head and neck cancers is a fundamental part of their care. [bib_ref] European Laryngological Society. ELS Recommendations for the follow-up of patients treated for..., Simo [/bib_ref] [bib_ref] Current trends in the follow-up of Head and Neck Cancer patients in..., Joshi [/bib_ref] [bib_ref] The follow-up of patients with head and neck cancer: an analysis of..., Kothari [/bib_ref] [bib_ref] Post-therapeutic surveillance strategies in head and neck squamous cell carcinoma, Digonnet [/bib_ref] The reasons of post-treatment follow-up include:
- Evaluation of treatment response - Early identification of recurrence Controversy exists in how these aims are achieved. [bib_ref] The dilemma of follow-up in head and neck cancer, Haas [/bib_ref] [bib_ref] On completion of curative treatment of head and neck cancer: why follow-up?, Morton [/bib_ref] Increasing efforts are being made to rationalise the structure and timing of head and neck follow-up clinics.
The general structure of follow-up clinics is to have initial high-frequency visits especially in the first two years when the risk of loco-regional recurrence is known to be high and then reduce frequency, with follow-up often finishing at five years. In the UK, the structure of these clinics is often arbitrary and reflects institutional and clinician-led practices with very little evidence to support any one system.
Evidence to support follow-up for early detection of tumour recurrence is lacking. However, there is a belief that follow-up clinics have inherent value and to date all published studies recognise this fact.In order to rationalise follow-up, patients could be divided into low and high risk. This is well recognised in thyroid cancer, but it is not the case in all other types of head and neck cancer especially squamous cell carcinoma (SCC). It is a belief that, this categorisation could help to determine which patients should be followed for more than five years. It would also help to establish which screening test may be needed in order to detect recurrence or second primaries.
## General considerations
## Length
The length of follow-up is generally five years although there are many clinicians who follow-up patients for longer periods or even for life. [bib_ref] Postradiotherapy surveillance practice for head and neck squamous cell carcinoma -too much..., Schwartz [/bib_ref] Follow-up of patients over five years would be justified for the following groups: high-risk patients, specific tumours (e.g. adenoid cystic carcinomas), patients who have undergone complex treatments who require on-going rehabilitation and support, detection of new primary tumours and patient preference. Fear of recurrence is prevalent in cancer patients and continued attendance at clinic helps to mitigate this.
## Recommendation
- Patients should be followed up to a minimum of five years with a prolonged follow-up for selected patients (G)
## Frequency
At present, there is no evidence that high frequency of follow-up visits confers any benefit in terms of morbidity and mortality. However, there is evidence that the majority of clinicians in the UK support the followup of patients, in regular high-frequency intervals in the first two years when the risk of locoregional recurrence is high followed by a decrease in frequency after the second year. The follow-up in the first two years should be between four to eight weeks and from three to six months thereafter. 7
## Recommendation
- Patients should be followed up at least two monthly in the first two years and three to six monthly in the subsequent years (G)
## Setting
At present, 90 per cent of the clinicians treating head and neck cancer in the UK see the patients in dedicated head and neck clinics for the duration of the follow-up.
## Recommendation
- Patients should be seen in dedicated multidisciplinary head and neck oncology clinics (G)
Type of health professional At present patients are followed up by their treating clinicians and their teams. Allied health professionals including speech and language therapists, dieticians and clinical nurse specialists may offer specific follow-up in their areas of expertise, but this is usually in addition to the medical follow-up. The introduction of the clinical nurse specialist and the key worker role in the management of patients with head and neck cancer has opened lines of communication between the patient and family and the clinical team [bib_ref] Follow-up in head and neck cancer: patient's perspective, Trinidade [/bib_ref] should any problems arise.
## Recommendations
- Patients should be followed up by the dedicated multidisciplinary clinical teams (G) - The multidisciplinary follow-up team should include clinical nurse specialists, speech and language therapists, dietitians and other allied health professionals in the role of key workers (G)
## Clinical assessment
Traditionally, clinical assessment has been the most important aspect of the follow-up in patients treated for head and neck cancer. The clinical evaluation is done by inspection, palpation and at present with fibre-optic rigid or flexible nasopharyngolaryngoscopy. Rigid stroboscopy can also be used in patients who have been treated for laryngeal cancer.
## Recommendation
- Clinical assessment should include adequate clinical examination, including fibre-optic rigid or flexible nasopharyngolaryngoscopy (R)
## Screening investigations
Currently there is evidence that magnetic resonance imaging (MRI) and positron emission tomography combined with computed tomography (PET-CT) scanning are superior at detecting recurrence and second primaries. [bib_ref] Can (18)F-FDG PET/CT reliably assess response to primary treatment of head and..., Ul-Hassan [/bib_ref] [bib_ref] A systematic review and meta-analysis of the role of positron emission tomography..., Isles [/bib_ref] This is especially true in some tumour sites such as the nasopharynx and following treatment with chemo-radiation. Positron emission tomography combined with computed tomography has also the advantage of being a systemic evaluation. Diffusion-weighted MR has been recently applied with promising results; however, its accurate interpretation requires specific training and experience. Narrow band imaging 12 (NBI), possibly associated with high definition television technology, has been shown to be an adjunctive imaging tool due to its specific capability to selectively address superficial persistences and/or recurrences or second primary tumours by enhancing their pathognomonic neoangiogenetic pattern. It has been reported that its use can detect 18 per cent more true positive laryngeal cancerous lesions than conventional white light endoscopy. This is true even after radiotherapy (RT) or chemoradiotherapy, due to the high accuracy (98 per cent) of NBI in differentiating between neoplastic disease and post-RT inflammatory and/or cicatricial changes.
## Recommendations
- Magnetic resonance imaging and PET-CT imaging should be used when recurrence is suspected (R) - Narrow band imaging can be used in the follow-up in selected sites (R)
## Second primary tumours
The incidence of second primary tumours varies between 5 and 12 per cent at five years. There is good evidence to indicate that patients with head and neck SCC have an increased risk of developing second primary malignant tumours. [bib_ref] Second neoplasm in patients with head and neck cancer, Leon [/bib_ref] [bib_ref] Risk of third and fourth tumours in patients with head and neck..., Leon [/bib_ref] This risk appears to be constant throughout the follow-up period, with an incidence ranging from 2 to 4 per cent per year. Traditionally, patients undergoing follow-up for head and neck cancer underwent a chest radiograph every year. However, there is evidence that these have not been able to identify metastasis with any confidence.
## Recommendation
- Second primary tumours should be part of rationale of follow-up and therefore adequate screening strategies should be used to detect them (G)
## Specific considerations
Second-look microlaryngoscopy In laryngeal cancer, especially in those patients treated with transoral laser microsurgical excision, it is advisable to perform second-look microlaryngoscopy, [bib_ref] Gunitinas-Lichius O. Second-look microlaryngoscopy to detect residual carcinoma in patients after laser..., Preuss [/bib_ref] especially in scenarios where there is lack of agreement between the intraoperative and histological findings regarding the completeness of resection. The rationale of this is to provide evidence of complete resection, detect residual tumour and to perform further treatment should this be necessary.
Patients with persistent or recurrent pain without clinical evidence of disease Pain complaints must be regarded as a serious warning sign of recurrent disease during follow-up of HNC patients, [bib_ref] Consensus statement on management in the UK: transoral laser assisted microsurgical resection..., Bradley [/bib_ref] [bib_ref] The role of pain in head and neck cancer recurrence and survivorship, Scharpf [/bib_ref] even in the absence of an endoscopically visible persistence and/or recurrence. Persistent neck pain can be the first symptom of recurrent disease in 70 per cent of patients and can be an independent predictor of both recurrence and five-year survival rate. Pain should always prompt the clinician to initiate a thorough set of investigations, both by imaging and/ or endoscopy under general anaesthesia, in order to reduce possible diagnostic delays. Pain without endoscopic evidence of disease is more frequently encountered after RT or chemoradiotherapy, but it is possible even after surgery. This symptom is usually caused by submucosal disease recurrence possibly hidden by oedematous mucosa, or associated with chondritis, chondronecrosis or osteonecrosis as a result of previous treatments.
## Tumour markers
There is no evidence that the use of tumour markers is any value in the follow-up of patients with head and neck SCCs. The use of tumour markers in the followup of patients with thyroid cancer is addressed elsewhere in these guidelines.
## Patient education
It has been recognised that the education of patients plays an essential role in the detection of recurrences.
The vast majority of recurrences are diagnosed following the occurrence of new symptoms and thus patients should be educated about the need to seek help when appropriate. It has also been recognised that continuing smoking and alcohol drinking increases the risk of recurrence and second primary tumours. It is therefore imperative that patients are advised and offered support with regards to the detrimental effects of tobacco smoking and alcohol addiction.
## Recommendations
- Patients should be educated with regards to the appearance and detection of recurrences (G) - Patients with persistent pain should investigate to exclude recurrent disease (R) - Patients should be offered support with tobacco and alcohol cessation services (R)
## Key points
- The aims of follow up of patients after treatment for head and neck cancers are manifold - The frequency of follow-up is higher in the first two years, with reduced frequency subsequently, finishing at five years - Medical, nursing and allied health professionals all play important roles in providing follow up care - Change in patient symptoms during follow up is the most frequent indication of recurrent disease and must be regarded seriously, even if clinical examination reveals no abnormalities.
[fig] •: Early detection of new primary tumours Monitoring and management of complications Optimisation of rehabilitation Provision of support to patients and their families. [/fig]
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https://www.cambridge.org/core/services/aop-cambridge-core/content/view/F50B9DE1A5EF8CAD06C095A5136E58F7/S0022215116000645a.pdf/div-class-title-follow-up-after-treatment-for-head-and-neck-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf
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Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. In the absence of high-level evidence base for follow-up practices, the duration and frequency are often at the discretion of local centres. By reviewing the existing literature and collating experience from varying practices across the UK, this paper provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition. Recommendations • Patients should be followed up to a minimum of five years with a prolonged follow-up for selected patients. (G) • Patients should be followed up at least two monthly in the first two years and three to six monthly in the subsequent years. (G) • Patients should be seen in dedicated multidisciplinary head and neck oncology clinics. (G) • Patients should be followed up by dedicated multidisciplinary clinical teams. (G) • The multidisciplinary follow-up team should include clinical nurse specialists, speech and language therapists, dietitians and other allied health professionals in the role of key workers. (G) • Clinical assessment should include adequate clinical examination including fibre-optic rigid or flexible nasopharyngolaryngoscopy. (R) • Magnetic resonance imaging and positron emission tomography combined with computed tomography imaging should be used when recurrence is suspected. (R) • Narrow band imaging can be used in the follow-up in selected sites. (R) • Second primary tumours should be part of rationale of follow-up and therefore adequate screening strategies should be used to detect them. (G) • Patients should be educated with regard to the appearance and detection of recurrences. (G) • Patients with persistent pain should be investigated to exclude recurrent disease. (R) • Patients should be offered support with tobacco and alcohol cessation services. (R)
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4e066f10b1d56075beab5d879f52225f660a54ed
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pubmed
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Reporting randomised trials of social and psychological interventions: the CONSORT-SPI 2018 Extension
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Reporting randomised trials of social and psychological interventions: the CONSORT-SPI 2018 Extension
Background: Randomised controlled trials (RCTs) are used to evaluate social and psychological interventions and inform policy decisions about them. Accurate, complete, and transparent reports of social and psychological intervention RCTs are essential for understanding their design, conduct, results, and the implications of the findings. However, the reporting of RCTs of social and psychological interventions remains suboptimal. The CONSORT Statement has improved the reporting of RCTs in biomedicine. A similar high-quality guideline is needed for the behavioural and social sciences. Our objective was to develop an official extension of the Consolidated Standards of Reporting Trials 2010 Statement (CONSORT 2010) for reporting RCTs of social and psychological interventions: CONSORT-SPI 2018. Methods: We followed best practices in developing the reporting guideline extension. First, we conducted a systematic review of existing reporting guidelines. We then conducted an online Delphi process including 384 international participants. In March 2014, we held a 3-day consensus meeting of 31 experts to determine the content of a checklist specifically targeting social and psychological intervention RCTs. Experts discussed previous research and methodological issues of particular relevance to social and psychological intervention RCTs. They then voted on proposed modifications or extensions of items from CONSORT 2010. Results: The CONSORT-SPI 2018 checklist extends 9 of the 25 items from CONSORT 2010: background and objectives, trial design, participants, interventions, statistical methods, participant flow, baseline data, outcomes and estimation, and funding. In addition, participants added a new item related to stakeholder involvement, and they modified aspects of the flow diagram related to participant recruitment and retention.Conclusions: Authors should use CONSORT-SPI 2018 to improve reporting of their social and psychological intervention RCTs. Journals should revise editorial policies and procedures to require use of reporting guidelines by authors and peer reviewers to produce manuscripts that allow readers to appraise study quality, evaluate the applicability of findings to their contexts, and replicate effective interventions.
# Background
When feasible and appropriate, randomised controlled trials (RCTs) are used to evaluate social and psychological interventions, and to inform policy and practice decisions [bib_ref] The Campbell collaboration Social, Psychological, Educational and Criminological Trials Register (C2-SPECTR) to..., Petrosino [/bib_ref] [bib_ref] Using evidence to improve policy and practice: the UK what works Centres, Bristow [/bib_ref] [bib_ref] Systematic reviews in the bulletin, Clark [/bib_ref] [bib_ref] Reflections on the genesis of the Campbell collaboration, Petrosino [/bib_ref]. To use reports of RCTs, readers need information about their design, context, conduct, analysis, results, and interpretation. Like other types of research, RCTs can provide biased estimates of intervention effects if they are not conducted well, and syntheses of these RCTs may be biased if the trials are not reported completely [bib_ref] Randomised controlled trials for policy interventions: a review of reviews and meta-regression, Oliver [/bib_ref] [bib_ref] Metabias: a challenge for comparative effectiveness research, Goodman [/bib_ref]. Consequently, accurate, complete, and transparent reports of RCTs are essential for maximising their value [bib_ref] Increasing value and reducing waste in biomedical research: Who's listening?, Moher [/bib_ref] , allowing replication studies to build the evidence base [bib_ref] Better reporting of interventions: template for intervention description and replication (TIDieR) checklist..., Hoffmann [/bib_ref] , and facilitating the comparison and implementation of effective interventions in real-world contexts [bib_ref] Developing standards for reporting implementation studies of complex interventions (StaRI): a systematic..., Pinnock [/bib_ref].
Recent reviews have shown that reports of RCTs of social and psychological interventions are often insufficiently accurate, comprehensive, and transparent to replicate trials, assess their quality, and understand for whom and under what circumstances an intervention should be delivered [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref] [bib_ref] Developing and evaluating complex interventions: the new Medical Research Council guidance, Craig [/bib_ref] [bib_ref] Specifying and reporting complex behaviour change interventions: the need for a scientific..., Michie [/bib_ref]. For instance, authors often do not report data on intervention implementation [bib_ref] Reporting implementation in randomized trials: proposed additions to the consolidated standards of..., Mayo-Wilson [/bib_ref] , such as the specific techniques employed by intervention providers; adaptation or tailoring of the intervention to specific groups or individuals; materials used to support intervention implementation; and participant behaviours [bib_ref] What is missing from descriptions of treatment in trials and reviews?, Glasziou [/bib_ref]. Inadequate reporting can make it difficult for researchers to replicate trials, for intervention developers to design effective interventions, and for providers to use the interventions in practice [bib_ref] Promoting an open research culture, Nosek [/bib_ref]. A lack of sharing trial protocols, outcome data, and materials required to implement social and psychological interventions has been identified as a major reason for limitations in the ability of behavioural and social scientists to reproduce trial procedures, replicate trial results, and effectively synthesise evidence on these interventions [bib_ref] Promoting an open research culture, Nosek [/bib_ref] [bib_ref] Replication and contradiction of highly cited research papers in psychiatry: 10-year follow-up, Tajika [/bib_ref] [bib_ref] Behaviour change techniques: the development and evaluation of a taxonomic method for..., Michie [/bib_ref]. The review of trials that we conducted in the first phase of this project (n = 239) revealed that many CONSORT items were poorly reported in the behavioural and social science literature. Such items included identification as a randomised trial in titles; information about masking, methods for sequence generation, and allocation concealment; and details about the actual delivery of the interventions. Only 11 of 40 journals we examined referenced reporting guidelines in 'Instructions to Authors' [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref]. This inefficient use of resources for research likely contributes to the suboptimal dissemination of potentially effective interventions [bib_ref] Increasing value and reducing waste in biomedical research: Who's listening?, Moher [/bib_ref] [bib_ref] Reducing waste from incomplete or unusable reports of biomedical research, Glasziou [/bib_ref] , overestimations of intervention efficacy [bib_ref] Does publication bias inflate the apparent efficacy of psychological treatment for major..., Driessen [/bib_ref] , and research waste of investment to the order of hundreds of billions of dollars [bib_ref] Reducing waste from incomplete or unusable reports of biomedical research, Glasziou [/bib_ref]. As in other areas of research, transparent and detailed reporting of social and psychological intervention RCTs is needed to minimise reporting biases and maximise the credibility and utility of this research evidence [bib_ref] Publication and other reporting biases in cognitive sciences: detection, prevalence, and prevention, Ioannidis [/bib_ref] [bib_ref] Improving transparency and reproducibility: registering clinical trials of psychological interventions prospectively and..., Cybulski [/bib_ref].
# The consort statement
To address the problems in scientific manuscripts outlined above, reporting guidelines have been developed that include minimum standards for describing specific types of research [bib_ref] Guidance for developers of health research reporting guidelines, Moher [/bib_ref]. Reporting guidelines do not provide recommendations for study design or conduct. Instead, they focus on reporting what was done (methods) and what was found (results). In 1996, a group of scientists and journal editors published the CONSORT (Consolidated Standards of Reporting Trials) Statement to help authors report RCTs in biomedicine completely and transparently [bib_ref] Improving the quality of reporting of randomized controlled trials. The CONSORT statement, Begg [/bib_ref]. In light of feedback and emerging evidence, the CONSORT Group updated this reporting guideline in 2001 [bib_ref] The CONSORT statement: revised recommendations for improving the quality of reports of..., Moher [/bib_ref] and again in 2010. CONSORT 2010 includes a 25-item checklist and flow diagram. An extensive Explanation and Elaboration (E&E) document serves as a user manual that explains the rationale behind each checklist item, provides the methodological rationale for each checklist item, and gives examples of trial details adequately reported in accordance with each checklist item [bib_ref] Guidance for developers of health research reporting guidelines, Moher [/bib_ref].
The CONSORT Statement has had an important impact in medicine. An early evaluation showed that reporting in the BMJ, Lancet, and JAMA improved after the publication of the first CONSORT Statement [bib_ref] Use of the CONSORT statement and quality of reports of randomized trials:..., Moher [/bib_ref]. Systematic reviews comparing articles in medical journals endorsing CONSORT compared with journals not endorsing it found that the former are significantly more likely to describe the method of sequence generation, allocation concealment, and participant flow [bib_ref] Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of..., Turner [/bib_ref]. These effects remain even after controlling for the impact factor of the journals and study outcomes [bib_ref] The reporting of methodological factors in randomized controlled trials and the association..., Devereaux [/bib_ref]. Over 600 journals and prominent editorial groups (including the International Committee of Medical Journal Editors, the Council of Science Editors, and the World Association of Medical Editors) officially endorse the CONSORT Statement.
## Scope of consort-spi 2018
The CONSORT 2010 Statement focuses on individually randomised two-group parallel trials. To address the varying amount of additional information needed for different types of trial, the CONSORT Group has created extensions (http://www.consort-statement.org/ extensions). These extensions target different types of trial designs, such as cluster randomised [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] , noninferiority [bib_ref] Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010..., Piaggio [/bib_ref] , pragmatic [bib_ref] Improving the reporting of pragmatic trials: an extension of the CONSORT statement, Zwarenstein [/bib_ref] , N-of-1 [bib_ref] CONSORT extension for reporting N-of-1 trials (CENT) 2015 statement, Vohra [/bib_ref] , and feasibility [bib_ref] statement: extension to randomised pilot and feasibility trials, Eldridge [/bib_ref] ; different types of trial data, such as patient-reported outcomes [bib_ref] Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension, Calvert [/bib_ref] , abstracts [bib_ref] CONSORT for reporting randomised trials in journal and conference abstracts, Hopewell [/bib_ref] , and harms [bib_ref] Better reporting of harms in randomized trials: an extension of the CONSORT..., Ioannidis [/bib_ref] ; and different types of intervention (see next section) [bib_ref] Methods and processes of the CONSORT group: example of an extension for..., Boutron [/bib_ref] [bib_ref] Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement, Gagnier [/bib_ref] [bib_ref] Revised STandards for reporting interventions in clinical trials of acupuncture (STRICTA): extending..., Macpherson [/bib_ref]. Intervention extensions of CONSORT are organised by techniques, such as non-pharmacologic [bib_ref] Methods and processes of the CONSORT group: example of an extension for..., Boutron [/bib_ref] , herbal medicinal products [bib_ref] Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement, Gagnier [/bib_ref] , and acupuncture [bib_ref] Revised STandards for reporting interventions in clinical trials of acupuncture (STRICTA): extending..., Macpherson [/bib_ref].
Social and psychological interventions go beyond simply adding techniques or using different techniques compared to biomedical interventions; they often use concepts, theories, and taxonomies that are distinct from those used by the biomedical scientists targeted by the CONSORT extension for non-pharmacologic treatments [bib_ref] Behaviour change techniques: the development and evaluation of a taxonomic method for..., Michie [/bib_ref] [bib_ref] The behavior change technique taxonomy (v1) of 93 hierarchically clustered techniques: building..., Michie [/bib_ref] [bib_ref] Theories of behaviour and behaviour change across the social and behavioural sciences:..., Davis [/bib_ref] [bib_ref] Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and..., Boutron [/bib_ref]. To delineate the scope of CONSORT for social and psychological interventions (CONSORT-SPI), we define interventions by their mechanisms of action: i.e., how these interventions function to affect desired outcomes. That is, social and psychological interventions are actions intended to modify processes and systems that are social and psychological in nature (such as cognitions, emotions, behaviours, norms, relationships, and salient aspects of the environment) and are hypothesised to be influences on outcomes of interest [bib_ref] Development of a CONSORT Extension for Social and Psychological Interventions, Grant [/bib_ref].
Social and psychological interventions can be complex in several ways [bib_ref] Developing and evaluating complex interventions: the new Medical Research Council guidance, Craig [/bib_ref]. For example, these interventions cover an assortment of coordinated actions-such as practices, programmes, and policiesthat often involve multiple interacting components. The units targeted by these interventions may include individuals, groups, or even places, and outcomes may be measured at any of these levels. The behaviours of both providers and recipients must be understood if the intervention and its effects are to be understood [bib_ref] Dark logic': theorising the harmful consequences of public health interventions, Bonell [/bib_ref] [bib_ref] Towards a general theory of implementation, May [/bib_ref]. Social and psychological interventions may not follow strictly standardised implementation procedures [bib_ref] Complex interventions: how 'out of control' can a randomised controlled trial be?, Hawe [/bib_ref] , and effects may depend on aspects of the hard-to-control dynamic systems in which they occur [bib_ref] The utility of randomized controlled trials of social interventions: an examination of..., Bonell [/bib_ref] [bib_ref] Complex systems and individual-level approaches to population health: a false dichotomy?, Sniehotta [/bib_ref]. For these reasons, readers of social and psychological intervention research are interested in more than just effect estimates-they require information about how and why these interventions work, for whom, and under what conditions.
# Methods
We developed an official CONSORT Extension that addresses the minimum criteria that need to be met when reporting RCTs evaluating the effects of social and psychological interventions (CONSORT-SPI 2018). We followed recommended practices for developing and disseminating reporting guidelines [bib_ref] Guidance for developers of health research reporting guidelines, Moher [/bib_ref] as described in the study protocol [bib_ref] Protocol for CONSORT-SPI: an extension for social and psychological interventions, Montgomery [/bib_ref]. The methods and results of the systematic review, Delphi process, and consensus meeting followed a pre-specified protocol reported in full elsewhere [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref] [bib_ref] Protocol for CONSORT-SPI: an extension for social and psychological interventions, Montgomery [/bib_ref]. We briefly summarise the process below [fig_ref] Figure 1: Flow of potential checklist items through CONSORT-SPI 2018 project [/fig_ref].
## Systematic reviews
We first conducted a systematic review to assess the adherence of RCTs evaluating social and psychological interventions to existing reporting standards, and to identify potential items for the CONSORT-SPI 2018 checklist and flow diagram [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref].
## Online delphi process
We then conducted an international online Delphi process between September 2013 and February 2014 to prioritise the list of potential items for the CONSORT-SPI 2018 checklist and flow diagram that were identified in the systematic review. To encourage Mechanism used to implement the random allocation sequence, describing any steps taken to conceal the sequence until interventions were assigned § Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions §
## Awareness of assignment 11a
Who was aware of intervention assignment after allocation (for example, participants, providers, those assessing outcomes), and how any masking was done 11b
If relevant, description of the similarity of interventions Analytical methods 12a
Statistical methods used to compare group outcomes § How missing data were handled, with details of any imputation method 12b
Methods for additional analyses, such as subgroup analyses, adjusted analyses, and process evaluations widespread participation, we published commentaries in several journals publishing trial reports in the fields of addiction, criminology, education, adult and child psychology and psychiatry, public health, and social work [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref] [bib_ref] Letter to the editor: new guidelines are needed to improve the reporting..., Grant [/bib_ref] [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref] [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Mayo-Wilson [/bib_ref] [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Mayo-Wilson [/bib_ref] [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Montgomery [/bib_ref] [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Montgomery [/bib_ref] [bib_ref] Editorial perspective: the need for new guidelines to improve the reporting of..., Gardner [/bib_ref] , directing readers to a recruitment website where they could register. We also invited members of professional bodies, funders, policymakers, journal editors, practitioners, user representatives, and other stakeholders to participate. We encouraged all identified stakeholders to invite any further colleagues to participate. We sent these participants a two-round survey to rate the importance of including proposed items in the CONSORT-SPI 2018 checklist and to provide qualitative feedback (survey items can be accessed at the . We synthesised the results of the first survey and sent these to participants, who then completed the second survey, which was designed to explore areas of disagreement and to resolve questions arising during the first round.
## Consensus meeting
Following the Delphi process, we held a three-day in-person consensus meeting to determine the content of the CONSORT-SPI 2018 checklist and flow diagram, as well as the accompanying E&E document (March 2014). We used established methods [bib_ref] Consensus methods for medical and health services research, Jones [/bib_ref] from previous CONSORT meetings [bib_ref] Improving the reporting of pragmatic trials: an extension of the CONSORT statement, Zwarenstein [/bib_ref] [bib_ref] Methods and processes of the CONSORT group: example of an extension for..., Boutron [/bib_ref] [bib_ref] Endorsement of the CONSORT statement by high impact factor medical journals: a..., Hopewell [/bib_ref]. Participants included 31 experts from the Delphi process (see in the Appendix), whom we selected purposively to include key stakeholders from targeted disciplines (e.g. public health, social work, education, criminology, and clinical psychology) and professional roles (e.g. trialists, funders, and journal editors) [bib_ref] Describing reporting guidelines for health research: a systematic review, Moher [/bib_ref].
Prior to the meeting, we sent participants background literature [bib_ref] Better reporting of interventions: template for intervention description and replication (TIDieR) checklist..., Hoffmann [/bib_ref] [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref] [bib_ref] Guidance for developers of health research reporting guidelines, Moher [/bib_ref] [bib_ref] CONSORT for reporting randomised trials in journal and conference abstracts, Hopewell [/bib_ref] [bib_ref] Protocol for CONSORT-SPI: an extension for social and psychological interventions, Montgomery [/bib_ref] [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Mayo-Wilson [/bib_ref] [bib_ref] explanation and elaboration: updated guidelines for reporting parallel group randomised trials, Moher [/bib_ref] , results from the Delphi process, and the meeting agenda. On the first day, participants discussed the background literature and its applicability to the various disciplines and professional roles represented at the meeting. During the second day, participants discussed and voted on potential checklist and flow diagram items nominated during the Delphi process using anonymous electronic ballots. On the third day, participants voted on the remaining items and discussed strategies for dissemination. Participants were asked to consider the value of each item based on the evidence presented and to vote on whether each item was essential when reporting all social and psychological intervention RCTs. When voting, participants could select 'exclude' , 'include' , or 'unsure'.
In the first round of voting, only items endorsed as 'include' by ≥70% of participants were included in the checklist [bib_ref] Consensus development methods, and their use in clinical guideline development, Murphy [/bib_ref] [bib_ref] Using the Delphi technique to determine which outcomes to measure in clinical..., Sinha [/bib_ref]. We excluded all other items unless at least two participants proposed they be reconsidered. In this second round of voting, items endorsed as 'include' by ≥80% of participants were also incorporated in the CONSORT-SPI 2018 checklist. Participants suggested that several 'excluded' items should be discussed in the E&E document.
## Post-meeting activities
After the consensus meeting, we finalised the CONSORT-SPI 2018 checklist and flow diagram. We then drafted the Extension Statement (this manuscript), as well as an E&E document that serves as a user manual for the checklist. We distributed these documents to consensus meeting participants for feedback and revision, and we incorporated their comments in the final version of this manuscript and the accompanying E&E. We also discussed how best to optimise our strategy for disseminating and implementing these documents.
# Results
## Systematic review
The systematic review of reporting guidance identified 14 relevant reporting guidelines and 5 reporting Noteworthy changes to CONSORT 2010 items in the CONSORT-SPI 2018 checklist
- Item 6a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Item 11. 'Blinding' has been changed to 'Awareness of assignment and 'masking' in the section heading and item wording, respectively.
These changes address concerns about the use of the term 'blinding' as well as the need to emphasise the issue of awareness of assignment by providers and participants in social and psychological intervention trials. - Item 12. The section heading 'Statistical methods' has been changed to 'Analytical methods' because some methods may be qualitative in social and psychological intervention RCTs. - Item 12a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Item 12b. Process evaluations are specifically highlighted.
- Item 13a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Items 13a and 16. The wording 'number of participants' has been changed to 'number' because the term 'participants' is not appropriate for RCTs in which the unit of intervention is a geographic area. While social and psychological interventions may target individual participants or groups of individuals, such as families or schools, they may also involve place-based techniques that target geographic units and examine area-level effects. However, for convenience and consistency with the CONSORT 2010 guidance [bib_ref] explanation and elaboration: updated guidelines for reporting parallel group randomised trials, Moher [/bib_ref] , the CONSORT-SPI 2018 checklist and E&E will refer to the unit targeted by the intervention as 'participants', though 'participants' throughout this guidance is meant to stand for 'participating units' or the unit being targeted by the intervention [bib_ref] Improving the reporting quality of nonrandomized evaluations of behavioral and public health..., Jarlais [/bib_ref] , which may include geographic units. - Item 15. The words 'clinical and demographic' have been removed because this checklist targets interventions that may not be medical in nature or have health outcomes, and thus to emphasise the need to report important baseline characteristics irrespective of their nature. - Item 16. The parenthetical '(denominator)' has been removed.
The term implied the use of dichotomous outcomes, whereas continuous outcomes are extremely prevalent in social and psychological intervention RCTs. - Item 17a. The distinction between 'primary' versus 'secondary' outcomes has been removed. - Items 23-25. The section 'Other Information' has been changed to 'Important Information' because consensus meeting participants had concerns that 'Other' makes the requested information appear to be of secondary importance to previous sections. - Item 25. The phrase 'such as supply of drugs' has been removed because drug trials are not in the purview of this extension by definition. - Item 26: New item. A new sub-section in 'Important Information' called 'Stakeholder Involvement' has been added because consensus meeting participants thought such a sub-section would best fit the three sub-items currently allocated to it. assessment tools. These tools included a total of 147 potential items to consider for the CONSORT-SPI 2018 checklist, 89 of which were not included in the CONSORT checklist [bib_ref] Developing a reporting guideline for social and psychological intervention trials, Grant [/bib_ref].
## Online delphi process
With input from the project's International Advisory Group, we included 77 potential checklist items from the systematic review in the first round of the modified Delphi process. We recruited 384 Delphi participants from 32 countries working in over a dozen areas of social and psychological intervention, including academics, researchers, practitioners, journal editors, research funders, policymakers, and recipients of social and psychological interventions. The Delphi process yielded 58 potential items as important to consider for inclusion in the CONSORT-SPI 2018 checklist.
## Consensus meeting
During the consensus meeting, participants voted to extend 9 of the 25 items in the CONSORT 2010 checklist: background and objectives, trial design, participants, interventions, statistical methods, participant flow, baseline data, outcomes and estimation, and funding. These extended checklist items addressed the need for reports of RCTs of social and psychological interventions to describe: the hypotheses for how the intervention might work, the eligibility criteria for settings and providers, the actual provider delivery and participant uptake of the interventions, the intervention materials, how missing data were handled, participant recruitment, socioeconomic baseline variables, availability of trial data, author declarations of interest, involvement of the intervention developer in the trial, and details of any incentives offered [fig_ref] Table 1: The CONSORT-SPI 2018 checklist [/fig_ref]. Participants also voted to add a new item about stakeholder involvement, and they recommended modifications to . The flow diagram [fig_ref] Figure 2: The CONSORT-SPI 2018 flow diagram existing CONSORT 2010 checklist items [/fig_ref] to address the unique needs of social and psychological intervention trials was also modified-specifically, the number of participants approached during enrolment and the number of providers, organisations, and areas (as appropriate) allocated to each trial arm. To further facilitate use of CONSORT-SPI 2018, we have provided a tailored CONSORT Extension for Abstracts [39] and a CONSORT Extension for Cluster Randomised Trials (Tables 4 and 5) [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] for social and psychological intervention trials.
# Discussion
The CONSORT-SPI 2018 Extension is designed to assist authors in writing reports of social and psychological intervention RCTs and to assist peer reviewers and editors in assessing these manuscripts. While we recommend that authors report items in the checklist in the relevant manuscript section (i.e., introduction, methods, results, or discussion), the format of an article will depend on journal style, editorial decisions, expectations within a particular research area, and author discretion. At a minimum, authors should address each checklist item somewhere in the article with the appropriate level of detail and clarity. We recommend subheadings within major sections-particularly the methods and results sections-to help ease of reading. The accompanying CONSORT-SPI 2018 E&E document is a user manual for the CONSORT-SPI 2018 checklist, providing a concise rationale for and description of how best to adhere to each checklist item. We recommend that authors preparing reports of social and psychological intervention RCTs consult the CONSORT-SPI 2018 E&E document when using the CONSORT-SPI 2018 checklist. This guideline may prove useful to several different stakeholders [bib_ref] Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration..., Shamseer [/bib_ref]. Researchers can use CONSORT-SPI 2018, along with the SPIRIT Statement, during trial design to ensure they consider the essential study aspects Items to report in journal or conference abstracts for social and psychological intervention trials [bib_ref] CONSORT for reporting randomised trials in journal and conference abstracts, Hopewell [/bib_ref] Section CONSORT abstract item Relevant CONSORT-SPI item If the unit of random assignment is not the individual, refer to CONSORT for Cluster Randomised Trials and report the items included in its extension for abstracts [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] Methods
## Participants
Eligibility criteria for participants and the settings where the data were collected When applicable, the eligibility criteria for the setting of the intervention delivery and the eligibility criteria for the persons who delivered the interventions they will have to describe in future manuscripts. Use of CONSORT-SPI 2018 throughout a trial (from design to reporting) can help improve the accuracy, completeness, and transparency of the final manuscript. Journal editors can enforce policies and procedures to ensure that CONSORT-SPI 2018 is actually used by authors, editors and peer reviewers to improve the social and psychological RCT manuscripts they publish [bib_ref] Effect of editors' implementation of CONSORT guidelines on the reporting of abstracts..., Hopewell [/bib_ref]. Research funders who adopt CONSORT-SPI 2018 and other reporting guidelines may receive higher quality grant applications, as well as facilitate the commissioning of the most important and rigorous studies while helping to reduce research waste. Policymakers, practitioners, and systematic reviewers who encourage researchers to use CONSORT-SPI 2018 may find this leads to higher quality publications, which these stakeholders can then use to identify and implement effective interventions for populations and settings of interest. In addition, faculty could use reporting guidelines to train the next generation of researchers, peer reviewers, and journal editors [bib_ref] Four proposals to help improve the medical research literature, Moher [/bib_ref].
In highlighting prospective trial registration [bib_ref] Trial registration: understanding and preventing reporting bias in social work research, Harrison [/bib_ref] , the publication of protocols [bib_ref] SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials, Chan [/bib_ref] , and increased sharing of trial data [bib_ref] Promoting an open research culture, Nosek [/bib_ref] [bib_ref] Are manufacturers sharing data as promised?, Mayo-Wilson [/bib_ref] , all of which are uncommon in social and psychological intervention research, CONSORT-SPI 2018 also complements other efforts to improve research transparency. Examples of such efforts include the Template for Intervention Description and Replication (TIDieR) checklist (which will replace CONSORT 2010 Item 5) [bib_ref] Better reporting of interventions: template for intervention description and replication (TIDieR) checklist..., Hoffmann [/bib_ref] , the Behaviour Change Technique taxonomy [bib_ref] Behaviour change techniques: the development and evaluation of a taxonomic method for..., Michie [/bib_ref] [bib_ref] The behavior change technique taxonomy (v1) of 93 hierarchically clustered techniques: building..., Michie [/bib_ref] , the Berkeley Initiative for Transparency in the Social Sciences [bib_ref] Promoting transparency in social science research, Miguel [/bib_ref] , the Data Access and Research Transparency Statement [bib_ref] DA-RT): a joint statement by political science journal editors, Access [/bib_ref] , the Center for Open Science, the Transparency and Openness Promotion guidelines [bib_ref] Promoting an open research culture, Nosek [/bib_ref] , and the Human Behaviour-Change Project [bib_ref] The human behaviour-change project: harnessing the power of artificial intelligence and machine..., Michie [/bib_ref].
# Strengths and limitations
We followed recommended best practices in the development of these reporting guidelines and advocate their use to future reporting guideline developers [bib_ref] Guidance for developers of health research reporting guidelines, Moher [/bib_ref]. A challenge that we experienced, and which other reporting guideline developers have faced [bib_ref] Developing a guideline for clinical trial protocol content: Delphi consensus survey, Tetzlaff [/bib_ref] , was the large number of potential checklist items that participants considered to be important for a CONSORT-SPI 2018 Items to report in the abstract for cluster randomised social and psychological intervention trials [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] [bib_ref] Guidelines for reporting of health interventions using mobile phones: mobile health (mHealth)..., Agarwal [/bib_ref].
In addition, as in the development of previous CONSORT guidelines, other items fundamental to an RCT have not been included (such as approval by an institutional ethical review board) because journals and institutions address these issues in other ways. We encourage users of this guideline to provide feedback on the appropriateness of the content in the CONSORT-SPI 2018 checklist and its accompanying E&E document.
## Endorsement
As a recognised extension of the CONSORT 2010 Statement, journals and organisations already endorsing the CONSORT guidelines can easily extend their support to CONSORT-SPI 2018. We encourage other journals and organisations that publish social and psychological intervention RCTs to endorse CONSORT-SPI 2018 and to register their official support on the CONSORT website (http://www.con sort-statement.org/about-consort/endorsement). Journal endorsement policies that include monitoring of adherence to the checklist are essential for complete and transparent reporting [bib_ref] Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of..., Turner [/bib_ref]. To maximise the potential impact of CONSORT-SPI 2018, editors should consider requiring authors to submit a completed CONSORT-SPI 2018 checklist as a separate document when Items to report in the main text for cluster randomised social and psychological intervention trials [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] Section
Item [fig_ref] Table 1: The CONSORT-SPI 2018 checklist [/fig_ref] Introduction Background and objectives Specification that allocation was based on clusters rather than individuals and whether allocation concealment (if any) was at the cluster level, the individual participant level, or both Implementation 10a Who generated the random allocation sequence, who enrolled clusters, and who assigned clusters to interventions 10b Mechanism by which individual participants were included in clusters for the purposes of the trial (such as complete enumeration, random sampling) 10c
From whom consent was sought (representatives of the cluster, individual cluster members, or both) and whether consent was sought before or after randomisation Analytical methods 12a How clustering was taken into account
# Results
Participant flow (a diagram is strongly recommended)
13a
For each group, the numbers of clusters that were randomly assigned, received the intended treatment, and were analysed for the primary outcome reporting social and psychological intervention RCTs, and we recommend that editors should check that all items have been included before sending manuscripts for peer review. Endorsing journals should consider adding the following statement to their 'Instructions to Authors' [bib_ref] CONSORT extension for reporting N-of-1 trials (CENT) 2015 statement, Vohra [/bib_ref] :
JOURNAL NAME requires a completed CONSORT-SPI 2018 checklist as a condition for submitting manuscripts about randomised trials of social and psychological interventions. We recommend that your submission addresses each item in the CONSORT-SPI 2018 checklist. Taking the time to ensure your manuscript meets these basic reporting requirements will greatly improve your manuscript, and may potentially enhance its chances for eventual publication.
We also recommend that researchers, editors, peer reviewers, funders, and educators consult the CON-SORT website (http://www.consort-statement.org) for other relevant CONSORT Extensions (e.g. the extension for cluster randomised trials) [bib_ref] Consort 2010 statement: extension to cluster randomised trials, Campbell [/bib_ref] , as well as the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network for up-to-date information on other reporting guidelines (http://www.e quator-network.org) that may be of relevance to their study.
# Conclusion
CONSORT-SPI 2018, like other CONSORT guidelines, is an evolving tool that requires regular reappraisal and modifications as new evidence emerges and as scientific consensus changes. We invite interested stakeholders to contact us with feedback or to contribute to the guideline's ongoing development, including individuals or groups who wish to translate the CONSORT-SPI 2018 checklist into other languages or those who wish to evaluate the impact of the CONSORT-SPI 2018 checklist on future trial reporting [bib_ref] Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of..., Turner [/bib_ref] [bib_ref] Relation of completeness of reporting of health research to journals' endorsement of..., Stevens [/bib_ref]. To provide feedback and access the most recent version of the CONSORT-SPI 2018 checklist and E&E document, visit the project (https://www.birmingham.ac.uk/schools/social-policy/ departments/social-policy-sociology-criminology/research/ projects/2017/Consort-SPI.aspx) and CONSORT websites (http://www.consort-statement.org).
[fig] Figure 1: Flow of potential checklist items through CONSORT-SPI 2018 project [/fig]
[fig] Figure 2: The CONSORT-SPI 2018 flow diagram existing CONSORT 2010 checklist items ( [/fig]
[table] Table 1: The CONSORT-SPI 2018 checklist [/table]
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Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group
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Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group
IntroductionThere is no consensus definition of acute renal failure (ARF) in critically ill patients. More than 30 different definitions have been used in the literature, creating much confusion and making comparisons difficult. Similarly, strong debate exists on the validity and clinical relevance of animal models of ARF; on choices of fluid management and of end-points for trials of new interventions in this field; and on how information technology can be used to assist this process. Accordingly, we sought to review the available evidence, make recommendations and delineate key questions for future studies. Methods We undertook a systematic review of the literature using Medline and PubMed searches. We determined a list of key questions and convened a 2-day consensus conference to develop summary statements via a series of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated recommendations and/or directions for future research. Results We found sufficient consensus on 47 questions to allow the development of recommendations. Importantly, we were able to develop a consensus definition for ARF. In some cases it was also possible to issue useful consensus recommendations for future investigations. We present a summary of the findings. (Full versions of the six workgroups' findings are available on the internet at http://www.ADQI.net) Conclusion Despite limited data, broad areas of consensus exist for the physiological and clinical principles needed to guide the development of consensus recommendations for defining ARF, selection of animal models, methods of monitoring fluid therapy, choice of physiological and clinical end-points for trials, and the possible role of information technology.
# Introduction
Acute renal failure (ARF) is a common complication of critical illness, which is associated with high mortality and has a separate independent effect on the risk of death [bib_ref] Independent association between acute renal failure and mortality following cardiac surgery, Chertow [/bib_ref] [bib_ref] Acute renal failure in the ICU: risk factors and outcome evaluation by..., De Mendonca [/bib_ref]. Despite several advances in treatment and in our understanding of the pathogenesis of ARF, many aspects in this field remain subject to controversy, confusion and lack of consensus. Important aspects beset by such problems include the definition of ARF [bib_ref] Acute renal failure: time for consensus, Bellomo [/bib_ref] ; the choice, validity and relevance of animal models of ARF [bib_ref] Difficulties in understanding human 'acute tubular necrosis': limited data and flawed animal..., Rosen [/bib_ref] ; and the choice regarding appropriate physiological and clinical end-points for trials of new treatments of ARF [bib_ref] Plasma clearance of iodine contrast media as a measure of glomerular filtration..., Erley [/bib_ref]. They also include principles that should govern fluid management in patients with ARF [bib_ref] Volume replacement in critically ill patients with acute renal failure, Ragaller [/bib_ref] and use of information technology to optimize all areas of patient care in this field.
The purpose of this consensus conference was to review the available evidence regarding optimal practice in these areas, make consensus-based recommendations and delineate key questions for future studies.
# Methods
Our consensus process relied on evidence where available and, in the absence of evidence, consensus expert opinion when possible [bib_ref] Use of consensus development to establish national research priorities in critical care, Vella [/bib_ref]. This combined approach has previously led to important practice guidelines that were widely adopted into clinical practice [bib_ref] Implications of the guidelines for the management of severe head injury for..., Chestnut [/bib_ref]. In contrast, expert opinion alone can ignore important evidence, whereas evidence-based reviews can be conceptually flawed without expert opinion [bib_ref] Appraising and using evidence in critical care, Kellum [/bib_ref]. We conducted the consensus process in three stages: preconference, conference and postconference.
Before the conference, we identified six topics relevant to the field of ARF: definition/classification system for ARF; clinical outcome measures for ARF studies; physiological end-points for ARF studies; animal models of ARF; techniques for assessing and achieving fluid balance in ARF; and information technology in acute dialysis. We selected these topics based on the level of possible clinical impact, the level of controversy, known or suspected variation in practice, potential importance for scientific outcome, potential for development of evidencebased medicine recommendations, and availability of evidence. For each topic we outlined a preliminary set of key questions. We then invited an international panel, predominantly from the fields of nephrology and intensive care, based on their expertise in the fields of analysis. Panelists were assigned to three-person workgroups, with each workgroup addressing one key topic. Each workgroup conducted literature searches related to their topic questions via Medline, PubMed, bibliography of review articles and participants' files. Searches were limited to English language articles. However, articles written in other languages were used when identified by workgroup members. During this stage, the scope of the conference was also more clearly defined.
We conducted a 2-day conference in May 2002 in Vicenza, Italy. We developed summary statements through a series of alternating breakout and plenary sessions. In each breakout session, the workgroup refined key questions, identified the supporting evidence, and generated recommendations and/or directions for future research as appropriate. We generated future research questions by identifying deficiencies in the literature and debating whether more evidence was necessary. Where possible, we also considered pertinent study design issues. Workgroup members presented their findings during plenary sessions, rotating responsibility for presenting to ensure full participation. The workgroup then revised their drafts as needed until a final version was agreed upon. When consensus was not achieved on any individual question by the conclusion of the meeting, deliberations continued by correspondence. When voting was required to settle an issue, a two-thirds majority was required to approve a proposal.
A writing committee assembled the individual reports from the workgroups and each report was edited to conform to a uniform style and for length. Finally, each report was submitted for comments to independent international experts. In this report we present a summary of the proceedings.
# Results
We achieved sufficient consensus for a total of 47 questions. We report a summary of the questions, proceedings and final recommendations for each individual workgroup below. A complete report of the findings, including a full discussion of the issues involved, along with rationale and independent comments by other international experts, can be found on the internet at the Acute Dialysis Quality Initiative (ADQI) Group website http://www.ADQI.net.
## Definition/classification system for acute renal failure
The clinical condition of ARF is said to occur in anywhere from 1% to 25% of critically ill patients [bib_ref] Independent association between acute renal failure and mortality following cardiac surgery, Chertow [/bib_ref] [bib_ref] Acute renal failure in the ICU: risk factors and outcome evaluation by..., De Mendonca [/bib_ref] , depending on the population being studied and the criteria used to define its presence. Furthermore, mortality in these populations ranges from 28% to 90% [bib_ref] Effect of acute renal failure requiring renal replacement therapy on outcome in..., Metnitz [/bib_ref] [bib_ref] Risk factors influencing survival in ICU acute renal failure, Consentino [/bib_ref]. Clearly, trials of prevention and therapy are not comparable because widely disparate definitions have been used. However, most definitions of ARF have common elements, including the use of serum creatinine and, often, urine output. Although the kidney has numerous functions, these are the only functions that are routinely and easily measured and that are unique to the kidney.
The accuracy of a creatinine clearance measurement (even when collection is complete) is limited because as glomerular filtration rate (GFR) falls creatinine secretion is increased, and thus the rise in serum creatinine is less [bib_ref] Plasma clearance of iodine contrast media as a measure of glomerular filtration..., Erley [/bib_ref] [bib_ref] A clinical appraisal of the plasma concentration and endogenous clearance of creatinine, Doolan [/bib_ref]. Thus, creatinine excretion is much greater than the filtered load, resulting in a potentially large overestimation of the GFR (as much as a twofold difference) [bib_ref] A clinical appraisal of the plasma concentration and endogenous clearance of creatinine, Doolan [/bib_ref]. However, for clinical purposes it is important to determine whether renal function is stable or getting worse or better. This can usually be determined by monitoring serum creatinine alone [bib_ref] Creatinine clearance in renal disease. A reappraisal, Kim [/bib_ref]. Like creatinine clearance, the serum creatinine will not be an accurate reflection of GFR in the non-steady-state condition of ARF. Nonetheless, the degree to which serum creatinine changes from baseline will reflect the change in GFR. Serum creatinine is readily and easily measured and it is specific for renal function, while urea (or blood urea nitrogen) is a nonspecific marker of renal function, making it a poor marker relative to creatinine. Urine output is far less specific, except when it is severely decreased or absent. Severe ARF can exist despite normal urine output (i.e. nonoliguric) but changes in urine output can occur long before biochemical changes are apparent.
In addition, we considered that the following features would be important in any definition of ARF: it should consider change from baseline; it should include classifications for acute on chronic renal disease; it should be easy to use and clinically applicable across different centres; and it should consider both sensitivity and specificity because of different popula-tions and research questions. A classification system should therefore include and separate mild (or early) and severe (or late) cases. This will allow such a classification to detect patients in whom renal function is mildly affected (high sensitivity for the detection of kidney malfunction but limited specificity for its presence) and patients in whom renal function is markedly affected (high specificity for true renal dysfunction but limited sensitivity in picking up early and subtler loss of function). Accordingly, we advocate a multilevel classification system in which a wide range of disease spectra can be included.
The resulting classification scheme, based on the above considerations, is shown in. In addition to the three levels of renal dysfunction, the RIFLE (acronym indicating Risk of renal dysfunction; Injury to the kidney; Failure of kidney function, Loss of kidney function and End-stage kidney disease) criteria also include two clinical outcomes: 'loss' and 'end-stage renal disease' (ESRD). These are separated to acknowledge the important adaptations that occur in ESRD that are not seen in persistent ARF. Persistent ARF (loss) is defined as need for renal replacement therapy (RRT) for more than 4 weeks, whereas ESRD is defined by need for dialysis for longer than 3 months.
Of course, many patients may present with acute renal dysfunction without any baseline measure of renal function. This presents a problem for a system that considers the change from baseline. One option is to calculate a theoretical baseline serum creatinine value for a given patient assuming a given normal GFR. By normalizing the GFR to the body surface area, a GFR of approximately 75-100 ml/min per 1.73 m 2 can be assumed, and thus a change from baseline can be estimated for a given patient. The simplified 'modification of diet in renal disease' (MDRD) formula provides a robust estimate of GFR relative to serum creatinine based on age, race and sex. Thus, given a patient without known renal disease but in whom a baseline creatinine is unknown, one can estimate the baseline creatinine. [fig_ref] Table 1: Estimated baseline creatinine [/fig_ref] solves the MDRD equation for the lower end of the normal range (i.e. 75 ml/min per 1.73 m 2 ). Note that the MDRD formula is used only to estimate the baseline when it is not known. For example, a 50-year-old black female would be expected to have a baseline creatinine of 1.0 mg/dl (88 µmol/l).
## Clinical outcome measures for arf studies
Appropriate selection and definition of outcome measures (end-points) are critical for the successful execution of clinical trials. An outcome is defined as either a measurement (i.e. serum creatinine) or an event (i.e. death or need for dialysis) that is potentially modifiable by a defined intervention. Several criteria must be considered in the selection of outcome measures, including clinical importance, responsiveness to the intervention, precision of their definition, accuracy of measurement and completeness of ascertainment. Because multiple Proposed classification scheme for acute renal failure (ARF) Proposed classification scheme for acute renal failure (ARF). The classification system includes separate criteria for creatinine and urine output (UO). A patient can fulfill the criteria through changes in serum creatinine (SCreat) or changes in UO, or both. The criteria that lead to the worst possible classification should be used. Note that the F component of RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease) is present even if the increase in SCreat is under threefold as long as the new SCreat is greater than 4.0 mg/dl (350 µmol/l) in the setting of an acute increase of at least 0.5 mg/dl (44 µmol/l). The designation RIFLE-F C should be used in this case to denote 'acute-onchronic' disease. Similarly, when theRIFLE-F classification is achieved by UO criteria, a designation of RIFLE-F O should be used to denote oliguria. The shape of the figure denotes the fact that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less specificity). In contrast, at the bottom of the figure the criteria are strict and therefore specific, but some patients will be missed. *GFR = Glomerular Filtration Rate; ARF Acute Renal Failure outcomes may be affected by a single intervention, a hierarchical ranking is required. It is critical that the primary outcome be prospectively identified.
Patient survival (or its reciprocal, mortality) has commonly been used as the primary end-point in clinical trials of RRT in ARF, although the timing has varied [bib_ref] Effects of different doses on continuous venovenous haemofiltration on outcomes of acute..., Ronco [/bib_ref] [bib_ref] Daily hemodialysis and the outcome of acute renal failure, Schiffl [/bib_ref] [bib_ref] A randomized clinical trial of continuous versus intermittent dialysis for acute renal..., Mehta [/bib_ref]. In critically ill patients without ARF, 28-day survival may miss more than 20% of acute mortality [bib_ref] Mortality of intensive care patients: at a fixed point in time or..., Capuzzo [/bib_ref]. In ARF, a stable survival rate is not achieved until after 30-60 days [bib_ref] A multicenter comparison of dialysis membranes in the treatment of acute renal..., Himmelfarb [/bib_ref] [bib_ref] Comparison of cellulose diacetate and polysulfone membranes in the outcome of acute..., Gastaldello [/bib_ref]. Several scoring systems for assessment of organ dysfunction and morbidity have been validated in the general ICU population [bib_ref] Use of the SOFA score to assess the incidence of organ dysfunction/failure..., Vincent [/bib_ref] [bib_ref] A new simplified acute physiology score (SAPS II) based on a European/North..., Gall [/bib_ref] [bib_ref] APACHE II: a severity of disease classification system, Knaus [/bib_ref] and have also been used on ARF patients, although validation studies in the ARF setting are rare. No internationally validated ARF-specific scoring systems exist.
Recovery from ARF can only be evaluated in the context of a specific definition of ARF. We propose that recovery may be partial or complete. Complete renal recovery exists if the patient returns to their baseline classification within the RIFLE criteria, whereas partial renal recovery exists if there is a persistent change in RIFLE classification (R, I or F) but not persistent need for RRT.
## Physiological end-points for arf studies
Lack of significant progress in the prevention and management of ARF has been attributed, in part, to failure to identify suitable physiological surrogate end-points for use in research studies testing the efficacy of new interventions. In fact, very few ARF studies have even demonstrated a beneficial effect on the most commonly used physiological end-points, namely the serum urea nitrogen and creatinine concentrations. We compared and critiqued a number of physiological end-points [fig_ref] Table 2: Physiologic markers of renal function [/fig_ref].
Because there are no pharmacotherapies that have been proven to alter clinical endpoints (dialysis, mortality) in patients with ARF, it cannot be discerned what changes in currently available serum GFR markers (urea, creatinine) are predictive in smaller phase II studies of success in subsequent phase III trials with clinical end-points. Thus, strategies for ARF prevention and therapy will need to continue to be based on results from studies (positive and negative) using surrogate endpoints (creatinine, urea) until definitive studies demonstrating effectiveness in altering clinical end-points are available. However, clinical decisions based on such evidence should be made cautiously and limited to the use of true surrogates (those that correlate with clinical outcomes). For example, urine output and renal blood flow are not reliable surrogates for outcome in studies of ARF and should not be used as such.
Although some data suggest the utility of urinary electrolyte or other chemistries in the differential diagnosis of ARF, none of these methods has proven reliable in clinical practice [bib_ref] Fractional excretion of sodium: exceptions to its diagnostic value, Zarich [/bib_ref]. It is unproven whether urine chemistries or microscopy are appropriate indices of renal function for efficacy studies for ARF prevention or therapy. We wish to emphasize that, in the end, interventions must be demonstrated to change major outcomes (survival or recovery of renal function) before they can be recommended for clinical use.
## Animal models of arf
We fully adopt the general recommendations, outlined by Piper and colleagues [bib_ref] Introducing critical appraisal to studies of animal models investigating novel therapies in..., Piper [/bib_ref] , in planning, conducting and critically evaluating studies utilizing animal models. summarizes these principles and other guidelines for the use of animal models in the study of ARF. Despite their limitations, animal models remain fundamental to improving our understanding of human ARF [bib_ref] The pathogenesis of septic acute renal failure, Wan [/bib_ref] [bib_ref] Endotoxin-induced renal failure: II. A role for tubular hypoxic damage, Heyman [/bib_ref] [bib_ref] Sepsis and septic shock: a review of laboratory models and a proposal, Wichterman [/bib_ref].
There are three basic types of animal models in use for study of ARF: ischemia; toxins and sepsis models; and several subtypes. Each has its own advantages and disadvantages, which are summarized in [fig_ref] Table 4: A comparison of leading animal models for the study of acute renal... [/fig_ref]. No one model has been shown to be universally applicable to the study of ARF. Indeed, no model currently available provides a reproducible model of clinical ARF as seen in the critically ill. Better models are needed.
## Techniques for assessing and achieving fluid balance in arf
Fluid therapy, together with attention to oxygen supply, is the cornerstone of resuscitation in all critically ill patients. It is important to recognize that fluid deficits can occur in the absence of obvious fluid loss because of vasodilation or alterations in capillary permeability. Hypovolaemia results in inadequate blood flow to meet the metabolic requirements of the tissues and must be treated urgently if ARF is to be avoided [bib_ref] The golden hour and the silver day: detection and correction of occult..., Blow [/bib_ref] [bib_ref] Persistent occult hypoperfusion is associated with a significant increase in infection rate..., Claridge [/bib_ref]. Special attention to volume status is therefore required in patients at risk for ARF. Although the importance of fluid management is generally recognized, the choice and amount of fluid, and assessment of fluid status are controversial [bib_ref] Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in..., Michard [/bib_ref] [bib_ref] Functional hemodynamic monitoring, Pinsky [/bib_ref] [bib_ref] Pulmonary artery occlusion pressure, Pinsky [/bib_ref]. Whereas volumetric parameters are more reliable for detecting intravascular volume changes, pressure monitoring may be more important for prevention of pulmonary oedema. Clinical assessment of peripheral oedema, body weight and radiological evaluation remain the most widely used parameters for detecting interstitial fluid excess. Objec-tive assessment of extravascular lung water can be achieved with transpulmonary indicator dilution [bib_ref] Radiologic determination of intravascular volume status using portable, digital chest radiography: a..., Ely [/bib_ref] [bib_ref] Findings on the portable chest radiograph correlate with fluid balance in critically..., Martin [/bib_ref] [bib_ref] Prognostic value of extravascular lung water in critically ill patients, Sakka [/bib_ref] [bib_ref] Improved outcome based on fluid management in critically ill patients requiring pulmonary..., Mitchell [/bib_ref] [bib_ref] High values of the pulmonary artery wedge pressure in patients with acute..., Ferguson [/bib_ref]. One recent study conducted in the emergency department on patients with sepsis [bib_ref] Tomlanovich for the Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in..., Rivers [/bib_ref] found an improvement in outcome using a resuscitation strategy ('early goal-directed' therapy), which involved the use of continuous central venous oxygen measurement. It is not known whether the monitoring method was a necessary or sufficient component of the intervention. A much larger study in much less sick, general surgery patients [bib_ref] A randomized controlled trial of the use of pulmonary-artery catheters on high..., Sandham [/bib_ref] found no benefit from routine pulmonary artery catheterization.
## Information technology and acute dialysis
The goals of information technology in its application to acute dialysis therapy are to improve our understanding of current practice and to improve patient care. In order to achieve these goals, six areas of focus were identified: patient safety, current practice pattern assessment, practice variation, patient assessment, dialysis machine technology and clinical trials. Medical errors have repeatedly been shown to affect patient Principles that should guide the development and study of animal models of acute renal failure
General principles that must be applied to design of animal model Additional issues that must be considered to optimize the model In the first column a list of recognized models used for the study of acute renal failure is presented. Then, in each column, an evaluation is presented regarding whether a given model contains certain features. '+' Indicates the presence of a given feature; '±' indicates only the partial presence of that feature; and the absence of any sign indicates the lack of such a feature. For example, warm ischemia is simple but does not match the dominant clinical scenario and is of limited clinical relevance. [bib_ref] Independent association between acute renal failure and mortality following cardiac surgery, Chertow [/bib_ref] Reproduces the type of injury seen in humans. [bib_ref] Acute renal failure in the ICU: risk factors and outcome evaluation by..., De Mendonca [/bib_ref] Cold ischaemia is more clinically relevant to renal transplantation, but it is less well characterized. [bib_ref] Acute renal failure: time for consensus, Bellomo [/bib_ref] Clinical relevance is limited because less toxic alternatives are now available. [bib_ref] Difficulties in understanding human 'acute tubular necrosis': limited data and flawed animal..., Rosen [/bib_ref] Resembles clinical rhabdomyolysis. morbidity and mortality significantly. In numerous fields information technology has been applied to work flow processes to minimize deviations from planned procedures [bib_ref] Human error in hospitals and industrial accidents: current concepts, Spencer [/bib_ref] [bib_ref] Error, stress, and teamwork in medicine and aviation: cross sectional surveys, Sexton [/bib_ref]. No studies are currently available that document potential sources of error in the acute dialysis setting. In delivery of acute dialysis care, errors may occur anywhere within the work flow process. The characteristics of each of these stages may prevent or predispose to potential errors, which may lead to patient harm. We recommend that newer methods for decreasing errors include real-time analysis of centralized patient information repositories to detect deviations or conflicts in intended care and computerized physician order entry. We also recommend that computerized provider order entry be progressively introduced, with consistent and predictable prompting for the parameters needed for therapy. In such computerized provider order entry, all new orders should be cross-checked against acceptable treatment parameters and compared with known patient data to determine whether potential conflicts may occur [bib_ref] Computerized protocols and bedside decision support, Morris [/bib_ref].
The most common method used to control practice variation within centres is by policy. Because in ARF the indications and methods for therapy have not adequately been determined, policies will need to remain flexible. Currently, no formal certification process exists to quantify competency. Computer technology can improve this area by creating simulated therapy sessions that both train and assess the skills of the nurses.
The human-machine interaction can also be improved. Machine displays should make it easy for the provider to detect the signal carrying the information about a patient's status from within the large quantity of excess noise presented by less useful data [bib_ref] Application of an intelligent graphical interface to electronic patient records, Simkus [/bib_ref]. Such display technology should be easy to read, easy to navigate and customizable for a specific user's needs or role. This could be accomplished either by displaying covariant variables simultaneously in a graph such as fluid balance and central venous pressure, or by displaying indices of patient status. These indices would represent validated summaries of multiple variables, which relate to a validated surrogate outcome marker such as a severity index. Currently, most dialysis devices operate independently from the information infrastructure within institutions. Focusing on integration with the information infrastructure should facilitate many of the key steps necessary for improved care. The dialysis machine should contribute information to automated assessment of patients and thus should be interfaced to such systems.
# Discussion
We found sufficient consensus on 47 questions to allow the development of recommendations. Importantly, we were able to reach broad consensus on a definition for ARF and various aspects of ARF research, including outcome measures and animal models. Full versions of the six workgroups' findings are available on the internet http://www.ADQI.net.
We hope that the results of this consensus process will help to standardize the study of ARF, both for prevention and treatment. Indeed, it must be understood that although our recommendations are based, to the best extent possible, on data, there are insufficient data to guide many important decisions. As a result, our findings should be considered a 'first step' in the process of standardization. For example, the RIFLE criteria for diagnosis of ARF will need to be validated in large patient series -efforts that are currently underway.
In addition, we recognize that some of our recommendations may seem arbitrary or attempt to balance utility and precision in a way that may limit both. For example, therapy can influence the primary criteria for the diagnosis of ARF. Hydration status will influence urine output and, to some degree, may even alter the volume of distribution for creatinine. Large dose diuretics may be used to force a urine output when it would otherwise fall into a category consistent with a diagnosis of ARF. Such influences are unavoidable and analogous to those in other disease processes, which require clinical classification. Similarly, one might hypothesize that the underlying disease process that results in ARF (e.g. radiocontrast versus sepsis) will alter the 'clinical meaning' of each degree of renal dysfunction. However, by applying the present criteria across these various aetiologies, it will be possible to test this hypothesis directly. It should also be noted that these criteria were developed to describe ARF occurring in the critically ill. Primary renal diseases such as glomerulonephritis should be excluded from this classification system. The ultimate value of a definition for The cycle of patient care and sites of potential errors The cycle of patient care and sites of potential errors. Any step in this continuous cycle of assessing and caring for a patient can be a site of error, which may lead to patient harm. ARF will be determined by its utility. A classification scheme for ARF should be sensitive and specific, and predictive of relevant clinical outcomes such as mortality and length of hospital stay. These too are testable hypotheses. Thus, despite limited data, broad areas of consensus exist for the physiological and clinical principles needed to guide the development of a consensus definition of ARF. They also exist for the need to evolve ARF models toward greater reproduction of common clinical scenarios, principles and monitoring technology of fluid therapy, choice of physiological and clinical endpoints for trials, and the possible role of information technology.
[table] Table 1: Estimated baseline creatinine [/table]
[table] Table 2: Physiologic markers of renal function [/table]
[table] Table 4: A comparison of leading animal models for the study of acute renal failure [/table]
[bib_ref] Acute renal failure in the ICU: risk factors and outcome evaluation by..., De Mendonca [/bib_ref]
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Update of the Brazilian Guideline on Nuclear Cardiology - 2020
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Update of the Brazilian Guideline on Nuclear Cardiology - 2020
Note: This guideline is for information purposes and should not replace the clinical judgment of a physician, who must ultimately determine the appropriate treatment for each patient.Correspondence: Sociedade Brasileira de Cardiologia -Av. Marechal Câmara, 360/330 -Centro -Rio de Janeiro -Postal Code: 20020-907.
## Declaration of potential conflict of interest of authors/collaborators of update of the brazilian guidelines on nuclear cardiology -2020
If the last three years the author/developer of the Update:
## List of abbreviations and acronyms
HED -11 C -meta-hydroxyephedrine labeled with Carbon-11 PIB-11 C -PET -pittsburgh B compound labeled with carbon-11 by PET imaging MIBG-Hg -mercury-201Tl -thallium-201Rb -rubidium-82Sr -strontium-82 Tc -technetium-99m MIBI-99m Tc -technetium-99m-labeled SESTAMIBI or MIBI P y r o p h o s p h a t e -99m Tc -t e c h n e t i u m -9 9 m -l a b e l e d pyrophosphate ACEI -angiotensin converting enzyme inhibitors ACS -acute coronary syndrome Aden -adenosine ADMIRE-HF -AdreView Myocardial Imaging for Risk Evaluation in HF AF -atrial fibrillation AHA -American Heart Association AL -light chain immunoglobulin ALARA -as low as reasonably achievable AMI -acute myocardial infarction angio-CT -angiotomography of coronary arteries ARB -angiotensin receptor blockers ATP III -Adult Treatment Panel, from the Program for Detection, Evaluation, and Treatment of High Cholesterol in Adults AUC -area under the curve AVB -atrioventricular blockage BMI -body mass index BNP -B-natriuretic peptide CA -cardiac amyloidosis CABG -coronary artery bypass graft CC -coronary calcium CAD -coronary artery disease CCA -coronary cineangiography CFR -coronary flow reserve CHF -congestive heart failure CIED -cardiac implantable electronic devices CMR -cardiac magnetic resonance CONFIRM -Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry COURAGE -Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation Trial CPU -chest pain unit CRP -C reactive protein CRT -cardiac resynchronization therapy CS -calcium score CTX -cardiotoxicity CV -cardiovascular Cx -circumflex coronary artery CZT -cadmium zinc telluride semiconductors DDD -artificial pacemaker stimulation mode DG1 -diagonal 1 coronary artery Dipy. -dipyridamole DM -diabetes mellitus Dobut. -dobutamine DS -duke score ECG -12-lead electrocardiogram ECHO -echocardiogram EDV -end diastolic volume ERASE Chest Pain -The Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain Trial ESV -end systolic volume ET -exercise testing FAME -Fractional Flow Reserve versus Angiography for Guidance of PCI in Patients with Multivessel Coronary Artery Disease FBP -filtered back-projection FDA -food and drug administration FDG-6-P -fluorodeoxyglucose -6 -phosphate FFA -free fatty acids FFR -fractional flow reserve FRS -Framingham risk score Gated-SPECT -myocardial perfusion imaging by single photon emission computed tomography technique synchronized with electrocardiogram HBP -high blood pressure HF -heart failure HFpEF -heart failure with preserved ejection fraction HFrEF -heart failure with reduced ejection fraction HMR -heart to mediastinum ratio HR -heart rate IAEA -International Atomic Energy Agency ICD -implantable cardioverter defibrillator ICNC -International Conference of Nuclear Cardiology IE -infectious endocarditis IFR -instantaneous flow reserve/instantaneous wave-free ratio
# Introduction
Nuclear cardiology is a non-anatomical, physiological imaging method. The use of radioactive or radiopharmaceutical substances makes it possible to study several physiopathological mechanisms of cardiovascular disease in vivo. Via this imaging technique, it is also possible to visualize and accompany an instituted therapy's physiological effects on cardiac function, on the cellular and biochemical level. Of all the applications of nuclear medicine in cardiology, scintigraphy or myocardial perfusion imaging with technetium-99m-labeled radiopharmaceuticals synchronized with electrocardiogram (Gated-SPECT), is the most common exam in clinical practice. For this reason, this technique will be the most discussed in these Guidelines.
Recent years have, however, seen a growing concern among the scientific community regarding rational and optimized use of ionizing radiation in medicine. Cardiovascular imaging, moreover, encompasses all functional and anatomical imaging techniques and should, in this context, be used rationally and cost-effectively. Other applications of nuclear medicine in cardiology have also emerged and gained prominence during the past decades, especially positron emission tomography (PET) for the study of coronary flow reserve, cardiac sympathetic activity, and inflammatory/infectious processes, and cardiac amyloidosis (CA). All of these aspects have been taken into consideration and will be covered in detail in the chapters developed herein.
Guidelines recommendations are highly valuable tools for medical activity of the highest quality. The objective is to support and aid doctors in making decisions regarding their patients, by elaborating orientations which may be useful as part of the decision-making process. No Guidelines, however, should be replaced by the abilities, experience, and clinical judgments of specialized professionals who are have the final say in their decisions concerning each individual patient.
In general, whenever possible and applicable, classifications of recommendation have been adopted for indicating cardiac scintigraphy, supported by levels of evidence, in accordance with the recommendations established by classical cardiology guidelines.
Based on current evidence, this document, which does not function as a substitute, practically and objectively adds important data to and updates the Brazilian Cardiology Society's (SBC) First Guidelines and Update on Nuclear Cardiology, both of which were published by the Brazilian Archives of Cardiology (Arquivos Brasileiros de Cardiologia), in 2002 and 2005, respectively.
As in the previously mentioned documents, those who participated in the elaboration of these Guidelines are considered specialists in their respective areas and were, for this reason, chosen to develop the chapters thereon. The committed involvement of all colleagues representing the SBC and the Brazilian Society of Nuclear Medicine (SBMN) have made the elaboration of these new update of Brazilian Guidelines on Nuclear Cardiology possible. It is our hope that they will be of great use, especially to Cardiologists and Nuclear Medicine and Clinical Physicians in Brazil. The Organizing Committee appreciates the collaboration of all those involved.
## Addendum to the ischemia study*
At the time of publication of this guideline, the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) had not been published yet, although the main findings were presented on November 16, 2019 at the American Heart Association (AHA) annual congress in Philadelphia, USA, available on the study's website. Considering its importance for medical decision-making and the potential implications for nuclear cardiology, a few relevant concerns should be highlighted on the findings available so far:
1. The main objective of the ISCHEMIA study was to assess whether patients (P) with at least moderate ischemia on a functional examination would benefit from myocardial revascularization (coronary artery bypass grafting or percutaneous coronary intervention) added to optimal medical therapy). Were randomized 5,179 patients with stable CAD and myocardial ischemia documented by one of many different methods (myocardial perfusion scintigraphy, stress echocardiography, cardiac magnetic resonance imaging, exercise testing not associated with cardiac imaging). These noninvasive methods were used to define the etiology of chest pain and for cardiovascular Update Update of the Brazilian Guideline on Nuclear Cardiology -2020
Arq Bras Cardiol. 2020; 114(2): risk stratification, a management approach established in clinical practice that is not invalidated by the findings of the study. Prior knowledge indicates that patients with lower ischemic burden have a better prognosis than individuals with larger and more intense ischemia;
2. The ISCHEMIA trial demonstrated no benefit of myocardial revascularization (Invasive Group -IG) versus optimal medical therapy (OMT) to reduce the major outcomes of "death" and "acute myocardial infarction." Despite the methodological differences, these results were somewhat similar to those of the COURAGE study. It is noteworthy that the mortality curves began to separate after two years of medical follow-up, apparently benefiting the IG and potential long-term implications, which justified the increased clinical follow-up of P, underway at the moment. Note that the IG had an improved quality of life assessment, reduced frequency of angina and lower use of specific medication compared to the OMT group;
3. The ISCHEMIA trial is one of the most relevant studies on stable CAD, with important messages for clinical practice. The validity of the results is emphasized for the population sample evaluated in the study and for the definitions of ischemia and its severity levels employed. However, for exclusion situations, such as P with left main disease, recent acute coronary syndrome, angioplasty in the previous 12 months, ejection fraction < 35% and progressive or unstable symptoms, prior knowledge remains unchanged. Both CAD and ischemic heart disease represent a broad spectrum of patients, with inherent heterogeneity and important prognostic implications (extensive evidence base in the literature and described in detail in the current guideline). Were excluded from the trial an impressive number of P that had at least moderate angina and ischemia in the absence of coronary obstructions, showing the diversity of the disease and the value of functional assessment;
4. The main question is whether the ISCHEMIA study has properly evaluated a significant number of P with moderate/severe ischemia, aiming to determine whether myocardial revascularization adds prognostic benefit to these patients, as documented by scintigraphy, which was not the exclusive method of documentation. There was the inclusion (randomization) of cases with nonexistent or mild ischemia (12% of the total randomized), which is surprising for a study that was initially intended to include only patients with moderate to severe ischemia. There was also a change in the criteria for inclusion of P with severe ischemia in the study, with a significant number based on the results of exercise testing, without imaging, a decision made after the study was in progress. From this change, the percentage of these P that would effectively have severe myocardial ischemia on scintigraphy is questioned;
5. Therefore, the Editorial Board of this guideline believes that the definitive analysis of the results will only be possible after the formal publication of the trial results.
# . introduction
Cardiovascular diseases are the main cause of death in Brazil, and they are responsible for 30% of deaths worldwide every year.They are responsible for approximately 8% of total healthcare costs in Brazil, a figure which has been increasingly annually, in parallel with population aging.Teich and Araújo estimated that in 2011, approximately 200,000 events associated with acute coronary syndromes occurred in Brazil, entailing a massive impact of 3.88 billion Brazilian reals, considering only hospital and indirect costs, associated with loss of productivity.Considering these findings, it has been demonstrated that (preventive) measures play a crucial role in reducing morbidity and mortality, and they should be a priority in national healthcare policy design, as they have profound additional impacts on reducing costs and maintaining productivity. Another significant point, however, which has contributed to reducing the outcome of "cardiovascular death" and to justifying expenses, involves the use of tools which make accurate diagnosis of a determined condition possible (?) and which aid and guide the conduct of physicians, based on these results. Myocardial perfusion scintigraphy (MPS) plays a significant role in justifying financial resources for attending patients with established or potential cardiovascular disease.
## Cost-effectiveness in comparison with cardiac catheterization
One of the main fundaments of MPS is its good ability to identify low-risk patients, who do not require invasive intervention, in spite of established coronary disease, such as anatomical lesions on coronary angiography.Observational studies in the 1990's have demonstrated that MPS was able to identify high-and low-risk groups, resulting in reduced costs for patients with coronary artery disease (CAD) and avoiding procedures that are not associated with improved patient health outcomes. A major prospective study carried out in the United States of America (USA) recruited 11,372 patients with stable angina, who were referred to either MPS or cardiac catheterization. Patients were adjusted by clinical risk, and the costs of direct cardiac catheterization (aggressive strategy) were compared to initial scintigraphy followed by selective catheterization in high-risk patients (conservative strategy). Although both strategies had similar adverse outcomes, such as cardiac death and non-fatal myocardial infarction, revascularization rates were higher (between 13% and 50%) in patients who underwent catheterization directly.This reflex of revascularizing anatomical lesions which do not determine ischemia led to unnecessary associated medical costs of around 5,000 dollars per patient in this study.Currently, the use of medical resources for conditions that do not have consequences for patients or that could be managed conservatively is known as "overtreatment."The study of *To access the Addendum bibliography, go to: https://sbc-portal.s3.sa-east-1.amazonaws.com/diretrizes/Publicacoes/2020/ Bibliografia-adendo/Bibliografia_ADENDO_INGLES_24-01-2020.pdf the impact of MPS on reducing costs has shown that its main function is to prevent patients who have low or moderate risks on single photon emission computed tomography (SPECT) from being treated with unnecessary catheterizations and revascularizations. Similarly to this North American study, Underwood et al.have demonstrated that strategies which incorporate myocardial scintigraphy to evaluate patients with stable coronary diseases are both cheaper than and as effective as strategies involving invasive anatomical assessment.Cerci et al.evaluated the impact of diagnostic exams on patients with CAD in different scenarios within Brazil's public Single Health System (SUS, acronym in Portuguese). The study's most relevant finding is that, although non-invasive functional tests are the most frequently solicited exams for evaluating patients with suspected or known CAD, the majority of healthcare costs for these patients are related to procedures/invasive treatment. In other words, in the Brazilian context, the costs of diagnostic exams continue to be significantly lower than those of invasive and therapeutic procedures. In this manner, it seems logical to affirm that, if scintigraphy exams are made available to patients attended by the SUS, there will be a similar impact on the reduction of healthcare costs, which has been the case in the USA and some countries in Europe. Another relevant piece of data from this study refers to the fact that the majority of patients who were revascularized had not undergone tests to document ischemic burden; only anatomical diagnostic techniques had been applied.
## Cost-effectiveness of myocardial perfusion scintigraphy in relation to coronary angiotomography
Angiotomography (angio-CT) of coronary arteries offers very accurate, non-invasive anatomical assessment, and it has proved to be an excellent technique for ruling out obstructive coronary disease in low-to intermediate-risk patients. Angio-CT, however, has presented results similar to those of cardiac catheterization in relation to triggering a higher number of myocardial revascularizations, which do not necessarily (means) reduced cardiovascular outcomes. In a recent meta-analysis comparing angio-CT to functional methods, no differences were observed regarding the outcomes of death or cardiac hospitalization, but there was a 29% reduction in the number of non-fatal infarctions. On the other hand, the use of this method was associated with 33% and 86% higher rates of invasive coronary angiography and myocardial revascularization, respectively. It is not known whether the reduction in non-fatal infarctions may be attributed to the higher number of revascularizations, which is (unlikely) considering in light of other studies on stable CAD, or to the higher use of statins and aspirin associated with the recognition of anatomical coronary lesions.With the objective of elucidating the role of angio-CT on cost-effectiveness of approaches to stable CAD in comparison with myocardial scintigraphy, the Randomized Evaluation of Patients With Stable Angina Comparing Diagnostic Examinations (RESCUE) study, which is being developed, is expected to compare these strategies in a prospective, randomized manner.The authors of a recent meta-analysis published by the American Heart Association (AHA)/Circulation, have reinforced 2 important aspects of cost-effectiveness:- The importance of performing appropriate exams as a way of (ensuring) their cost-effectiveness, especially techniques like MPS.
- The results of appropriate exams should effectively lead to appropriate decision making in clinical conduct and patient management.
## Indications for myocardial perfusion scintigraphy
Over the past years, different medical societies have published criteria for defining scenarios in which myocardial scintigraphy may be adequately utilized. In addition to traditional classification of recommendation and levels of evidence, more recent criteria on appropriate MPS exam referral have been suggested, dividing indications into appropriate, possibly appropriate, and rarely appropriate, resulting from the application of scores constructed based on clinical scenarios and specific methodologies.In this classification, indications with scores from 1 to 3 are considering rarely appropriate; 4 to 6, possibly appropriate; and 7 to 9, appropriate. Published documents are based on evidence from American and European Guidelines, as well as the recently published Brazilian Guidelines on stable coronary disease.Regardless of classification type, there is consensus that symptomatic patients with intermediate risks of ischemic heart disease are the ones who most benefit from MPS in terms of diagnostic and prognostic evaluation. The exam should preferably be performed in association with physical exercise in patients with sufficient physical and clinical conditions (estimated ability for activities of daily living with metabolic expenditure greater than 5 METs), in order to measure their functional capacity, hemodynamic responses (heart rate and blood pressure behavior), stress-induced arrhythmias, and other responses. It is recommended that patients with complete left bundle branch block, regardless of functional ability, undergo MPS under pharmacological stress (dipyridamole or adenosine). In the same manner, regardless of pretest probability of ischemic heart disease, patients with low functional ability or uninterpretable electrocardiogram (ECG) are indicated to undergo MPS. On the other hand, patients with low probability of ischemic heart disease, higher functional ability, and interpretable ECG are not indicated for MPS .
In patients with heart failure (HF) and left ventricular systolic dysfunction or recent-onset atrial fibrillation (AF), ventricular tachycardia (VT) or syncope, the indication for MPS is appropriate or possibly appropriate, unless the patient in question is low risk or has low pretest probability. Asymptomatic patients with no history of ischemic heart disease and without abnormal exercise testing (ET) generally do not benefit from undergoing MPS. In specific situations, in patients with high calcium scores (greater than or equal to 400), diabetes, chronic renal insufficiency, or a prevalent family history of ischemic heart disease, performing MPS may aggregate value to the medical decision-making process, with satisfactory cost-effectiveness. Asymptomatic patients with abnormal stress ECG who are re-stratified Update Update of the Brazilian Guideline on Nuclear Cardiology -2020
Arq Bras Cardiol. 2020; 114(2):325-429
## -indication criteria for myocardial perfusion scintigraphy in symptomatic patients
## Assessment of patients with non-acute chest pain or ischemic equivalent score
Low pretest probability of CAD, with interpretable resting ECG and ability to exercise 3
Low pretest probability of CAD, with uninterpretable resting ECG or inability to exercise 7
Intermediate pretest probability of CAD, with interpretable resting ECG and ability to exercise 7
Intermediate pretest probability of CAD, with uninterpretable resting ECG or inability to exercise 9
High pretest probability of CAD, regardless of interpretable resting ECG and ability to exercise 8 ACS: acute coronary syndrome; CAD: coronary artery disease; ECG: 12-lead electrocardiogram.
## Table 3 -indication criteria for myocardial perfusion scintigraphy in asymptomatic patients and/or patients with prior exams asymptomatic patients -detection of cad/risk stratification score
Low risk (ATP III criteria) 1
Intermediate risk (ATP III criteria) -interpretable Intermediate risk (ATP III criteria) -uninterpretable High risk (ATP III criteria) 7
High risk and calcium score (Agatston) between 100 and 400 7
Calcium score (Agatston) > 400 7
Low-risk Duke score (> +5) 2
Intermediate-risk Duke score (between −11 and + 5) 7
High-risk Duke score (< −11) 8
Agatston: score that defines the presence and quantity of calcium in coronary arteries, characterizing atherosclerosis; ATP III: Adult Treatment Panel, from the program for detection, evaluation, and treatment of high cholesterol in adults; CAD: coronary artery disease.
with the use of prognostic scores, such as the Duke score, may also benefit from complementary investigation via MPS, especially if their risk scores are intermediate or high . Diverse examples of clinical situations cited in may also be found in the section on integration of diagnostic modalities.
When patients have established ischemic heart disease and are asymptomatic, early myocardial perfusion studies with radiopharmaceuticals should be avoided following percutaneous coronary intervention and/or myocardial revascularization surgery procedures. In the event of percutaneous coronary intervention and myocardial revascularization surgery, the application of MPS has been observed to have a favorable cost-benefit ratio for follow up after more than 2 and 5 years, respectively, even in asymptomatic patients. Symptomatic patients with specific clinical conditions (or equivalent manifestations) may benefit from the exam before this period .
For patients with previous exams who manifest new symptoms or who require assessment of the repercussion of diagnosed intermediate lesions and characterization of arteries with obstructive lesions "responsible" for a larger myocardial area at risk, as well as patients with multivascular diseases, the indication for MPS is classified as appropriate or possibly appropriate. In patients with established coronary disease and worsening symptoms, MPS may aid in quantifying ischemic burden (extent and intensity of defects) and in determining medical management. In clinically stable patients with previous exams performed more than 2 years prior, MPS may be appropriate .
In patients who present acute chest pain, with clinical suspicion of acute coronary syndrome (ACS), normal or uninterpretable ECG (old left bundle branch block or pacemaker) and normal biomarkers, resting myocardial scintigraphy may exclude acute cardiovascular events with a high degree of safety (high negative predictive value [NPV]), allowing patients to be discharged from the emergency room. If the exam is normal, investigation may continue with outpatient tests involving physical or pharmacological stress, whether associated or non-associated with non-invasive imaging, and even anatomical assessment via coronary angio-CT, in specific conditions. For patients with ACS who are clinically stable, with neither recurring chest pain nor HF, and who have not undergone any invasive exam, MPS is useful for detecting presence and extent of myocardial ischemia .
Indications for MPS to assess pre-operative risk of noncardiac surgeries and vascular surgeries have also been recently revised.Patients who will undergo low-risk surgeries do not need to undergo MPS. If the surgery is not low-risk, functional capacity is the factor that determines whether MPS will be necessary. In patients with functional capacity estimated at greater than or equal to 4 METs, without cardiac symptoms, regardless of clinical or surgical risk, noninvasive assessment of myocardial ischemia is generally not recommended. However, for patients with low functional capacity and elevated clinical/surgical risks, there is an indication to perform MPS under pharmacological stress. The following are considered clinical risks: history of ischemic heart disease, congestive heart failure (CHF), cerebrovascular disease, diabetes mellitus (DM), and renal insufficiency (creatinine > 2.0 mg/dl). In the absence of these risk factors, regardless of functional capacity, surgery may be performed without complementary functional exams .
In patients with accentuated left ventricular dysfunction who are eligible for myocardial revascularization, assessment of myocardial viability may aid selection of patients who will benefit from this treatmentMPS is, therefore, an appropriate indication in diverse clinical manifestations of ischemic heart disease, from acute manifestations in the emergency room to diagnostic investigation of stable patients, aiding in therapeutic decision making through various tools which make it possible to define disease severity, as well as in pre-operative assessment in specific situations and in defining the benefits of revascularization for patients with significant myocardial viability. It is worth noting that, for diagnostic investigation, patients with intermediate probability of ischemic heart disease are those who most benefit from MPS and that it is rarely appropriate in patients with low probability.
## Myocardial perfusion scintigraphy
Methods -types of Cardiovascular Stress
## Radiopharmaceuticals used to perform myocardial perfusion scintigraphy
In Brazil, the main radiopharmaceuticals available for obtaining images of the myocardium are thallium-201 ( 201 Tl) and those labeled with technetium-99m ( 99m Tc), which mainly include 2-methoxy-isobutyl-isonitrile, known as Sestamibi (or MIBI), and tetrofosmin. Given that these are the most widely used, the specific methods used for acquiring images with them will be presented.
Thallium-201 or 201 Tl 17 is a monovalent cation with biological properties analogous to those of potassium. It is both intracellular and absent in scar tissue, and it is thus designated for differentiating ischemic myocardium from fibrosis. It has a physical half-life of 73 hours, and it decays by electron capture to mercury-201 ( 201 Hg), and the photons emitted for imaging are primarily x-rays (ofHg itself) between 68 and 80 kiloelectron volts (keV), in addition to lower quantities of gamma radiation in the energy range of 135 keV and 166 KeV. Upon intravenous injection, initial myocardial uptake is proportional to regional blood flow, depending on the integrity of the cellular membrane. It penetrates the cellular membrane via active transport, involving energy expenditure (Na + /K + ATPase system), with a high first-pass extraction fraction in the myocardium (the proportion of 201 Tl which is extracted from blood and absorbed by myocytes), of around 70% to 85%.
Maximum concentration of thallium-201 in the myocardium occurs approximately 5 minutes after injection, which is generally administered during peak exercise or clinical and/ or electrocardiographic alterations triggered during an ET or a pharmacological test. It presents rapid disappearance or clearance from the intravascular compartment. Following initial distribution of the radioisotope throughout the myocardium, related to blood flow, the phenomenon of redistribution begins 10 to 15 minutes after injection. This is dependent on clearance or washout of thallium-201 from the myocardium, which no longer depends on blood flow but rather on the concentration gradient between myocytes and blood levels. Redistribution of thallium-201 is quicker in normal myocardium than in ischemic myocardium, resulting in different activities in these tissues (differential "washout"). Due to the characteristics described and the ability to evaluate the integrity of the cellular membrane, thallium-201 has the additional property of studying myocardial viability, predominantly related to hibernating myocardium .This represents the condition of resting left ventricular dysfunction, resulting from chronic hypoperfusion in myocardial regions where, although the myocytes have remained viable (alive), they have chronically depressed contractile function. Hibernation may also be seen as a "flow-contraction" agreement process, where metabolism remains dependent on residual myocardial flow in a manner sufficient for minimum substrate supply and inhibitory substance removal. Therefore, the condition of hibernation, notwithstanding reduced resting coronary flow, is not necessarily associated with the presence of chronic ischemia, given that oxygen supply and consumption ratio may be preserved.Technetium-99m-labeled SESTAMIBI or MIBI (MIBI-99m Tc):The most frequently used marker for myocardial perfusion studies, is 2-methoxy-isobutyl-isonitrile, a stable, lipophilic, cationic compound belonging to the isonitrile family, which has the property of crossing cellular (sarcolemmal) membranes and binding to myocyte mitochondria through the mechanism of passive diffusion, depending on the electrochemical transmembrane gradient. It therefore involves no energy expenditure. It has a lower first-pass extraction fraction in the myocardium than thallium-201, of approximately 60%.It does not expressively present the phenomenon of redistribution, largely remaining retained within mitochondria. This property makes it necessary to deliver 2 separate injections of the radiopharmaceutical, 1 during the resting and 1 during the stress phase. This may be done either on the same day or on different days. As MIBI is not radioactive, it must be labeled with technetium-99m ( 99m Tc), which has a physical half-life of 6 hours and emits gamma photons in the energy range of 140 keV (photopeak). Similarly to thallium-201, initial myocardial uptake is proportional to regional blood flow, depending on the integrity of the cellular membrane. In this manner, a linear relationship is observed between the intravenous dose per gram of myocardium and blood flow per minute , starting at minimal flow ranges of approximately 2.0 to 2.5 milliliters per gram. minute -1 , values normally found in maximum exercise testings. When very high coronary flow are reached, generally over 3.0 mililiters per gram.minute -1 , the linear relationship between this variable and myocardial uptake is lost, with decreased blood extraction of the radiopharmaceutical, in a phenomenon known as "roll off".Nonetheless, owing to higher energy emission (higher photopeak), measured in keV, it presents higher quality images, in comparison with thallium-201. Finally, the elimination of MIBI-99m Tc takes place through the hepatobiliary system, whereas elimination of thallium-201 is mainly achieved through the renal system. Regarding other isonitriles approved by the FDA for assessment of obstructive CAD, only tetrofosmin, whose properties are similar to those of MIBI-99m Tc, has been made available for clinical use.
## Myocardial perfusion scintigraphy with tomography imaging (spect)
Technological evolution of computerized systems has made it possible to divide the myocardium of the left ventricle (LV) into tomographic slices measuring only a few millimeters. In conventional gamma cameras (with iodide sodium crystals) the size of a pixel (the smallest component of a digital image) is 6.4 mm, and in CZT (cadmium zinc telluride semiconductors) technology it is 4 mm, representing related cross sections and, consequently, the method's spatial resolution. 29-31 The resulting images facilitate the separation of nearby regions, improving contrast resolution and allowing for better detection of differences in concentrations of radioactivity in the myocardium. The SPECT technique also allows for detection of ischemic regions, even those that are small in size, i.e., approximately 2% of LV mass, in tissue with relatively normal tracer concentration.
## Protocols:
The preferred means of obtaining perfusion images of the myocardium and LV function with tracers labeled with technetium-99m ( 99m Tc) is known as the "1-day protocol", made up of 2 stages, (resting-stress or stress-resting). During the first step, the injected dose of MIBI-99m Tc, measured in millicuries (mCi) or megabecquerels (mBq), is three times lower than the dose administered during the second phase, thus avoiding the residual activity effect or "shining through" phenomenon. Another option is the "2day protocol", where in each phase is performed on a separate day. In this case, similar doses and acquisition parameters are used. It is important to emphasize that, in situations where stress images are taken before resting ones, even if the perfusion images are normal, it is nevertheless important to obtain resting images, except in specific cases, given that analysis of LV function in both situations may provide relevant information, including the possibility of detecting patients with homogenous tracer distribution due to balanced severe coronary diseases. Furthermore, the detection of transient LV dilatation may also be useful in this case, and this requires that both phases be performed. However, in asymptomatic patients who have intermediate/low risks and no clinical evidence of CAD, who have undergone the stress phase as the initial MPS stage and whose perfusion images are normal, it is possible to dispense with the resting phase, in what is known as the "stress only protocol." In this situation, recent studies have provided evidence that the test's prognostic value is maintained and that diagnostic ability is similar to the costs of high sensitivity. Furthermore, the patient receives a lower dose of radioactive activity, and total exam time is reduced. 32,33
## Myocardial perfusion scintigraphy with tomographic
Images Synchronized with Electrocardiogram (Gated-SPECT)Cardiac images should be acquired synchronized with patient ECG, allowing for additional analysis of ventricularConsidering this aspect, in situations where there are doubts between persistent perfusion defects and/or artifacts (due to breast or diaphragmatic attenuation), analysis of ventricular wall motility and thickness may contribute to differentiating these two causes. When apparent reduced relative uptake of a radiopharmaceutical is due to an artifact, the motility and systolic thickness of this wall are normal.
The estimated results of left ventricular ejection fraction (LVEF) that are conventionally considered normal vary according to technique and methodology employed. With the Gated-SPECT technique, this value is ≥ 50% for both sexes; there are few references with differentiated values for men and women, in addition to different established limits of normality. Due to specific aspects related to methodologies used to calculate LVEF, values found in individuals who are shorter and individuals with smaller ventricular cavities and/ or hypertrophic ventricles, especially in women, may be overestimated, at times exceeding values of 75% to 80%.
Calculations of LVEF and ventricular volumes obtained by Gated-SPECT may be utilized for prognostic stratification. LVEF < 45% and end systolic volume (ESV) > 70 ml are associated with increased risks of cardiac death.This analysis may be carried out either while resting or under stress; it should preferably be done during both steps, however, considering the possibility of detecting transient LV dysfunctions induced by physical exercise or pharmacological stress.
Cardiac arrhythmias pose difficulties to the acquisition of ECG-synchronized images and may significantly influence the results obtained for ejection fraction and produce artifacts in myocardial perfusion images. There is a technically defined time window for RR interval variation, generally around 20%, after which point heartbeats are rejected. This situation means that if there is an arrhythmia which produces variations between RR intervals above these established limits, such as persistent AF, the corresponding data from that specific cardiac cycle will be rejected, and there will consequently be lower counting statistics. In these cases, images should be acquired without ECG synchronization in order to avoid the occurrence of artifacts.
## Cardiovascular stress
The basic principle of using cardiovascular stress associated with myocardial perfusion images consists of creating heterogeneity in blood flow between vascular territories irrigated by normal coronary arteries with significant obstructive stenoses.The use of myocardial perfusion agents makes it possible to visualize this heterogeneity in regional blood flow. In practice, of all existing cardiovascular stressors, only ET and pharmacological tests have been used.
Both stress modalities, physical exercise and pharmacological vasodilation, have similar sensitivity and specificity for the detection of CAD via analysis of perfusion images.Physical stress: ET is the associated method of choice for diagnostic and prognostic values, which have already been established in conformity with clinical, hemodynamic, and electrocardiographic variables obtained during exercise, which add incremental data to myocardial perfusion study. Stress tests have a higher chance of revealing abnormalities in patients with more severe and extensive obstructive arterial disease. Chest pain and/or decreased systolic blood pressure (SBP) during low levels of exercise are highly important findings that are associated with adverse prognoses and multivessel coronary disease. Other markers of unfavorable prognosis include high-magnitude ST segment depression, with a horizontal or downsloping aspect, which may appear early during low workloads or be characterized by late recovery after stress has ceased, present in multiple leads, among others.
Some studies have incorporated stress test variables into diagnostic and prognostic scores.The most widely used in our context is the Duke prognostic score. Using Cox's regression analysis, Mark DB et al. proposedoccurs, and 2 (two) if the pain is impeditive (growing intensity) as exercise proceeds. In accordance with the results of the regression equation, patients are classified as follows:
- High-risk group: patients with scores ≤ -11, with an annual cardiovascular mortality rate ≥ 5%.
- Low-risk group: patients with scores ≥ 5, with an annual cardiovascular mortality rate < 1%. In clinical practice, when patients are considered high-risk, this reinforces a priori the indication for invasive study with the aim of managing and directing medical treatment, be it interventional or not, while always taking the possibility of improving morbimortality and quality of life into account.
In patients with intermediates results, i.e., scores between > -11 and < +5, in order to reclassify risk, complementary exams associated with imaging, such as the following, may be required:
-Myocardial perfusion scintigraphy (MPS) with ET or vasodilators.
-Vasodilator stress cardiac magnetic resonance (technique associated with inability to exercise).
-Doppler echocardiogram under stress or specific conditions.
-Computerized angiotomography of coronary arteries.
Finally, in patients considered low-risk, medical management is related to prevention measures. On the other hand, based on a growing base of evidence, these methods,especially MPS, have become of paramount importance for quantifying ischemic area, even in patients who are considered high-risk, with the aim of assisting and directing the medical approach to be adopted,notwithstanding the unavailability of information from randomized clinical trials such as the "Ischemia Study," which will be able to assist in better management of patients with extensive areas of the myocardium at risk.Furthermore, emphasis given to exercise as the primary stress-producing agent of choice within the cardiovascular system has become clear, given that it is the most physiological method for triggering myocardial ischemia, based on sympathetic stimulation and the increase in the main determinants of myocardial oxygen consumption (MVO 2 ), such as HR, blood pressure, and myocardial contractility. Likewise, exercise leads to coronary vasodilation through biochemical mechanisms, resulting in increased blood flow to the myocardium and greater oxygen supply, thus meeting the necessary demands imposed during the application of extreme effort. This ability to increase coronary blood flow, which reaches three to four times baseline values during peak exercise, in the absence of significant obstructive coronary lesions, conceptually represents the phenomenon known as "coronary reserve," considered the main characteristic of MPS with radiopharmaceuticals. Moreover, with respect to the limitations and contraindications of this methodology, 60 joint analysis of both stress test and cardiac imaging exams will play a fundamental role in the medical decision-making process, albeit in view of previous clinical information or pretest probability of obstructive CAD.
With relation to the main methodological aspects, the following stand out:
- Prior venous access in an arm, in a "Y" shape (separate routes), for radiopharmaceutical injection during peak exercise and subsequent flush with saline solution, respectively.
- Safety criteria for administering and interrupting stress should be in accordance with established guidelines, reinforcing the need for a maximum test.- Fo l l o w i n g i n t r a v e n o u s a d m i n i s t r a t i o n o f t h e radiopharmaceutical, stimulate continuation of stress for 1 more minute.
- When using MIBI-99m Tc (absolute preference in Brazil), image acquisition follows conventional protocols (30 to 60 minutes after stopping stress). Variations in initial acquisition time depend on patient type (obesity, prior abdominal surgery, prominent extracardiac activity in the resting images phase.
- When using thallium-201, considering the phenomenon of redistribution, images should be taken 10 to 15 minutes after stopping stress.
Pharmacological tests: Represent excellent alternatives for evaluating patients with physical limitations or clinical impediments to undergoing efficacious exercise testing . The most frequent conditions are found in. They represent around 20% to 30% of all cases of scintigraphy referral and approximately 50% of elderly patients.The drugs used in these circumstances are dipyridamole, adenosine or regadenoson, and dobutamine. These drugs induce maximum vasodilation and increase coronary flow, allowing for assessment of coronary reserve, with diagnostic and prognostic power similar to that of exercise,which has recently been extended to elderly patients and women.In cases of left His bundle branch block or artificial pacemaker with ventricular stimulation, the first option is a pharmacological test with dipyridamole or adenosine, with the aim of avoiding what are known as false-positive results (alterations in relative radiopharmaceutical uptake, in the absence of obstructive lesions). These are caused by atypical movement of the interventricular septum, which occurs in these situations and is accentuated when myocardial scintigraphy is performed with ET. Reduced radiopharmaceutical uptake is often observed in these patients and is most frequently related to the septal region, which may be exacerbated by the stress test, as increased HR increases paradoxical septal motion and, consequently, reduces perfusion in this wall.Primary vasodilators: Dipyridamole, adenosine, and regadenoson (not available for routine clinical practice in Brazil) provoke a significant increase in coronary flow in normal arteries and a small or nonexistent increase in arteries with functionally significant stenosis, thus resulting in relative heterogeneity of flow between LV walls. During maximum vasodilatation, when the radioisotope is injected, the difference in relative radiopharmaceutical uptake in LV walls will also be observed, making it possible to diagnose coronary disease: solution (SS). It may, alternatively, be injected manually (with a 20-ml syringe), using the same dilution. Alternatively, a more elevated dose of 0.84 mg.kg -1 may be used in select cases. The radiopharmaceutical is administered IV during hyperemia or maximum vasodilation, 2 to 4 minutes after the end of dipyridamole infusion. Dipyridamole inhibits the action of the enzyme adenosine deaminase, wich degrades endogenous adenosine, in addition to blocking reuptake of adenosine into the cellular membrane, with a consequent increase in extracellular concentration and resulting coronary vasodilation. Its biological half-life is approximately 45 minutes.
- Adenosine: The usual dose is 140 μg.kg -1 .min -1 , and it must mandatorily be administered via a 6-minute continuous infusion pump, diluted in 50 ml of SS, with the injection of the radiopharmaceutical administered during the third minute via a different intravenous access. It is, also, possible to inject the solution for 4 minutes, in which case the radiopharmaceutical is administered during the second minute.Because xanthines block the vasodilation effect, patients should be instructed to suspend them for 24 hours before a scheduled exam with dipyridamole or 12 hours before a scheduled exam with adenosine, in addition to any other drug or product, food, or drink that contains methylxanthines or theophyllines, including coffee, tea, soft drinks, chocolate, energy drinks, compound analgesics containing caffeine, especially for treatment of muscular pain or migraines, et al. Reference lists are available for consultation.Adenosine induces coronary vasodilation via specific activation of A 2A receptors in the cellular membrane, resulting in increased coronary flow up to 4-or 5-fold resting values.
Accuracy for detecting CAD with the use of MPS is comparable between both drugs. It is worth reiterating that, in exams using dipyridamole and adenosine, modifications in the ST segment occur relatively infrequently, even in patients with obstructive CAD (lower sensibility). In some instances, only the relative difference in flow observed in patients with different degrees of luminal obstruction and coronary reserve will determine perfusion defects, and ischemia will not necessarily be present. For this condition, collateral circulation is necessary, which causes coronary steal, with consequent alterations in contractility. Nevertheless, the sensitivity of scintigraphy images associated with the use of pharmacological agents or stress tests is similar. Adverse effects or "paraeffects" of using these drugsoccur in approximately 50% of patients with dipyridamole and in up to 80% of patients with adenosine. Common side effects include headache, dizziness, flushed face, feeling hot, chest pain, ST alterations and others.These manifestations generally do not last long, and in most cases they may be reversed by administering intravenous aminophylline at 1 to 2 mg.kg -1 or 72 mg (3 ml) to 240 mg (10 ml or 1 vial) 2 minutes after injecting the radiotracer, when MPS is associated with dipyridamole. When adenosine is used, there is no need to inject an antagonist, given its ultrashort half-life, from 2 -10 seconds, the recommendation being simply to interrupt the infusion. When it is not medically possible to perform either the physical stress or the pharmacological dilation modality with dipyridamole or adenosine, intravenous administration of dobutamine solution may be the best option for assessing coronary reserve flow, with regards to increased MVO 2 . Contraindications to dipyridamole and adenosine use are listed in.
It is, finally, important to stress that, with both dipyridamole and adenosine, no significant increases are observed in MVO 2 , which, in clinical practice, is translated as the product of heart rate (HR) × systolic blood pressure (SBP), or the double product. During pharmacological stimulation, SBP values generally drop by around 10% while HR increases by approximately the same proportion, with no consequent increase in MVO 2 .
Drugs that promote elevated myocardial oxygen consumption: These drugs represent an alternative for patients who cannot undergo ET or pharmacological stress with dipyridamole or adenosine. Examples include patients respectively. The most commonly used is dobutamine, which acts on beta-1 (β-1) adrenergic receptors, with chronotropic and inotropic stimulation, depending on the infused dose, in addition to direct effects on beta-2 (β-2) receptors, with peripheral vasodilation response. This results in an increase in cardiac output, HR, and SBP, leading to an increase in MVO 2 and, consequently, in coronary vasodilation. Protocol: The protocol begins with venous administration of the solution (250 mg of dobutamine diluted in 250 ml of saline solution -1 mg per 1 ml) via infusion pump at a dose of 10 ug.kg -1 . min -1 for 3 minutes (first step), followed by 20 μg.kg -1 .min -1 for 3 minutes (second step), adding 10 μg.kg -1 .min -1 every 3 minutes (third and fourth steps) until the maximum dose of 40 μg.kg -1 .min -1 has been reached .In patients who have not reached submaximal HR and who do not have evidence of ischemia, it is possible to associate intravenous atropine (0.25 to 2 mg) and perform isometric stress with hand grip maneuvers (e.g., compressing a tennis ball).
A Brazilian study has demonstrated that early use of atropine (following the first phase of dobutamine infusion) is safe and that it reduces infusion time and complaints during stress, without affecting diagnostic precision.Furthermore, the presence of perfusion defects induced by pharmacological vasodilatation and motility abnormalities triggered by stress aggregate incremental prognostic value to the test, which has recently been validated with the use of ultrarapid cameras (CZT technology).Contraindications to dobutamine use may be found in. Patients on betablockers should stop taking these medications for 48 to 72 hours before the test. Special attention should be given to patients with bronchospasm undergoing MPS with dobutamine, whose plasma half-life is around 2 to 3 minutes, considering that its antagonist is metoprolol at an intravenous dose of 5 mg and that it is contraindicated in the presence of pulmonary obstructive disease. The most frequent adverse events or paraeffects associated with administration of dobutamine solution are listed in. To reverse them, in addition to metoprolol, other intravenous short-acting betablockers, such as esmolol (0.5 mg.kg), which is available, should be injected after the first minute of radiotracer injection.
## Combined stress:
The association of dynamic stress with low workloads (e.g., until the second stage of the Bruce protocol or until feeling light fatigue, equivalent to the number 13 on the subjective Borg stress scale) and vasodilators has been shown to reduce subdiaphragmatic (hepatic) activity and improve the ratio of radiation activity emitted between the target organ and the viscera (background), with consequent improvements in image quality.It has similarly shown a decrease in the occurrence of adverse effects resulting from the infusion of dipyridamole or adenosine, as well as the incidence of atrioventricular blockage. This protocol is ideal for patients who are able to Update Update of the Brazilian Guideline on Nuclear Cardiology -2020
Arq Bras Cardiol. 2020; 114(2): exercise but who are using medications that limit increases in HR (betablockers, antiarrhythmic drugs, et al.).
## New drugs:
There are 3 types of adenosine receptors. The use of specific selective antagonists to A 2 receptors has shown evidence of adequate coronary hyperemia and lower intensity of systemic effects, especially chest pain and atrioventricular blockage. A double-blind, randomized (regadenoson or adenosine), multicenter studyinvolving 784 patients has shown that diagnostic information is similar and that there were no serious adverse effects; regadenoson, however, was tolerated better than adenosine. Second-degree atrioventricular blockage occurred in 3 patients with adenosine and in no patients with regadenoson. Regadenoson's short biological half-life minimizes and limits the duration of adverse effects, diminishing monitoring time. It is administered via bolus, and it is not necessary to adjust dose to body weight. Its use is promising in patients with chronic obstructive pulmonary disease. The incidence of serious complicationswith the performance of cardiovascular stress is related in.
## Injection of the radiopharmaceutical
After reaching 85% maximum heart rate, the radiopharmaceutical is injected and the Dobutamine infusion continues for 1 more minute.
## Image generation and perfusion defects in myocardial scintigraphy with radioisotopes
Resting coronary flow is 1 ml.g.min -1 , increased 3-to 5-fold during maximal vasodilation or hyperemia, under physical or pharmacological stress.In the presence of obstructive coronary lesions, resting coronary flow decreases when luminal narrowing is greater than 80%, due to exhaustion of the coronary reserve. When physical or pharmacological stress are applied, early exhaustion of the coronary reserve is observed, and it then exhibits a drop, generally beginning with lesions with luminal narrowing of 50%.This information has currently been validated based on invasive measures of coronary flow reserve (CFR), fractional flow reserve (FFR), and instantaneous flow reserve (IFR), considered "standard" for characterizing myocardial ischemia; some have also been reproduced by non-invasive PET methods.Tests with pharmacological stimulation using dipyridamole or adenosine associated with MPS are considered frequently to result in coronary flows in the range of 4 ml per gram of myocardium per minute, 87-89 generating homogenous relative uptake patterns of the radioisotopes in the myocardium, and scintigraphy images are considered normal when the coronary arteries are free of atherosclerotic processes. There are, however, specific situations in which patients with balanced multivessel disease (lesions in 3 arteries with similar coronary reserve) in which perfusion images appear with apparently homogeneous radiopharmaceutical distribution.From the conceptual point of view, it is necessary to comprehend that the generation of scintigraphy images is based on relative radiopharmaceutical uptake, which is injected intravenously during physical exercise or pharmacological test, predominantly in the LV myocardium. Comparison of radiopharmaceutical uptake between ventricular walls is expressed in images based on a scale of colors, created by specific computer programs, which, in addition to allowing for subjective analysis of perfusion, make semi-quantitative and quantitative evaluation of affected myocardial area possible.
## Possible scintigraphy imaging results, using
Qualitative, Semi-quantitative, and Quantitative Analyses Visual or qualitative analysis: By simply inspecting images resulting from perfusion tomography and ventricular function exams (Gated-SPECT technique), it is possible to assess blood flow and regional contractility of the LV myocardium indirectly. Tomography images are reconstructed as multiple slices along the anatomical axis of the LV, defined as corresponding regions and respective relations with coronary territory. The slices are taken on the short, long vertical, and long horizontal axes. Characterization of uptake of the radiopharmaceutical MIBI-99m Tc or Tetrofosmin-99m Tc during both exam stages (resting and stress, 1 day protocol) and thallium-201 during the stress and redistribution phases focuses on the anterior, septal, inferior , lateral, and apical regions of the LV. The short-axis projection uses transverse tomographic slices of the LV, sweeping from the apex or distal portion, through the middle of the cavity, to the basal portion. All regions and subdivisions are numerically identified, in accordance with the established scoring system, with the aim of standardizing segmentary analysis of the LV myocardium for perfusion study. Division into 17 segments has consensually been accepted, resulting in less interpretation subjectivityand. Different radiopharmaceutical uptake and retention patterns allow for differentiation of normal, ischemic, and fibrotic tissues. The normal myocardium has similar uptake during both the stress and resting/ redistribution phases, whereas the ischemic myocardium shows reduced relative uptake in stress images and normal uptake during resting/redistribution. Fibrotic tissue, on the other hand, shows reduced relative uptake during both study phases. If fibrotic tissue coexists with an ischemic yet viable myocardium, reduced relative uptake will be observed during the stress phase, with partial improvement during the resting/redistribution phase. Hibernating myocardium will also show persistent reduced uptake, or be it, reduced uptake that is similar in both the stress and the resting phases.
To differentiate it from fibrotic tissue, it is possible to perform assessment of viable myocardium with thallium-201, in , representing the myocardial regions; furthermore, correspondence of segments may be seen as presented in the polar map, which represents radiopharmaceutical distribution throughout the left ventricular myocardium in the form of a polar map, whose center corresponds to the apex and whose peripheries correspond to the basal portions. The correspondence between the numerical classifications and their respective segments is described in.
## Distal
Mid-short axis Basal Long vertical axis Polar map.
which case it is sometimes necessary to add another phase or stage, namely that of late redistribution or reinjection, interpreted in the same manner.
# Semiquantitative analysis:
With the aim of numerically assessing the intensity of radiopharmaceutical uptake (perfusion), within the established standards (17-segment model), specific scores have been developed: a) perfusion -considers the following numerical scale: 0 = normal; 1 = mildly reduced radiopharmaceutical uptake; 2 = moderately reduced uptake; 3 = severely reduced uptake; 4 = absence of radiopharmaceutical uptake. Scores of 3 or 4 are normally associated with coronary stenosis of > 90%. Therefore, the higher the number of affected segments is; the more extensive the process; the higher the summed scores, and the greater the severity will be. This has an unquestionable prognostic value for patients with CAD. The following calculations are achieved by the sum of values attributed to each segment: the sum of the values attributed to each segment during the stress phase is known as the "summed stress score" (SSS); this is repeated during the baseline or redistribution phase to obtain the "summed rest/redistribution score" (SRS). The difference between the SSS and the SRS is known as the "summed difference score" (SDS). According to Hachamovitch et al.numerical SSS values < 4 are considered normal; between 4 and 8, mildly abnormal; between 9 and 13, moderately abnormal; and > 13, severely abnormal. It is worth emphasizing that SSS values < 4, which may not necessarily be zero, are understood as normal, because there are myocardial regions which show lower radiopharmaceutical concentrations in and of themselves and may, consequently, receive values other than zero.
Quantitative analysis: Polar maps are two-or threedimensional reconstructions of the LV, initially elaborated with the proposal of encompassing relative radiopharmaceutical distribution throughout the heart in a single image. They are shown in circular form, resembling a target, for which reason they are also known as "bull's eye plots." Radiopharmaceutical uptake, which is representative of perfusion, is shown on a color scale, with the LV apex occupying the center of the target, while basal regions of the heart are represented by the outermost circle of the target. Programs capable of reconstructing these images also allow for percentage quantification of areas with reduced uptake by comparing the images to a databank of normal individuals of the same age and sex. Perfusion defects may also be quantified by the number of pixels in a determined region and by existing standard deviations in relation to normal perfusion areas.
We may also obtain polar maps with parameters relative to ventricular function, such as LV wall motility and systolic thickness. These methods of quantitative analysis serve as complements to assist in qualitative or semiqualitative visual analysis.
## Evaluation of ventricular function with perfusion agents:
In a manner analogous to that described for perfusion study, segmentary contractile analysis of the LV makes use of motility and systolic thickness scores for each segment, also considering division into 17 segments, visualized in the cross sections of the minor axis (distal, mid-cavity, and proximal regions) and the long vertical axis (anteroapical and inferoapical regions). Numerical values are attributed. Analysis of motility of LV walls is performed directly on the computer monitor, making the subendocardial contour visible. Analysis of systolic thickness should be directed to the color scale chosen for a group of images. When thickness is within normal limits, the color increment is observed toward the bottom of the scale. Furthermore, it is possible to obtain percentage of thickness in each region. For distal and middle slices of the minor axis, as well as for the apex, average normal thickness is around 40%, with a score of zero (0) Thicknesses between 30% and 40% are interpreted as borderline; those between 20% and 30% receive a score of 1 (mild reduction); 10% to 20%, a score of 2 (moderate to severe reduction); and less than 10%, a score of 3 (absence of thickness). In the proximal (or basal) cross section of the minor axis, thickness of around 20% is considered normal. A score of 1 is not used, but rather only scores of 2 and 3. Abnormalities in motility and thickness generally go hand-inhand, with slight differences in gradation between the twoand in the resulting sums. In some cases, we may observe discrepancy between results, for instance, following revascularization surgery and in the presence of left bundle branch block, in which the motility of the interventricular septum is compromised, whereas thickness is not.
Whenever possible, analysis of ventricular function should be performed at the baseline phase and after stress, with the purpose of detecting additionally indicative alterations in stunned or hibernating myocardium. The validated scores, which have been previously described, are recommended. Regarding the effect of global analysis of LV systolic function, LVEF is the parameter with the best reliability, and scores predominantly concentrate on segmentary analysis. Furthermore, the subjective or qualitative assessment of images regarding results related to myocardial perfusion study, which have been previously described (homogenous distribution or normal uptake of the radiopharmaceutical in the myocardium; transient low uptake suggestive of ischemia; fixed low uptake suggestive of fibrosis; partially reversible low uptake suggestive of ischemia associated with fibrosis), should take the presence of the following types of artifacts into account:
- Technical artifacts, resulting from inadequate image processing.
- Motion artifacts.
- Attenuation artifacts, due to interposition of mammary or diaphragmatic tissue (intestinal handles), which are factors that interfere with the specificity of the exam.
## Current utilization of myocardial perfusion and ventricular function studies with radiopharmaceuticals as part of the medical decision-making process
MPS with the injection of radiopharmaceuticals associated with ET or the administration of coronary vasodilators is an established method for diagnosis and risk stratification of obstructive CAD, 91-100 with the aim of guiding more effective clinical management of patients as part of the medical decision-making process.It currently integrates other non-invasive cardiovascular imaging techniques, such as Doppler echocardiography with color flow mapping, CS, coronary angio-CT, PET, and cardiac magnetic resonance (MR), to characterize risk and functional expression of atherosclerotic disease.Accuracy of method was, until recently, based on invasive coronary cineangiography, considered the standard for this comparison. The following stand out as highly relevant aspects, considered of paramount importance to the modality:
- Obtaining variables and parameters that are fundamental to incremental prognostic characterization of CAD, such as electrocardiographic response to exercise, functional capacity , chronotropic response, blood pressure, et al. Of all forms of stress associated to MPS, the exercise testing is, without a doubt, the one that adds the greatest amount of information.- When analyzing perfusion images, the possibility of quantifying area of myocardial ischemia or myocardium at risk has advanced a great deal over the past decades, undoubtedly participating in risk stratification and medical decision making for stable CAD, where it provides assistance for the choice between maintaining clinical treatment and interventional treatment.Even in the absence of randomized studies published to date, which might reaffirm this information (the Ischemia Study -report to the Addendum of this guideline),the evidence which has currently been accumulated and made available documents better evolution in patients with severe ischemic burden who undergo myocardial revascularization.- When analyzing ventricular function images, indirect observation of thickness and motility of the LV walls and comparison of resting and exercise ejection fractions greatly improve the method's specificity for characterizing true ischemia and aggregate incremental prognostic value with the definition of markers of severity, such as transient ischemic dilatation (TID), representing ventricular dysfunction and / or subendocardic ischemia induced by applied stress.
- The ability to infer coronary flow reserve under applied stress or stimulus with elevated accuracy, superior to other conventional methods, with the exception of PET, is the most important physiological parameter for characterization of ischemia and the medical decisionmaking process, currently available in clinical practice with direct invasive measures of FFR and instantaneous wave-free ratio (IFR). Software currently in development for calculating coronary reserve in association with SPECT methodology and other non-invasive methods will likely aggregate unquestionable value to appropriate clinical or interventional treatment choices, in the near future, encompassing not only obstructive atherosclerotic disease, but also physiopathological conditions, including microvascular disease and endothelial dysfunction in the scenario of ischemic heart disease.The main applications with the best cost-effectiveness are shown in patients with intermediate pre-test probability of CAD, estimated based on the integration of clinical variables which have been established and documented in Brazilian and international guidelines, with their respective recommendations and levels of evidenceand. Ideal diagnostic and prognostic capacities have for decades been considered with regard to severe coronary lesions. Nonetheless, exercise testing are indicated as the ideal and preferred association for myocardial scintigraphy, considering the physiological nature of the form of applied exercise and the established clinical value of the variables obtained during and after work.Pharmacological tests performed in nuclear cardiology represent good alternatives for assessing patients with physical limitations or clinical limitations to undergoing efficient exercise testings. They include approximately 20% to 30% of all cases referred for scintigraphy and approximately 50% of elderly patients.In these circumstances, the drugs utilized are dipyridamole, adenosine,and regadenoson.and major adverse events in stable chest pain patients or asymptomatic patients, such as Framingham Risk Score (FRS), PROCAM, SCORE, Diamond Forrester,or Global Risk;the estimated prevalence (EP) of the disease is observed to be significantly higher than the observed prevalence (OP), when coronary angio-CT is used to characterize luminal obstruction, ≥ 50% and ≥ 70%, respectively. In this situation, an international multicenter study (CONFIRM) 127 of 14,048 consecutive patients with clinical suspicion of coronary obstructive atherosclerosis who underwent angio-CT showed that, in all age and sex categories, guidelines for calculating probability overestimated prevalence in the general population (51% EP × 18% OP for lesions ≥ 50% and 42% EP × 10% OP for obstructions ≥ 70%, p < 0.001), directed by accentuated differences between patients with typical angina (86% EP × 29% OP for lesions ≥ 50%) and atypical angina (47% EP × 15% OP for lesions > 50%). Considering this information to be true, more evidence has arisen within the literature in the search for new markers which might aggregate value and assist in more objective and realistic restratification of cardiovascular risk, with specific guidelines 128 dealing with critical questions regarding, for instance, what types of evidence will contribute to risk assessment or reclassification when new markers are added to traditional scores, with emphasis on functional capacity and CS.
## The application of bayes' theorem to analysis of myocardial perfusion images with radiopharmaceuticals
Even when isolated analysis of images is used to describe perfusion findings, interpret data, and write reports, medical comments and conclusions should be the result of the
## Recommendations
Class of recommendation
## Level of evidence
CV risk assessment in individuals with family history of premature CV disease, family history of dyslipidemia, major risk factors (smoking, HBP, DM, raised lipid levels), or specific comorbidities that increase CV risk.
I C Repeat risk assessment every 5 years; repeat more often in individuals with risks close to levels which treatment is mandatory I C Consider CV risk assessment in men > age 40 and women > age 50 or post-menopausal with no known risk factors IIb C CV risk assessment in men < age 40 and women < age 50 with no known risk factors is not recommended III C integration of all available pretest clinical data and data obtained during the performance of the stress or associated stimulus test within the denominated incremental prognostic value. In this sense, Bayes' theory of conditional probability or the application of Bayesian principles assists in decision making by establishing that the risk of an event occurring after a test is influenced by the sensitivity and specificity of an applied method, as well as the pretest prevalence of the disease, all of which are incorporated into the estimation of post-test probability for characterization of myocardial ischemia and, consequently, CAD.In this way, the diagnostic ability of a test is related to the population type selected, and it is may create tendencies or biases. For example, the selective referral of patients with "positive," "altered," or "ischemic" results for coronary cineangiography studies, in conjunction with few referrals of individuals with negative results, increases the chance of falsepositive results with respect to true-negative results. This would be an equivocal methodology for evaluating the accuracy of a test, artificially decreasing the method's specificity or its ability to select healthy individuals within a population.On the other hand, sensitivity will expressively increase in patients referred with a high prevalence of symptoms.
Many possibilities may be present for medical management within different prevalences of clinically estimated CAD, emphasizing that the diagnostic power of conventional exercise testing or tests associated with MPS is at a maximum when the pretest probability of CAD is intermediate. However, for a given pretest probability, the post-test probability increases progressively with the severity of the alterations found, such as the amount of myocardium at risk or the sum of extent and intensity (ischemic burden) of perfusion modifications in the perfusion images with radiopharmaceuticals. In the extreme case of a study with severe abnormalities, post-test probability will be elevated regardless of pretest probability.Furthermore, not only Bayesian analysis, but also statistical techniques that use multivariate analysis to estimate post-test risk may also provide important diagnostic information, with the following advantages: they do not require the tests to be independent of each another or the diagnostic indexes (sensitivity and specificity) to remain constant in populations with different disease prevalences. Thus, in the condition of continuous-scale diagnostic tests, changes in percentages of sensitivity and specificity should be taken into consideration when cutoff values for classifying individuals with and without a disease vary. Some results may even be expressed as the sum of sensitivity and specificity for an "optimal" cutoff value. However, owing to the fact that an optimal cutoff value is not relevant to a specific application, it is recommendable to plot these indexes under a range or scale of values of interest, generally distributed under a receiver operating characteristics (ROC) curve, expressed in a 2-axis graph, where the y axis represents sensitivity and the x axis = 1 − specificity, for variable cutoff values.
## Value of the diagnosis-prognosis binomial to integrated assessment of perfusion images
The presence of transient or reversible defects in radiopharmaceutical uptake reflect ischemia, which is in itself associated with greater incidence of future events, when comparing normal images or images with persistent perfusion defects. Thus, in patients with suspected or proven chronic coronary disease, estimation of the quantity of myocardium at risk as assessed by semi-quantitative and quantitative analyses, extent, intensity, and degree of reversibility of existing defects, as well as measures of LVEF following physical or pharmacological stress, have prognostic value, indicating risk of events during clinical follow up.Other scintigraphy markers of severity may stand out, such as apparent transient dilation of the LV, induced or accentuated by exercise or pharmacological tests,which may translate to extensive subendocardial ischemia, in addition to high pulmonary uptake, translating to LV dysfunction. Furthermore, increased uptake in the walls of the right ventricle (RV) in multi-arterial patients whose lesions are predominantly in the left coronary territory, may suggest an imbalance in perfusion between ventricles.Considering the scope and accumulated experience of MPS with radioisotopes in diverse clinical scenarios relating to CAD, guidelines and consensuses have suggested the main applications based on levels of evidence in the literature, and created scores that numerically classify indications as inappropriate; possible, but questionable; and appropriate(additional details described in the Indications section).
## Radiopharmaceuticals for performance of myocardial perfusion scintigraphy and image generation and perfusion defects
Nuclear cardiology is connected to the assessment of cardiovascular physiology, currently encompassing metabolism, innervation, myocardial perfusion, ventricular function, and synchronism. It has a capability for early detection of cardiovascular physiopathological alterations, allowing for interventions which may interrupt or revert the disease condition before structural alterations are established in a definitive, evolutive, and irreversible manner. To represent cardiac physiology, images are formed using the principle of radiotracers or tracers, 29 in which the exchange of stable atoms with their isotopes does not alter the biological properties of the organism where the images are being obtained.
Radioactive labeling is performed with minimal quantities of chemical substances, resulting in a radiopharmaceutical that may be used to truly represent physiological or biochemical state of unlabeled molecules . In this manner, alterations to the physiology being evaluated and toxicity effects do not occur. These characteristics are different from other imaging methods which use elevated concentrations of chemical substances to create sufficient contrast and, consequently, obtain images of the functional situation and anatomical aspects of the organ under study.The images in this specialty are digital; they either use "pixels" as units of measurement for resolution or are transformed into a digital matrix, emphasizing that "pixel" values of images of the ventricular myocardium are directly proportional to physiological cardiovascular properties. Physical phenomena such as the "Compton scattering effect," the "photoelectric effect," and geometric distortions should, however, be considered,given that they tend to interfere with direct proportionality, in a manner that is decreasing as equipment and image reconstruction techniques technologically evolve. Furthermore, another factor related to acceptance and preference of nuclear cardiology for detecting myocardial perfusion defects is the elevated, superior resolution contrast (allowing for differentiation between normal and decreased perfusion) in comparison with other imaging methods, 147,148 even considering lower spatial resolution. There is also a peculiar aspect, namely, that the myocardium (organ of interest) appears emphasized due to the greater brightness in comparison with underlying structures (background) and, consequently, provides excellent signaling, which facilitates the development of integrated, computerized algorithms for SPECT and PET techniques. These programs, which automatically process and objectively quantify images, have good comprehension, and they are well validated and internationally utilized.From the conceptual point of view, it is necessary to grasp that scintigraphy image generation is based on relative uptake of the radiopharmaceutical in the myocardium of the LV, when it is injected intravenously during physical exercise or pharmacological tests. The comparison of radiopharmaceutical uptake between ventricular walls is expressed in images based on a color scale, created by specific computer programs which, in addition to allowing for subjective analysis of perfusion, make it possible to conduct semi-quantitative and quantitative evaluation of affected myocardial area. During visual evaluation of scintigraphy images, the following are taken into consideration: homogenous distribution patterns or normal radiopharmaceutical uptake in the myocardium, transient low uptake suggestive of ischemia, fixed low uptake suggestive of fibrosis, and partially reversible low uptake suggestive of ischemia associated with fibrosis(Examples are provided in the Methodology and Tutorial Cases sections).
## Evaluation of patients with potential
Acute Coronary Syndrome -Algorithms in the Chest Pain Unit
# Introduction
Continuous chest pain is one of the most common symptoms in emergency units, accounting for approximately 8 million annual visits in the USA.Although approximately 50% of patients are admitted for diagnostic definition, only 30% of visits will correspond to the condition of acute coronary syndrome (ACS), 2% to 4% of whom will be inappropriately discharged from the hospital, leading to serious risks of severe events, in addition to legal-medical problems. Considering these implications, as well as hesitation to discharge patients with acute myocardial infarction (AMI), assessment of patients with atypical chest pain in emergency unit has emphasized admission for posterior clarification and risk stratification. With the development of more sensitive cardiac biomarkers in conjunction with more precise noninvasive exams and validated clinical parameters, early identification of low-risk patients has been carried out more rapidly. In this process of diagnostic and prognostic assessment, the following play an important role: resting ECG, cardiac enzymes, and non-invasive exams such as ET, MPS, Doppler echocardiogram, and coronary angio-CT, in addition to cardiac resonance in specific cases. The choice of recommended imaging method should be based on the procedures available, local institutional experience, and present clinical situation. The exam with the highest diagnostic accuracy and negative predictive value (NPV) will offer more precise risk stratification, which is fundamental to decision making regarding need for hospital admission or safe discharge from the emergency unit.
In addition to the 2 physiopathological conditions described (Non-ST segment Elevation Myocardial Infarction -NSTEMI and ST segment elevation myocardial infarction -STEMI), unstable angina also stands out, which does not feature myocardial necrosis as an initial consequence. Nevertheless, unstable plaque and evolutive phenomena of erosion and rupture may progress to infarction and related complications, such as severe arrhythmias, ventricular dysfunction, and death. Conditions of vasospasm, in epicardial coronary arteries or with microvascular disease, have additionally been implicated in ACS without thrombosis and myocardial infarction, in the absence of obstructive lesions.It is, finally, important to emphasize that, in patients with documented ACS and intermediate-to high-risk patients, invasive coronary cineangiography and percutaneous revascularization represent the most frequent forms of initial assessment, and non-invasive imaging methods are reserved for clinically stable situations and low-to intermediate-risk patients, with the aim of reclassifying risk, diagnosis, and stratification in the post-event phase.7.2. Goals for Evaluating Acute Chest Pain and Participation of Non-invasive Methods in Assessing ACS- Precise diagnosis for appropriate conduct in UA or AMI, whether with clinical treatment or invasive strategy via catheterization and angioplasty.
- Early, safe discharge from the hospital if clinical data and exams show no abnormalities. Probability of severe cardiac events < 1% over 30 days of evolution following discharge from the emergency unit or hospital.
Following serial evaluation of ECG, without modifications, in addition to normal cardiac enzymes and clinical situation characterized as low-to intermediate-risk, non-invasive functional exams may play an important role in risk stratification of patients with acute chest pain. The choice of MPS, cardiac resonance, or angio-CT will depend on the objective and the clinical question to be answered.
Exercise testing: constitutes an important strategy for assessing patients with suspected ACS following stabilization, and it aids prognosis and medical management . Patients with chest pain in the emergency room, once they have been identified as low-risk, may undergo ET, a normal result of which confers low annual risk of cardiovascular events, allowing for earlier and safer discharge from the hospital.Brazilian and international guidelines recommend ET as a first-choice exam for risk stratification in patients who are able to exercise, as the procedure is low-cost and widely available, and it has a low rate of complications, similar to that of tests conducted in normal conditions.A treadmill or a cycle ergometer may be used, following appropriate protocols for the patient's clinical conditions, such as the ramp protocol or the modified Naughton or Bruce protocol. Logistics related to performing ET in the emergency unit may, however, be compromised as a result of unavailable operational personnel or infrastructure during certain periods (e.g. weekends or night shifts).
## Summary of indications for et in acs (characterize low-risk after initial clinical stratification)
- Baseline ECG and biomarkers (necrosis) without alterations.
- Absence of symptoms (precordial pain or dyspnea).
- Hemodynamic stability and adequate conditions for physical effort.
If ET results are normal and the patient has shown good functional capacity, other procedures may be unnecessary, in virtue of the test's high NPV. 165
## Summary of recommendations and evidence
## Class of recommendation i. level of evidence: b
- Low-risk (clinical and ECG) patients with normal biomarkers should be referred for exercise test after 9 to 12 hours. Within the routines of chest pain units, these exams may be used as discharge criteria.
If it is not possible to perform ET or if ECG is uninterpretable, the patient may undergo provocative tests for ischemia associated with non-invasive imaging.
## Doppler echocardiogram (echo)
: This is fundamental for evaluating patients with acute chest painand evolving ACS, initially considering LVEF, segmentary contractile alterations, and the presence of thrombi, in addition to mechanical complications (rupture of interventricular septum or papillary muscles) that result in severe events, such as cardiorespiratory arrest. Moreover, this method may also evaluate chest pain with non-coronary etiology, such as pericardial disease, hypertrophic cardiomyopathy, aortic dissection in the presence of renal insufficiency that makes it impossible to perform angio-CT, and others. In addition to assessing the presence and extent of ventricular dysfunction, it is able to quantify severity of valvular abnormalities that may be present and associated with ischemic etiology.
## Summary of recommendations and evidence
## Recommendation class i
- Transthoracic ECHO is indicated when there is clinical suspicion of aortic and pericardial diseases, pulmonary embolism, and valvulopathies (level of evidence: C).
- In cases with complications resulting from unstable ACS, such as interventricular communication and mitral insufficiency (level of evidence: C).
- Stress echocardiography is considered an alternative to exercise testing in patients who cannot exercise (level of evidence: B).
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2):325-429
## Recommendation class iia
- Patients suffering from chest pain -resting ECG to determine whether or not pain is of ischemic origin (level of evidence: B).
- Patients with uncomplicated anterior wall AMI, with the objective of determining the exact size of the ischemic lesion (level of evidence: B).
In stable patients with evolving ACS, echocardiography associated with pharmacological stress before hospital discharge may identify induced ischemia and assist in risk stratification and medical management of immediate followup (6 to 12 weeks), especially if LVEF values are below 40%.
Coronary angiotomography: Many studies have shown that coronary angio-CT is an important tool for evaluating acute chest pain, especially in low-to intermediate-risk patients.It is a safe procedure for diagnosing ACS, and it is able to reduce intra-hospital follow-up time and contribute to cost reduction. In the Rule Out Myocardial Infarction by Cardiac Computed Tomography II (ROMICAT II) Study, duration of hospital stay was significantly lower in patients stratified via angio-CT in comparison with the group submitted to conventional evaluation (23.2 ± 37 hours vs.
30.8 ± 28 hours).There was also a significant increase in percentage of patients discharged from the emergency unit in the group stratified with this method (46.7% vs. 12.4% p < 0.001), in spite of higher costs associated with angio-CT and the greater tendency to refer patients for catheterization and revascularizations.
Based on recent publications, low-to intermediate-risk patients with acute chest pain, non-diagnostic ECG, and negative markers of necrosis have Class-I recommendation and level of evidence A for undergoing angio-CT, especially considering the method's NPV. There are, nevertheless, limitations in the presence of STEMI and NSTEMI(with the exception of coronary dissection) and known CAD or prior revascularization where the existence of intracoronary prostheses (stents) and calcium may negatively influence the exam's specificity for its proposed aim, leaving the possibilities of functional evaluation and global repercussion. Finally, it is necessary to consider exposure to elevated doses of radiation and lower image quality for the exclusion of pulmonary embolism, aortic dissection, or ACS (triple rule-out). 174
## Myocardial perfusion scintigraphy (mps):
Within the scope of its applications (See the Indications chapter), the following stand out: indirect evaluation of coronary reserve The study known as the PREMIER trial by N Better et al.evaluated the performance of resting MPS in investigating chest pain in the emergency room with 356 low-to intermediate-risk patients, from 8 developing countries, including 2 Brazilian centers. The primary outcome considered included the compound events of death, nonfatal AMI, recurring angina, and coronary revascularization over 30 days, and the results reaffirmed the association between normal images and a good NPV (99.3%) for severe events (death or AMI).Moreover, it is worth highlighting that the presence of resting perfusion alterations (abnormal scintigraphy) was the only variable independently associated with the primary outcome (adjusted OR = 8.19, 95% CI: 4.10-16.40, p = 0.0001), with even higher expression when only patients who received injections during episodes of pain were considered (adjusted OR = 17.35). On the other hand, results considered high-risk indicated worse prognoses for future cardiac events (death, AMI, myocardial revascularization surgery, or percutaneous intervention).The Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain (ERASE) Study, which evaluated patients with ACS and normal or non-diagnostic ECG who were still in the emergency room, observed admission rates of 54% in patients who underwent MPS and 63% in other patients, suggesting that the initial strategy of resting scintigraphy is satisfactory, based on the fact that it demonstrates good risk stratification capability.International guidelines recommend the use of resting myocardial perfusion images for acute chest pain as a class I recommendation with level of evidence A for risk stratification of patients with suspected ACS and nondiagnostic ECG.Time of radiopharmaceutical injection: The main applications of MPS within the first hours of a patient's arrival at the hospital are:
## Symptoms suggestive of acs
- Radiopharmaceutical injection (technetium-99m-labeled sestamibi / MIBI or tetrofosmin, also known as 99m Tcsestamibi and 99m Tc-tetrofosmin), while resting, during an episode of chest pain, with normal or non-specific ECG, with the objective of rapid diagnostic definition.
- Radiopharmaceutical injection while resting, in the absence of chest pain, with normal or non-specific ECG, when the symptom has ceased less than 6 hours prior, but preferably within the 2 preceding hours. Wackers et al.have demonstrated that, in cases where injections are administered up to 6 hours after pain, in ACS, there is an 84% incidence of perfusion abnormalities; this decreases to 19% when intravenous radiopharmaceutical administration occurred between 12 and 18 hours after the last episode of pain. Kontos et al.found no reduction in sensitivity for identifying patients who evolved to AMI or revascularization when the injection was administered during the moment of pain or up to 6 hours after the cessation of the symptom.
Ta k e n a s a w h o l e , p e r f u s i o n i m a g i n g w i t h radiopharmaceuticals for evaluation of acute chest pain does not present any formal contraindications; it is well tolerated by most patients, and the quantitative assessment of information about ischemia is of special importance to the clinical decisionmaking process.
PET: In a retrospective study conducted with more than 7,000 patients who presented at the emergency unit with chest pain,.5% of patients with positive stress or resting PET were diagnosed with ACS, by cardiac catheterization, electrocardiographic alterations, or positive cardiac biomarkers. In patients with reversible perfusion defects while resting or under stress (positive PET) who underwent cardiac catheterization, 87% were considered to have significant CAD. For patients without reversible perfusion abnormalities whose exams were classified as negative, no deaths were informed during the 30-day follow-up period. PET has a significantly better spatial resolution and higher sensitivity when compared to MPS. In Brazil, the elevated costs and low availability of this technology for patients with ACS are, however, limiting factors to its routine use.
UA and NSTEMI: Patients whose clinical conditions indicate a high risk of AMI or UA should undergo hemodynamic study. For those with low to intermediate risks whose unstable angina (UA) has been clinically stabilized, MPS has shown an important value for risk stratification.Additionally, it assists in diagnosis and medical management. It is recommended within the first hours of the patient's arrival at the hospital. Cases with a history of chest pain, whose biochemical markers, nevertheless, show no alterations, with normal or non-diagnostic ECG are considered candidates. When patients are symptomatic or immediately following cessation of symptoms, intravenous administration of Sestamibi-99m Tc or Tetrofosmin-99m Tc occurs, preferably while resting, followed by image acquisition directly after or up to 6 hours following radiopharmaceutical injection. To perform MPS associated with physical stress or vasodilator drugs in appropriate patients (those with low to intermediate risks), symptoms should be under control or angina should be stabilized for at least 48/72 hours.Patients without ischemia or infarction and preserved LV function have good prognosis and they may be managed conservatively, while patients with significant ischemia induced during associated tests should be referred for invasive exams.
The simultaneous information provided by myocardial perfusion and ventricular function via scintigraphy synchronized with ECG (Gated-SPECT) is of fundamental importance, given that both the absolute LVEF value and the extent and intensity of perfusion defects have prognostic value for the occurrence of future cardiac events.
Finally, with the advent of chest pain units and emergency units for the evaluation of patients with suspected ACS and with new tools which have become available, such as clinical risk scores, biomarkers, or multimodalities (noninvasive exams), algorithms have been proposed to support investigation and treatment of different clinical presentation scenarios. Their implementation aims to improve cost-effectiveness and to lower morbidity and mortality in the management of this subpopulation, within the spectrum of ischemic heart disease.
## Recommendations and evidence
## Class i
Stress and resting MPS as an alternative to cases with limitations to ET (level of evidence: C).
## Class ii
Patients suffering from chest pain may be evaluated via resting MPS to determine whether the pain is of ischemic origin or not (level of evidence: A). STEMI: Coronary cineangiography is a priority indication for initially attending patients with ACS and ST-segment elevation, seeing that coronary reperfusion is the primary objective. However, in cases in which clinical condition, ECG, and biochemical markers are inconclusive, MPS may aggregate incremental diagnostic and prognostic value. These situations are generally characterized by atypical clinical conditions in patients with non-specific electrocardiographic alterations in the ST segment, left bundle branch block, and, mainly, in those who are attended before or after the onset of the condition, while they are already outside of the ideal period for dosage of biochemical markers.
## Recommendations and evidence for stress and resting mps following stemi
## Class i
- Before being discharged from the hospital, in stable patients who have not undergone coronary cineangiography for risk assessment and therapeutic decision making (level of evidence B).
- Complementary evaluation following coronary cineangiography, in cases where there are doubts, with the aim of defining and quantifying ischemia for eventual myocardial revascularization (level of evidence B).
## Positron emission tomography in cardiology
# Introduction
Myocardial perfusion defects evaluated with the use of radiopharmaceuticals and induced by stress are well established as a technique with diagnostic and prognostic capability for the identification of flow-limiting coronary diseases. In MPS, interpretation has mainly been qualitative, semiquantitative, and quantitative, assessing regional perfusion in relative terms.
## Basic principles of positron emission and main indications
PET consists of a specific method in nuclear medicine. It is different from the widely used gamma camera or Anger camera employed in MPS for the technique commonly known as SPECT. PET, differently from SPECT, uses emitters of positrons, particles similar to electrons (except for the fact that they have a positive electric charge), with very short half-lives. The principle of PET consists of the detection of 2 photons (gamma rays) that are emitted in diametrically opposite directions to occasion annihilation of the positron upon encountering an electron in the periphery of the atom. This detection occurs through a series of crystals arranged throughout the 360 degrees of a ring-shaped detector surrounding the patient. The detection of the 2 photons emitted in diametrically opposite directions, at exactly 180 degrees, with an existing coincidence circuit in the PET equipment, making it different from SPECT, which uses single photons.Since PET cameras have incorporated electronic collimation, mechanical collimators made of lead have not been made necessary, allowing for greater sensitivity than in SPECT systems. The sensitivity of current 3D PET systems is 5 times greater than of the older 2D PET ones. On the other hand, there is more attenuation in PET studies than in SPECT, making attenuation correction necessary to the reconstruction of PET images. The most current systems, which have a resource known as time of flight (TOF), are based on the speed of light to localize the annihilation event in a much smaller directional ray than in conventional PET cameras, resulting in increased spatial resolution. This method has already been established as the standard for assessing myocardial viability (See the Myocardial Viability section), with the use of a glucose analogue labeled with fluorine-18 ( 18 F-FDG), a technique which, although it is not widely used in Brazilian clinical practice, is widely viable in most nuclear medicine centers where PET is available in Brazil. Its use for the assessment of myocardial perfusion is not necessarily a new technique, as it dates back to more than 30 years ago and has since been evolving.Nonetheless, its clinical use has remained restricted for many years owing to its methodological complexity, high operational costs, and low availability of devices and tracers. Recent technological advances have reduced the costs, and its increasingly frequent use in oncology has resulted in increased equipment availability. Nowadays, non-invasive estimation of absolute coronary flow and flow reserve with this technique has become possible and has been validated.The scenario is contrary in Brazil, however. In spite of a small amount of experience using research protocols, this method is not available in clinical practice. Even though PET cameras are distributed throughout the country, there is a lack of other radiotracers for the modality as well as a lack of economic viability.
## Radioactive tracers for use in positron emission tomography
Different available radiotracers make it possible to identify vasoactive, metabolic, or neurological processes that are present in diverse cardiomyopathies and atherosclerosis, on the molecular level. The images acquired allow for evaluation of the cardiovascular system on different levels, including: perfusion, 201-203 metabolism,sympathetic innervation,and inflammation; 210-212 depending on the tracer utilized. Myocardial perfusion studies using PET may be performed using different tracers, each of which possesses specific characteristics, advantages, and disadvantages.
Rubidium-82 ( 82 Rb) and ammonia labeled with nitrogen-13 ( 13 NH 3 ) have been approved for clinical use by the Food and Drug Administration (FDA), and they are the most commonly used in the USA. On the other hand, water labeled with oxygen-15 ( 15 O-H 2 O) has been used mainly for research in the USA, as it diffuses freely between blood and the myocardium, which makes it ideal for quantitative flow measures. In South America and Brazil, associated costs, especially with tracers, have limited their use. Initial experience with myocardial perfusion using PET and 82 Rb have been conducted at the Heart Institute of São Paulo (InCor, acronym in Portuguese).As 82 Rb is the only one of these tracers produced in a generator system, from strontium-82, it has an advantage in relation to the others whose production depends on a cyclotron. These generators may be transported, and, specifically in case of Brazil, they may be imported especially for this purpose. Their short physical half-life of 76 seconds constitutes another favorable aspect, given that it implies very low dosimetry for the patient, with estimated exposure lower than 2 milliSieverts (mSv), in a stress and resting protocol, including tomography for attenuation correction. On the other hand, stress with exercise becomes unviable, considering the elevated costs, making it possible only in high-volume centers that perform around 40 exams weekly.Payment tables for medical procedures in Brazil, to date, restrict the payment of PET for oncological indications, which complicates its use for cardiology. The use of 13 NH 3 requires a cyclotron, the installation of which has extremely high costs, but it provides high contrast images, due to its high first-pass extraction fraction. It offers good accuracy for absolute measure of myocardial blood flow (MBF), and its relatively long half-life of approximately 10 minutes, makes physical exercise viable.18 F-flurpiridaz is a new tracer. Although its production requires a cyclotron, its labeling with fluoride-18 makes it possible to utilize the production and distribution systems that are already widely available for oncological use of PET. Due to its relatively long half-life of 110 minutes, it is appropriate for associated use with an exercise testing, and its high first-pass extraction fraction also makes it ideal for flow quantification. Its use is currently being evaluated in a phase-III study.
## Use of pet for assessment of myocardial ischemia
PET has advantages over conventional SPECT, including higher spatial resolution and contrast rate, higher sensitivity than the tracers classically used in MPS (thallium-201 and technetium-99m-labeled radiopharmaceuticals), and higher specificity, considering the attenuation correction system based on coupled CT, which results in better capability to differentiate true perfusion defects from attenuation artifacts.These advantages are notably applied to some special populations, such as obese patients and women with voluminous breasts, in whom gamma ray attenuation in soft tissue may be a factor of greater importance to the final quality of cardiac images.
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2): The objective of evaluating myocardial perfusion via PET is to detect physiologically significant coronary stenoses, aiding clinical management of patients with known or suspected CAD and patients who, although they have no known diseases, possess risk factors, in order to evaluate atherosclerosis progression. Other objectives include determining the cause of ischemic symptoms to recommend clinical treatment or revascularization, estimating potential for future adverse events, and improving patient survival. One of its strengths is that it is the non-invasive modality of choice for accurately quantifying MBF. It allows for quantification in absolute terms of ml.min per gram of myocardium in stress and resting phases. The ratio between the 2 flows is known as the myocardial flow reserve (MFR), a valuable parameter that makes it possible to overcome one of the currently existing limitations to conventional perfusion imaging with SPECT when evaluating patients with multivessel CAD.
Results of invasive studies (FAME-1 and FAME-2) that analyzed FFR demonstrated its value in evaluating functional significance of single-vessel stenoses.Some studies have provided evidence of a correlation between regional MFR and FFR measured invasively without comparing them directly, however.Quantitative PET measures of MBF in absolute terms represent a paradigm change in the evaluation and management of patients with CAD, with a disassociation from the anatomical gold standard of coronary cineangiography, which had previously been established for decades, and a return to functional assessment. These measures additionally make it possible to expand the use of perfusion imaging within the current scenario, with the aim of detecting flowlimiting epicardial lesions, for earlier stages of atherosclerosis, microvascular dysfunction, and evaluation of balanced flow reductions in triple-vessel disease. They also offer an opportunity to monitor responses to changes in lifestyle or risk factors and therapeutic interventions.Two recent meta-analyses evaluating methodology have indicated that PET has superior accuracy in comparison with SPECT. The first meta-analysis compared PET with SPECT synchronized with ECG and associated with attenuation correction. In analysis with a ROC curve, the area under the curve for PET and SPECT was, respectively, 0.95 and 0.90 (p < 0.0001), showing a small superiority for PET. The second meta-analysis indicatedRb as the most used tracer, resulting in higher sensitivity for PET. Specificity, on the other hand, although superior, was not statistically significant.Regarding prognosis, similarly to SPECT, for which data are abundant, robust, and well established, normal myocardial perfusion with PET is indicative of good prognosis, with cardiac events varying between 0.09% and 0.9% during 1 year of follow-up, depending on the population analyzed. On the other hand, adverse events increase with the extent of perfusion defects on PET. A recently published register including more than 7,000 patients demonstrated that the hazard ratio of cardiac death increased with every 10% increment of extent of perfusion defects, classified as mild, moderate, and severe, respectively, hazard ratio: 2.3 (95% CI: 1.4-3.8; p = 0.001); hazard ratio: 4.2 (95% CI: 2.3-7.5; p < 0.001), and hazard ratio: 4.9 (95% CI: 2.5-9.6; p < 0.0001), in relation to a normal exam.
## Patient preparation, types of stress, and dosimetry
Preparations include a 6-hour water-only fast. Patients should avoid caffeine and foods or medications containing xanthines (theophylline, theobromine) for at least 24 hours. Generally speaking, stress protocols are generic for all types of perfusion agents, bearing similarities to those of MPS with SPECT, with specific differences in accordance with acquisition protocols.
Current dosimetry for studies with rubidium-82 ( 82 Rb) in adults, considering maximum administered activity per 60-mCi dose, may vary from 1.1 to 3.5 mSv of total effective dose. With the current advances in instrumentation of PET cameras, studies with good diagnostic quality may be acquired with injected activities that vary from 20 to 40 mCi per resting and stress dose, resulting in even lower exposure. In studies with ammonia labeled with nitrogen-13 ( 13 NH 3 ), the habitual activity is 10 to 20 mCi per dose (which corresponds to 1.48 mSv per dose). Doses of up to 25 to 30 mCi may be used in patients with high body mass index (BMI), with relatively lower dosimetry as a function of its shorter half-life and the low energy of its positron.
The evolution of imaging systems has allowed for the development of PET/CT capable of performing hybrid imaging , or be it, using CT not only for attenuation correction but also for quantification of CS and acquisition of coronary angio-CT, in addition to allowing for the fusion of these images, facilitating the integration of anatomical and functional information. Another great advance is that of PET systems incorporated to PET/MR. This new hybrid imaging modality has enormous potential for structuralfunctional evaluation, tissue characterization, and reduced exposure to radiation.This, thus, amplifies the possibility of developing new studies, with the aim of expanding data on clinical applications and diagnostic and prognostic benefits of PET in studies of more diverse cardiovascular conditions.
Objective measures of coronary flow reserve will certainly be able to be extended to the MPS-SPECT method, providing evidence of nuclear medicine's ability to carry out quantifications of MBF and allowing for additional parameters for evaluating perfusion, as well as myocardial reserve, with a resulting impact on clinical management of patients, which will objectively orient decisions about revascularization.Provided that availability barriers are overcome and costs of both imaging systems and tracers are reduced, especially in developing countries such as Brazil, the growing application of this new methodology has a promising outlook in cardiology. Technological evolution has facilitated the development of excellent tools for both establishing diagnosis and estimating prognosis of CAD. These advances allow us to evaluate different aspects of anatomy and physiology of the heart non-invasively, with great accuracy. Most importantly, today we are able to rely on methods which help establish the best course of treatment in the most diverse clinical situations of patients with suspected or known diseases, whether they are symptomatic or asymptomatic. This wide range of alternatives presents an additional challenge to doctors, namely, that of defining the best strategy and the most rational complementary sequence of evaluation possible, regarding use of resources for diverse clinical situations, guaranteeing not only the highest accuracy in evaluation, but also the best benefits, considering healthcare costs. Doctors generally should seek to orient initial investigation with the aim of using the lowest number of diagnostic exams for an effective evaluation. However, in this era of multimodalities, it has become necessary to perform more than 1 exam in order to make the best therapeutic decision. Combined assessment of different phenomena of the heart is often necessary, for instance, to define physiological repercussions of an anatomical lesion.
Two questions linked to the bases of medical semiology and to the essence of medicine ask, "Who is the patient?" and "What information is the doctor looking for?" In this approach, the application of good techniques, such as anamnesis and complete physical examination, has become clear in clinical medicine, enabling doctors to formulate their initial patient profiles and to establish the most probable diagnostic hypotheses. Joint estimation of the pre-test probability of the diseaseand knowledge regarding the accuracy of a test to determine post-test probability of a true or false result (Bayes' Theorem) are implicit and no less important. The application of this basic principle, associated with knowledge regarding what different diagnostic tools may offer, allows for the elaboration of better investigation strategies. Confirming or excluding the presence of CAD from the anatomical point of view or, alternatively, investigating the physiological repercussions of myocardial ischemia via stress tests have distinct implications for patient management. Whether to look for one response or another will depend on the patient at hand and the question the doctor wishes to answer. 9.2. Integrating Physiology (Exercise Testing and Nuclear Cardiology) and Anatomy (Calcium Score and Coronary Angiotomography)
Exercise testing (ET), also known as ergometric test, stress or exercise tests, showing evidence of good performance (high workload) with normal results and MPS showing absence of ischemia do not represent absence of CAD indeed . In the presence of CAD, however, these findings are associated with better prognosis in relation to patients with ischemia, given that their use is extremely useful for risk stratification of patients with or without this disease. On the other hand, it is important to know that methodologies based on the anatomy of coronary arteries, such as coronary angio-CT, may also stratify risk, but the presence of atherosclerosis detected by this modality does not necessarily imply poor prognosis or, much less, mean that the patient will necessarily benefit from myocardial revascularization procedures. It may merely represent that prognosis is worse that that of an individual without atherosclerosis. It is, thus, worth reaffirming that it is necessary for doctors to possess global knowledge of their patients and also to delineate clearly the investigation strategy for the question they are seeking to answer. Basic knowledge regarding advantages and disadvantages of available procedures are implicit, making the absolute most of the technological evolutions that have occurred in recent years. Initially speaking, all modalities which have been covered may be used for diagnosis and prognosis. It is, however, evident that they all have strengths and limitations, which are not necessarily uniform for all patients; or be it, there are determined patient characteristics which may make one test superior or inferior to another. Once the doctor has answered the 2 initial questions, "Who is the patient?" and "What is the main diagnostic hypothesis?" he or she needs to answer the third question: "What is the most appropriate test for this patient and for the question I want to answer?" To answer this question, it is essential to know the main advantages and disadvantages of the exams, integrating the results of Bayes' theorem and, thus, defining post-test probability. It is, moreover, necessary to identify when continuous or complementary analysis will be required in order to obtain additional information for better patient management.
Of the techniques that have been covered, angio-CT is the most recent, showing great technological evolution, notably over the past 10 years. Data from important clinical studies have consolidated and recognized the value of this modality, as well as how to integrate it with other available tools. Before the advent of angio-CT, studies of patient anatomy presented greater difficulties, as it was mainly obtained via cardiac catheterization, with all the limitations, complications, and costs associated with invasive interventions. The development of a non-invasive, relatively simple and quick imaging technique has, in recent years, made it possible to recover the role of anatomical evaluation of the heart as a diagnostic and prognostic tool, thus integrating angio-CT into the multimodality scenario. Tests that allow for evaluation of cardiac physiology, such as ET and nuclear cardiology with MPS, have been routinely utilized for many decades, and, as they are not invasive, they have been employed for a large number of patients with suspected or known CAD. A great deal has been learned about these tools' capabilities for diagnosis-The importance of integrating information about different diagnostic modalities in an era of multimodalities. Generally speaking, the diagnostic modalities most used in Brazil are: exercise testing, echocardiogram, myocardial perfusion scintigraphy, angiotomography to evaluate coronary anatomy and calcium score, cardiac magnetic resonance, and, finally, invasive coronary cineangiography (cardiac catheterization). In this scenario, the doctor is central to establishing the best strategy and should ask the following questions: (1) and, especially, for establishing prognosis and defining better courses of treatment.
Since the beginning of ET, initially in the 1950's, followed by MPS in the 1970's, information obtained has emphasized the great value of physiology, especially for evaluated coronary reserve flow, with highly consistent data for stratifying risk of cardiac death in patients with known or suspected CAD. Different physiological variables assist in characterizing patients as low-, intermediate-, or high-risk. The results of these tests, however, are not always in agreement, when comparing physiological tests to each another (ET with MPS) or to anatomical tests (angio-CT and catheterization). Potential "disagreements" and situations that may generate doubts are more common when comparing anatomy and physiology, especially at this moment, with the expanded use of angio-CT.
The scope of this text is not to revise details in relation to the variables involved, but rather to integrate information obtained from different available non-invasive tools, especially the interrelations between MPS, angio-CT, and ET. Summarily, the main variables of ET that represent high risk are: low functional capacity, greater magnitude of ST depression, occurrence in multiple leads, descending ST segment, ST-segment elevation in leads without Q waves, depressed chronotropic response, drop in blood pressure during stress, the presence of complex ventricular arrhythmia, manifestations of angina during low workloads, among others. In MPS, the principal markers of severity are: extensive perfusion defects with severe intensity, especially transient defects (transient reduced uptake) in more than 1 territory and mixed fibrosis patterns associated with ischemia (persistent reduced uptake associated with transient reduced uptake), stress-induced LV dilation, tracer uptake in the RV and the lungs, low LVEF, and LV with or without transient dilation associated with stress.
Conversely, aspects associated with low risk on the ET are represented by high functional capacity, absence of important ST-segment abnormalities or stress angina, good hemodynamic response with appropriate increase in HR and blood pressure, and absence of complex ventricular arrhythmias. In relation to MPS, markers of good prognosis are associated with normal myocardial perfusion and preserved LV ventricular function. Most of the time, especially in the most severe cases, diagnostic modalities are in agreement, or be it, a patient with high-risk ET findings will, likely, show significant MPS defects, corresponding to coronary anatomy compatible with advanced CAD. There are, however, different scenarios in which disagreeing results present challenges to better patient management.
The cases subsequently exposed are intended to integrate clinical data with the use of multimodalities, extending discussions within the medical decision-making process for understanding, interpreting, and suggesting conduct for dealing with agreements and, especially, disagreements. illustrates a concept in which the doctor begins evaluation using medical procedures of anamnesis and physical examination during the initial phase (I), formulating the main diagnostic hypotheses, which are fundamental aspects for defining the best investigation strategy. Subsequently, depending on the questions formulated, relatively simple or more basic diagnostic tests are obtained (II), such as: resting ECG, ET, resting ECHO and, eventually, CS. Subsequently, in accordance with the need for additional information and depending on the diagnostic hypotheses considered, the doctor may consider the application of more advanced non-invasive imaging techniques (III), such as angio-CT, MPS, and, potentially, cardiac magnetic resonance. Applying scientific knowledge regarding diagnostic and prognostic value, to both basic tests and more advanced non-invasive imaging methods, it is possible to establish filters for selecting patients who will really require invasive testing, such as cardiac catheterization (IV), notably with the aim of planning for myocardial revascularization. Comments: This is one of the most common situations in nuclear cardiology laboratories. The first questions to be formulated refer to the risk defined by the ET. Abnormal responses may characterize low, intermediate, or high risks. For MPS, the best indication is for intermediate risk, which was the case with this patient. It should ideally be associated with physical exercise instead of pharmacological alternatives; when this is normal, the patient is stratified as low risk and, in most cases, the exam will indicate a probability of death lower than 1% per year, implying conservative medical management. At this moment, investigation may cease, based on the conclusion that the patient's symptoms are not related to significant myocardial ischemia and that he or she requires prevention with the objective of controlling hypertension and dyslipidemia. Other findings in clinical practice include patients with functional capacity similar to the case described but with higher magnitude of ST-segment depression, resulting in a high-risk Duke score. Due to the absence of angina during stress and good functional capacity, however, the doctor may suspect that the calculation is overestimating the risk via ET. Such findings may be observed more frequently in patients with hypertension, possibly related to myocardial hypertrophy. In Brazil, Vitola et al. studied patients with high-risk Duke scores and MPS results, finding perfusion abnormalities in 70% of these individuals.However, the other 30% showed normal MPS, and it was demonstrated that these patients had excellent prognosis. Thus, in specific cases, even in the presence of high risks characterized by the same score, the application of multimodalities, such as the association of physical stress with non-invasive MPS imaging, are appropriate before proceeding to investigation via catheterization. Furthermore, it may also be possible to utilize angio-CT in some cases, considering its high NPV, with the aim of clarifying diagnosis and excluding important CAD, especially in young patients, where the probability of a "falsepositive" result is higher.
## Practical examples of integration of modalities
## Patient with normal et and abnormal mps
Clinical history: male, age 36, long-standing DM, insulin dependent, obese and hypertensive. Atypical symptoms, notably related to fatigue during stress. Referred for MPS to investigate ischemia, following ET which was normal but which had low sensitivity owing to electric axis deviation to the left, suggestive of left anterior fascicular block (LAFB) on resting ECG.
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2): and moderate to severe intensity, suggestive of ischemia, involving predominantly the inferolateral, lateral, anterior, and anteroseptal walls of the LV, extending to the apex. Observe how the LV cavity dilate after physical exercise, with the appearance of diffuse hypokinesis and a drop in LVEF from 55% to 45% when comparing both stages.
Comments: Given a normal ET, with a high workload or good performance, with neither angina nor ST-segment alterations, patients are generally considered to have low post-test risk, but this is not always the case, as can be seen here. Nor does a normal ET represent the absence of CAD, as potentially shown by the presence of calcium in the coronary arteries on angio-CT or by ischemia detected by a more sensitive technique, such as MPS. In accordance with the evolution of medical knowledge in this era of multimodalities, restratification, even of patients with low risk on exercise testing, has become possible, as an exception. These possibilities should be considered more frequently in patients with family history of early CAD, DM, or multiple combined risk factors, and especially in those with high clinical risk (Framingham score) or LAFB on resting ECG. The case presented exemplifies precisely this scenario of a clinically high-risk patient (multiple risk factors, including DM), with LAFB on resting ECG and low risks on ET, who was restratified to a higher level of risk via perfusion imaging, due to the presence of important ischemia and LV dysfunction during stress, which are highrisk indicators. In this condition, when these tests are in disagreement, in a young, symptomatic patient (probable ischemic equivalent) with high clinical risk confirmed on
## Figure 25 -case 2 -myocardial perfusion scintigraphy showing important myocardial perfusion abnormalities, with multivessel ischemia and transient left ventricular cavity dilatation, representing high-risk indicators. images acquired with dedicated cardiac equipment (gamma camera), equipped with conventional sodium iodide crystals.
an imaging exam, referral for coronary cineangiography is supported as part of medical management.
## Patient in pre-operative evaluation for non-cardiac surgery, with mild abnormalities on mps, high calcium score, and non-obstructive cad
Clinical history: male, age 65, hypertensive, obese (BMI = 45), stroke 5 years prior, asymptomatic, in pre-operative evaluation for cholecystectomy and bariatric surgery. Interpretable resting ECG, unable to exercise. Referred for MPS with dipyridamole as initial investigation exam.
## Findings: ecg tracings show no modification during and after intravenous administration of dipyridamole.
Perfusion images reveal mild defects (small extension) in radiopharmaceutical uptake in the inferior and inferolateral/ lateral walls and in the LV apex (the latter being transient), with preserved LV function. Considering the 2 protocol series of image acquisition, resting and under pharmacological stimulation, interpretation is limited due to the significant obesity. The finding may even represent an attenuation artifact. With the patient in an asymptomatic conditions, with the reported alterations in perfusion and preserved LV function, additional information is required before making the important decision of approving the patient for surgery, and anatomical evaluation via angio-CT is thus recommended. The findings indicate a CS of 1,621 measured by the Agatston score, corresponding to the 96% percentile, when compared to individuals of the same sex, age, and race.Moreover, there is evidence of non-obstructive lesions (< 30%) in all coronaries and an absence of significant obstructions > 50%.
## Comments:
In the presence of multiple risk factors, considering the patient's age and stroke history, the probability of CAD is intermediate to high. Pre-operative risk stratification is necessary, and, although the resting ECG was interpretable, the patient was unable to perform exercise. MPS with dipyridamole is well indicated, given that normal results could lead to the patient being approved for surgery. On the other hand, faced with abnormalities in perfusion and/or function, with indicators of high risk, there is a sufficient base of evidence for indicating catheterization. In this case, however, the result showed normal LV function and mild alterations in perfusion, with the possible presence of artifacts or results of small vessel CAD (microcirculation) and/or endothelial dysfunction. The angio-CT findings indicated high CS compatible with a high atherosclerotic burden and poor long-term prognosis,which was not surprising given the profile of this patient whose coronary calcium (CC) was in the 96% percentile, meaning that 96% of individuals of the same age, sex, and race had lower coronary calcification indexes than the case described. Nonetheless, the contrasting anatomical evaluation revealed non-obstructive coronary lesions (< 30%), which reinforces the possibility that the patient might have small vessel CAD, which already bears physiological repercussions, implying more aggressive clinical management. The absence of significant obstructive lesions or high-risk anatomy serves as an additional filters for avoiding invasive examination (catheterization) and confirming that surgical risk would not be prohibitive. The most appropriate form of management for this patient, likewise, appears to gear toward aggressive preventative measures, with risk-factor control and follow up, in addition to medical treatment of CAD, which does not, however, require myocardial revascularization. Bariatric surgery itself may perhaps assist in controlling these risk factors.
## Patient with elevated cs normal mps and et
Clinical history: male, age 52, asymptomatic, diagnosed with DM 5 years prior, hypertensive and dyslipidemic. Calculated CS.
Findings: CS resulted in a high Agatston score of 1,143, in the 99% percentile. MPS with physical exercise was indicated. Patient underwent stress in the Bruce protocol for 10 minutes, reaching HR of 158 bpm (94% of the recommended maximum HR), with no clinical, electrocardiographic, or hemodynamic alterations. MPS (with a CZT camera) showed homogenous radiopharmaceutical distribution in the LV walls, as well as normal LV systolic function.
Comments: This situation has occurred more frequently in clinical practice, to the extent that CS has gone on to be incorporated as a screening method for CAD and risk stratification in the subgroup of asymptomatic patients (DM and intermediate Framingham score). This disagreement between results is understandable given that the presence of atherosclerosis will not necessarily result in ischemia detected by functional methods. For instance, an ET may indicate low risk according to the Duke score in a patient who has performed only 5 minutes of exercise in the Bruce protocol but who showed neither ST alterations nor angina. It is intuitive to grasp that, in the presence of coronary disease (most cases with high CS), this does not represent exactly the same low risks as in a patient without CAD (absence of coronary calcification or zero CS). Regarding these facts, there is extensive literature on the prognostic value of CS, with long follow-up periods (> 15 years).In this manner, it is feasible to expect the group characterized as low-risk by the Duke score to be heterogeneous, and patients should thus be treated individually, considering the intensity of prevention. In the case demonstrated, as the patient has DM, there had already been an indication for statin use, with the very high CS (in the 99% percentile) reallocating the patient into an even higher risk within the group with DM. As part of data revision which has been occurring over the past 20 years, cases have been found which showed normal but which, nonetheless, presented coronary events during medium-term evolution, in a manner similar to the discrepancies recently observed between ET and CT. Likewise, a recent study by Chang et al.observed the same discrepancies in patients with low-risk Duke scores from ET and CS > 400. They evaluated 946 patients with the Framingham score, classifying the majority as intermediate-risk (estimated 11.1% average for events over 10 years) and, basically, asymptomatic, as evaluated by ET and CS. The average Duke score was 8.4, categorized as low-risk (≥ 5). Stress tests were positive or altered in 12.3% of patients, while CS > 100 were found in 54.2% of patients. MPS was abnormal in 10.9% of the same population. It was demonstrated that CS restratified risk for patients with low-risk Duke scores, identifying individuals with atherosclerosis and higher propensity for events. Furthermore, a current register known as CONFIRM has accumulated data that definitively suggest that, in the presence of non-obstructive CAD, 240 evolution may be worse in patients without CAD. It has, thus, become evident that the anatomical technique with angio-CT is identifying coronary atherosclerosis earlier. This set of information definitively represents a change of paradigm in the medical decisionmaking process. In this situation where CAD is identified, medical management will be geared toward more aggressive prevention of modifiable risk factors and minute observation of possible symptoms that translate to disease instability. In the absence of ischemia, revascularization procedures should not be considered.
## Patient with high cs and abnormal mps
## Images: reproduced with permission of vitola jv. 234
Findings: The resulting CS was high, at 1,282, according to the Agatston score, placing this patient in the 99% percentile. With this finding, functional evaluation was indicated, using MPS with MIBI-99m Tc associated with exercise. The patient exercised for 7.5 minutes in the Bruce protocol, showing STsegment depression of up to 3 mm during peak stress, with a varying aspect which tended toward descending in multiple leads, without symptoms. With these findings, the Duke score (DS) = exercise time in minutes -(5 × ST deviation) -(4 × angina index), or DS = +7.5 -(5 × 3) -(4 x 0) = -7.5, resulting in classification as intermediate risk. In the perfusion images, the presence of transient reduced uptake was evidently observed, involving the middle and distal portions of the anteroseptal and anterior walls and apex of the LV, with accentuated intensity and medium extent, compatible with significant ischemia in the territory of the anterior descending artery. Furthermore, mild transient dilation of the LV cavity was observed during stress, in addition to radiopharmaceutical uptake in the RV wall, which are high-risk markers.
Comments: Evidence in the literature has supported the use of CS for risk restratification in patients who have intermediate clinical risks (using, for instance the Framingham or the global risk score), but who are in asymptomatic phases. The higher the CS, the higher the risk will be; not coincidentally, the probability of silent ischemia will also be higher, and this, in turn, increases the patient risks even further. Data have demonstrated that, when CS values are between 400 and 999, the probability of perfusion defects reaches up to 29%, and when values are > 1,000, the probability increases to 39%.consensus, or evidence regarding benefits based solely on CS results. On the other hand, recommendations exist for individuals with high-risk anatomy, at least moderate ischemic burden (in terms of extent and intensity), and the presence of symptoms refractory to clinical treatment. 14 Notwithstanding indications documented in guidelines, levels of evidence demonstrating the benefits of myocardial revascularization with the aim of reducing mortality in patients with stable CAD, based both on information about anatomy and ischemia quantification (retrospective data), 245 have been questioned, considering the absence of randomized studies published to date. With this in mind, what is known as the ISCHEMIA studywas designed (report to the addendum of thi guideline), randomizing patients who have at least moderate ischemia (more than 10% of the myocardium affected by ischemia of significant intensity or severity) from 400 centers worldwide into 2 treatment scenarios: "optimized clinical treatment" versus "optimized clinical treatment associated with revascularization of ischemic territory," excluding patients with left main trunk lesion > 50% on angio-CT. The study objective was to attempt to identify subgroups where revascularization benefits stable patients, filling in this important gap in current scientific evidence. Considering the available information (current evidence and guidelines), it seems appropriate to investigate ischemia in patients with CS over 400 in the attempt to identify individuals with high ischemic burdens (extent and intensity of perfusion defects), who may benefit from invasive strategies.
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2):325-429
## Patient with abnormal et, normal mps, and normal coronary angio-ct results
Clinical history: male, age 33, atypical chest pain, recent onset of DM, high blood pressure (HBP) and family history of early CAD, ET resulting in intermediate-risk Duke score (+3).
## Findings:
The stress phase of the ET revealed high estimated metabolic expenditure (11 METs), with 9 minutes in the Ellestad protocol. ST-segment depression of up to 1.5 mm (measured in the J point), with a descending aspect, were observed in multiple leads, during the recovery phase only, and they were sustained until the end of this phase. The Duke score was +3 (intermediate-risk), and MPS showed homogenous radiopharmaceutical distribution throughout the walls of the LV, considered within normal limits. Due to persistence of symptoms during evolution, coronary angio-CT was solicited 2 months later, showing an absence of obstructive lesions and a CS of zero. important physiological impact. Like Case 1, the situation presented in Case 6 is common in routine coronary angio-CT. In cases where ET shows intermediate or low risk and, especially, in those where the patient has intermediate or low pre-test probability, angio-CT has one of its most precise indications. The main diagnostic virtue of angio-CT is its high NPV which essentially excludes CAD. Thus, if the probability of disease is intermediate or low, the chance of excluding it is greater, and the test shows better benefits. In the case described, as symptoms persisted, complementary evaluation with angio-CT was highly useful to the medical decision-making process. Furthermore, prognosis in a patient without CAD on angio-CT is excellent, with nearly zero risk of AMI and coronary events for up to 5 years,owing to its high NPV and to the fact that characteristic evolution of CAD habitually progresses slowly, with individual variations, and this lowers the chances of an individual developing CAD culminating in a coronary event over a period of 5 years. Integrated analysis of these exams, in the case therefore, infers an excellent prognosis, notwithstanding the altered ET, and its rules out CAD quite safely, in the
## Patient with artificial electric pacemaker, abnormal mps and normal angio-ct
Clinical history: female, age 49, diagnosed with Chagas heart disease, using an artificial pacemaker, pain during effort, type II DM, non-insulin-dependent, diagnosed 4 years prior.
Findings: MPS performed with dipyridamole, considering the presence of artificial pacemaker stimulationsuggestive of DDD mode (resting ECG with atrial spikes, without clear visualization of ventricular command). Perfusion defects associated with pharmacological stress were characterized as moderate intensity and medium extent, involving the inferior (mediobasal portion) and inferolateral walls and the apex of the LV, and they were partially transient (predominance of ischemia). Angio-CT showed left dominant coronary circulation, with no signs of atherosclerosis. The presence of atrioventricular pacemaker electrodes limited assessment of the image via angio-CT.
Comments: Returning to the basic and appropriate principles of questions about pre-test probability and characterization of severity based on MPS findings, it is necessary to give special emphasis to the synergy between methods in this case. Symptomatic female patients with DM generally have an intermediate probability of obstructive CAD, mainly depending on the duration and aggressiveness of DM. On the other hand, they also have a high prevalence of endothelial dysfunction and microvascular disease, which may cause alterations in myocardial perfusion.There also exists the condition of Chagas heart disease, which features angina as a manifestation in the absence of obstructive epicardial coronary disease. The doubt which the doctor likely faces upon receiving the MPS results is the following: "What is the chance of obstructive CAD? And of endothelial dysfunction?" This is due not only to the diagnostic question, but also to the therapeutic implications, such as aggressiveness in reducing low density lipoprotein (LDL) cholesterol and the use of acetylsalicylic acid (ASA), for example. Another question is, "Does the perfusion modification in the apex represent an alteration related to Chagas heart disease?" Other questions similarly arise regarding the possibility of silent infarction related to CAD or a defect associated with artificial electrical stimulation resulting in customary atypical movement in the interventricular septum (component of an artifact). In this scenario, a safe and non-invasive way to exclude CAD is to perform angio-CT, which showed normal results in this case. It is important to underline the additional incremental prognostic value of angio-CT in this scenario, given that prognosis for this patient who does not have atherosclerosis, with mild ischemia (likely due to endothelial dysfunction), is considerably better than it would be were there conditions of mild ischemia in a patient suffering from uni-or bi-arterial obstructive CAD, or even in a patient with multivessel non-obstructive CAD.Other considerations refer to the possibility of MPS artifacts, not only related to the pacemaker in this case, but mainly to attenuation artifacts, when attenuation correction is not available, or
## Resting ecg
when the prone position is not routinely used, in addition to the previously described Chagas heart disease. If an artifact is highly suspected, corroborated by the presence of systolic thickness of LV walls without alterations, angio-CT may avoid unnecessary catheterization, even in patients with higher probabilities of CAD. Within Brazilian experience, in a laboratory with a high nuclear cardiology volume, only 24% of patients with mild myocardial ischemia on MPS referred for angio-CT have obstructive CAD. The majority are women
## Patient with abnormal angio-ct and normal mps
Clinical history: male, age 51, atypical symptoms, active, with positive family history for early CAD.
Findings: Angio-CT showed a CS of 1,445 on the Agatston score (99% percentile); significant obstructive CAD involving the left anterior descending artery in its distal portion (> 70%), with occlusion of the first diagonal branch, which receives collateral circulation; and non-obstructive CAD in the circumflex and right coronary arteries. MPS with perfusion and LV function were considered within normal limits, and ET revealed optimal physical performance (estimated metabolic expenditure of 18 METs) and normal electrocardiographic, clinical, and hemodynamic responses.
Comments: This is a challenging clinical situation, which expresses a fundamental example of integration of non-invasive anatomical and physiological modalities with the goal of avoiding unnecessary revascularization procedures. Performing angio-CT as an initial exam had the objective of excluding obstructive CAD in a young patient with intermediate pre-test probability. Meta-analysis of recent studies has demonstrated a probable benefit of this initial anatomic strategy in this scenario, with reduced AMI, when compared to initial functional test,recently incorporated into guidelines in the United Kingdom.This investigation, however, leads to an increase in the number of invasive procedures and revascularizations, with the risk of these procedures not being appropriate. 245,246 Thus, in the described scenario, with evident anatomy of obstructive CAD, which nevertheless does not meet the criteria for high risk (left main coronary lesion or triple-vessel lesions involving affected areas proximal to the left anterior descending artery), the management considered most appropriate is certainly ischemia quantification, considering that revascularization would be indicated in the presence of at least moderate ischemic burden.In this specific case, the patient should be clinically treated, with an aggressive secondary prevention approach, with close monitoring of modifiable risk factors and special attention to the manifestation of symptoms, postponing revascularization, at least in this moment where there is a lack of evidence regarding its benefits.
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2):325-429
## Patient with abnormal angio-ct and abnormal mps
Clinical history: male, age 51, with atypical chest pain (not always related to effort). Dyslipidemia and family history of early CAD (Both his father and brother had AMI resulting in death at the age of 53). Referred for coronary angio-CT to rule out obstructive CAD as the cause of the symptoms.
Findings: Angio-CT showed a CS of 12.2 (Agatston score, 67% percentile), mild, non-calcified atherosclerosis in the left main coronary and partially calcified atheromatous plaque in the middle third of the left anterior descending branch, resulting in moderate to significant luminal reduction (60% to 70%). The patient was referred for MPS associated with physical stress, exercising for 11 minutes in the Bruce protocol, with no significant ST-segment alterationsand without reproducing the symptoms. MPS images showed mild transient reduced uptake (ischemia) in the anteroseptal and septal walls and the apex of the LV.
## Comments:
Considering that a male patient with stable chest pain is characterized as having an intermediate pretest probability of CAD, the routine non-invasive methods for diagnostic and prognostic evaluation are indicated. If the resting ECG is normal and the patient has informed ability to exercise (performing daily activities with estimated metabolic expenditure of > 5 METs), the ET is then the consensual indication, provided that its limitations are taken into account. In the case in question, the early family history of CAD stands out. This fundamental clinical information is not always incorporated into traditional methods of estimating pre-test probability. In this context, coronary angio-CT was chosen, in part to rule out obstructive CAD (high NPV), which is present in only 23% of symptomatic patients within the same probability range, according to the CONFIRM register.This register demonstrates lower observed prevalence of 50% to 70% obstructive lesions on angio-CT, in comparison with the expected prevalence calculated by conventional algorithms, establishing the concept that the routine algorithms for characterizing pre-test or expected probability of events during long follow-up periods, such as the Framingham, PROCAM, Diamond Forrester, SCORE, and Global Risk; overestimate CAD. This is also the case with detection of early, nonobstructive CAD (present in 34% of patients in this register), especially in patients with family history. This investigation strategy has already been shown to be effective and likely to reduce AMI,as previously discussed in this section; it is, however, necessary to be careful with excessive interventions. This was precisely the role of functional evaluation via MPS in this case. Detection and quantification of ischemia are fundamental for determining patient management, given that the presence of moderate to severe ischemia alone would justify a more invasive strategy, such as revascularization, in the absence of refractory angina. This case was thus started on optimal clinical treatment, similar to that of patients included in the COURAGE study.
## Patient with abnormal et, normal mps, and abnormal angio-ct
Clinical history: female, age 67, with fatigue related to effort. Hypertensive ex-smoker, diagnosed with diabetes 1 year prior. Referred for MPS following abnormal ET with intermediate risk.
## Findings:
The patient exercised for 9 minutes in the Bruce protocol, reaching a HR of 136 bpm (89% maximum HR predicted based on age), triggering stress arrhythmias (ventricular and supraventricular extrasystole, in addition to periods of nonsustained ventricular tachycardia [NSVT]). ST-segment depression reached 3 mm in multiple leads, but the patient was asymptomatic. Duke Score = -6, characterized as intermediate risk. On MPS, there was an absence of signs of ischemia. Considering the clinical profile and the finding of complex ventricular arrhythmia (NSVT), concomitant with descending ST-segment depression, in spite of normal perfusion on MPS, the clinical option was to perform an angio-CT, which showed advanced atherosclerosiswith a CS of 829 on the Agatston score (97% distribution percentile) and non-obstructive lesions (< 30%) in multiple vessels.
## Comments:
In this patient, analysis of ET plays an important role in case management. MPS study with the radiopharmaceutical MIBI-99m Tc showed no abnormalities, which, in itself, determines excellent short-term prognosis. The presence of ventricular tachyarrhythmia during stress, however, adds a risk that is not, in practice, incorporated into risk prognosis by the Duke score. Furthermore, it limits analysis of the ST segment and may give rise to diagnostic doubts. One study which stands out in the literature verified that the inclusion of ventricular arrhythmia as a variable in the Duke score during ET increased its restratification potential in 30% of patients.Once again, questions may arise related to the lower sensitivity of MPS, which was apparently normal in this case (a false-negative result?). Another question is, "Should differential diagnoses such as cardiomyopathy, specific conduction tissue disease, among others, be additionally considered?" Although functionally severe obstructive CAD is improbable when MPS is normal, anatomical data from angio-CT complement and clarify many of these doubts which arose due to the conflicting results of the two functional tests. One alternative would be to perform CS, but, particularly in symptomatic patients, more detailed evaluated of anatomy via angio-CT, which quantifies degree of obstruction and determines the presence and extent of non-calcified atherosclerosis, adds incremental prognostic value.In this specific case, the presence of non-obstructive atherosclerosis, even with normal perfusion, denotes worse prognosis than in patients with normal perfusion and the absence of atherosclerosis.Moreover, the presence of atherosclerosis in multiple segments, as in the present case, confers a prognosis similar to that of uniarterial obstructive CAD.In conclusion, clinical translation of such findings could be resumed in the following manner: there are no indications that the ET alterations are secondary to ischemia, and there are thus no accrued benefits to coronary intervention, whether percutaneous or surgical revascularization. Orientation should be toward aggressive treatment of atherosclerosis to reach lipid goals recommended in current guidelines, in addition to strict control of other modifiable risk factors. The patient's current profile confers medium-and long-term prognosis similar to that of a patient with obstructive CAD in a single coronary artery.
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2):325-429
## Patient unable to exercise, abnormal mps associated with pharmacological stimulus with dipyridamole and angio-ct showing non-obstructive cad, ischemia suggestive of microcirculatory abnormalities
Clinical history: female, age 68, with stress fatigue. Hypertensive and obese, diagnosed with diabetes 8 years prior. Referred for MPS due to difficulty performing physical exercise test.
## Findings:
During the attempted test with physical exercise, the patient exercised for only 6 minutes in the Bruce protocol, with a peak HR of 115 bpm (75.6% the expected upper limit, based on age). The stress phase was discontinued due to fatigue and calf-muscle pain, also establishing suspected chronotropic incompetence. As an alternative, the protocol was initiated with dipyridamole, and it was considered altered due to ST-segment depression of 1.0 mm, in 2 leads, following completion of intravenous administration. MPS was considered abnormal due to transient reduced uptake suggestive of ischemia, involving the anterior and anterolateral (predominantly in the middle distal portion) walls of the LV, with moderate intensity and medium extent, characterized as mild to moderate ischemic burden, in addition to preserved LV function. Considering the high clinical risk profile, the findings of probable chronotropic incompetence, ST-segment alterations with dipyridamole, and ischemia in the anterior descending territory; the option was to complement with angio-CT, which showed non-calcified and non-obstructive atherosclerosis, with a CS of zero and a mild lesion (< 30%) in the anterior descending branch.
Comments: This is a classic example of a symptomatic patient with a combination of factors which, in association, may result in phenomena of endothelial and microcirculatory dysfunction, with the consequent condition of myocardial ischemia. This physiopathological condition, little over a decade ago, would have led to coronary cineangiography study in order to rule out obstructive CAD. As a consequence, "normal" coronary arteries were often observed, in what were known as "white catheterizations." With the findings described in specific populations, especially in female patients, the recent use of the term "ischemic heart disease" has gone on to express the conditions of obstructive atherosclerosis, endothelial dysfunction, and microvascular dysfunction more adequately. A recent review published by Pepine et al. in 2015 258 described important differences in the CAD spectrum in both sexes, pointing out that symptomatic women have a lower prevalence of obstructive CAD than men with the same symptoms. On the other hand, they tend to have more microvascular dysfunction, plaque erosion, and thrombus formation. In this specific case, the following factors stand out: female sex, obesity, DM, altered functional tests (both the post-dipyridamole ECG and perfusion imaging via MPS), and non-obstructive CAD on angio-CT. flow reserve (CFR), associated with non-obstructive CAD, the risk of cardiovascular events is significantly higher, and it is similar to that of individuals who have obstructive CAD, but who are not indicated for revascularization.Thus, as the prevalence of obstructive CAD is lower in women, angio-CT has been growing as a preferential diagnostic method for ruling out obstructive CAD in patients with intermediate probability, especially when there are limits to the physical exercise test.In the case in question, the combination of functional (ischemia) and anatomical (non-obstructive CAD) data was essential to the diagnosis of endothelial dysfunction and to guiding therapeutic management. uptake in the septum and apex of the LV, which was exerciseinduced, characterized by severe intensity and medium extent (moderate ischemic burden), associated with the component of persistent reduced uptake in the described territory. Apical and septal akinesis (predominantly distal) were also observed following exercise, as well as apparent transient dilation of the LV cavity and uptake of MIBI-99m Tc in RV walls, which are additional markers of severity.
## Abnormal et characterized as intermediate-risk and abnormal mps with high-risk indicators
Comments: This is an example of a case where functional methods are in agreement regarding detection of ischemia.
Cardiac imaging, here, provides additional information to the ET (intermediate-risk Duke score), which is known as "incremental prognostic value." Quantification of ischemia via MPS restratifies this patient as high-risk. In this situation, revascularization procedures may be considered based on current evidence, although the results of the ISCHEMIA study (ISCHEMIA study Addendum -report to item 2 of this guideline) have not been yet published. This case is complementary to the discussion elaborated in Case 1, where non-invasive images via MPS added prognostic value and guided patient management.
## Evaluation of myocardial viability via myocardial perfusion scintigraphy
# Introduction
In some patients with chronic CAD and ventricular dysfunction, revascularization may significantly improve symptoms, ventricular function, and mortality. Physiopathological conditions and acute and chronic mechanisms of adaptation to temporary reduction of coronary flow include stunning , hibernation, and preconditioning, either separately or coexisting in the same patient.Evaluation of myocardial viability is, consequently, important to the therapeutic decision-making process for patients with ventricular dysfunction (class of recommendation I, level of evidence B) without angina,given that functional improvement will not occur in the presence of fibrosis. Several non-invasive imaging techniques are available for detection of viable myocardium, including stress echocardiography with dobutamine, cardiac resonance, and nuclear imaging with SPECT or PET. These methods evaluate different myocardial characteristics and,
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2): thus, present variations in sensitivity and specificity.In the SPECT technique, the use of thallium-201 ( 201 Tl) is the established method for evaluating myocardial perfusion and the integrity of the cellular membrane. In comparison with other radiopharmaceuticals and available techniques, this has become the choice for determining viability.Additionally and in conjunction with these non-invasive techniques, whose aim is to obtain functional and/ or anatomical information, constituting the basis of the physiopathological approach to underlying HF, multiple detector CT is also appropriate.
However, the selection of imaging modalities, whose purpose is to assess CHF and, specifically, viability of a dysfunctional myocardium, depends on the clinical information that is required for adequate patient management , with inherent questions and affirmations, such as:
- Is the etiological cause of the cardiomyopathy in question ischemic or non-ischemic?
- In patients considered "ischemic," the need for revascularization should be evaluated with respect to characterization of the quantity of myocardium at risk/viability.
- Evolving assessment of LV function and the possibility of remodeling are mandatory elements for analysis within the clinical decision-making process; 269 other elements include secondary mitral regurgitation,implantable devices, such as defibrillators and/or resynchronization therapy.- Moreover, when the etiology of LV dysfunction, considered of the utmost magnitude for therapeutic decision making, is mandatorily under discussion, it has been verified that the majority of patients will have ischemic cardiomyopathy. Data from 24 multicenter studies on CHF, published in high-impact periodicals between 1986 and 2005 and summarized in 2006, including 43,568 individuals, showed a 62% prevalence of CAD. This frequency is probably underestimated to the extent that coronary cineangiography was not performed in all patients.
## Morphology
It had initially been established that the recovery of ventricular function, when a hibernating myocardium was revascularized, should indicate that structural changes were absent or minimal, as observed in experimental models of stunned myocardium. However, since the beginning of the 1980's, it has been known that chronically dysfunctional myocardial segments demonstrate distinct morphological changes under microscopy.There is a combination of normal, atrophic, and hypertrophic myocytes, with or without evidence of necrosis. Electron microscopy shows loss and/or disorganization of myofilaments and alterations in sarcoplasmic reticulum and mitochondria. These structural changes may contribute to slow functional recovery following revascularization.
## Evaluation of viable myocardium
The differentiation between the presence and absence of viability is highly relevant in patients under consideration for revascularization. Many patients who demonstrate viability associated with severe LV dysfunction may still be candidates for revascularization, but not for cardiac transplant.
## Physiopathology and definitions
- The term viable myocardium, regardless of the contractile state of the myocardium, should be understood differently in the context of CHF and viability study, given that the main objective is to predict improvement in LV function following revascularization.
- Persistent contractile dysfunction of the LV may be related to chronic hibernation and/or stunning, and not merely associated with fibrotic tissue. Revascularization may improve function and survival if the dysfunctional myocardium is still viable. Functional improvement will not occur in the presence of fibrosis.
- The initial point for discussion of viability implies regional dysfunction, detected by various non-invasive methods, including echocardiography as an initial line of investigation.
- Differentiation between hibernation and stunning may be established based on blood flow to the myocardium. While resting flow is chronically diminished in hibernation, it may still be preserved in the stunned myocardium, with a compromised flow reserve however.- Clinically speaking, it may not always be feasible to separate the 2 physiopathological conditions; nor is it always necessary, considering that both entities require revascularization in order for there to be improvements -Clinical situations where nuclear cardiology should be considered a preference for assessing myocardial viability, in the following order of choice: PET with 18F-FDG, resting scintigraphy with thallium-201 and reinjection protocol, and resting scintigraphy with Sestamibi -99m Tc sensitized with oral nitrite
- Evaluation of extent/localization of dysfunctional myocardium at risk, through significant hypoperfusion (hibernating myocardium)
- Clinical situations in which sensitivity is sought for assessment of viability in ventricular function. Affected areas are referred to as viable myocardium or myocardium at risk.- The coexistence of normal myocardium, however, and the formation of subendocardial scarring will not result in improved function, which is now considered "nonjeopardized" area of viable myocardium.
- Most experience in assessing viability has been obtained with nuclear imaging, utilizing SPECT and PET, with assessment of perfusion and metabolism. Moreover, using SPECT, cellular and mitochondrial membrane integrity may be characterized.
- It has been demonstrated that 40% to 50% of dysfunctional segments without contractile reserve may still have preserved perfusion and metabolism, some of which will recover function following revascularization procedures. The loss of contractile reserve is associated with structural damage characterized by greater severity and fibrosis formation.
- Several viability standards have been recognized in areas of contractile dysfunction, for instance: I) any region with > 50% of radiopharmaceutical uptake in resting images; II) any perfusion defect with > 10% increase in uptake of late images.It is, however, necessary to emphasize that areas with > 50% uptake often do not improve in function, given that these regions contain mixtures of normal myocardium and non-transmural scarring.
- Uptake and retention of tracers (sestamibi and tetrofosmin, labeled with technetium-99m) depends on perfusion, cellular membrane integrity, and mitochondrial function, where radiopharmaceutical uptake of > 50% to 60% in dysfunctional areas is frequently used as a sign of viability, when observed in resting images.
## Stress and redistribution -two steps or image acquisition series/one injection of 201 tl:
This is a conventional technique with image acquisition between 2 and 10 minutes (a maximum of 15 minutes) following injection ofTl during peak stress (first step). These images reflect initial distribution of the radioisotope dependent on blood flow and, thus, regional myocardial flow. Two to four hours after initial intravenous administration of the radioisotope, in the resting condition (second step), a new series of images is obtained, representing the "redistribution phase," related to the continuous exchange ofTl throughout the myocardium and extracellular behavior. This protocol has been designed to study ischemia, and it is not sufficient for characterization of viability, given that viable tissues may not exhibit improvement in radiopharmaceutical uptake (reversibility) within conventional time periods for redistribution images, giving the apparent impression of persistent reduced radioisotope uptake or fibrosis.: In addition to the conventional protocol, which contains only 1 injection ofTl during stress (at a dose of up to 3.0-3.5 mCi), this includes the reinjection ofTl (generally at a dose of 1 mCi) immediately after the redistribution phase, with the aim of elevating blood concentration of the radioisotope, with a new image acquisition series that may vary in terms of time (between 6 to 24 hours). There is evidence that up to 50% of regions with perfusion defects that are apparently "fixed or persistent" improve in terms of relative radioisotope uptake. This information is predictive of improvement in regional function following revascularization. Areas with sustained or severe reduced uptake following reinjection show a low probability of recovering ventricular function. Further variations are demonstrated in3. Stress/redistribution and late imaging -three steps or image acquisition series/one injection of 201 Tl: The addition of late imaging 24 hours after injection of thallium-201 during the stress or distribution phase (first step) allows more time for the phenomenon of redistribution to occur and, consequently, for increase in myocardial uptake of the radiopharmaceutical. This technique shows good predictive value for improvement of ventricular function following revascularization, but suboptimal NPV owing to the technical quality of images obtained after this period, as well as to the fact that some patients do not demonstrate redistribution during very prolonged periods.
## Stress/redistribution and reinjection -three steps or image acquisition series/two injections of 201 tl (
## Resting/redistribution -two steps or image acquisition series/one injection of 201 tl while resting:
This protocol eliminates the stress phase, based on knowledge of the physiopathology of temporal variations in coronary flow in hibernating myocardium or in unstable patients, leading to perfusion defects that may occur in resting studies, with redistribution in late images. Qualitative studies using the resting-redistribution protocol to evaluate efficacy of revascularization have shown that the majority of myocardial regions with reversible defects during pre-operative periods presented post-operative normalization in perfusion and/or improved ventricular function. Some viable regions, however, may not present redistribution, even in images at 24 hours, unlessTl blood levels are elevated following reinjection. Practically speaking, most of the clinical information necessary to the medical decision-making process, related to viability study, will have been obtained during the stress-redistribution-reinjection sequence, and late images will generally not be necessary. There is no established consensus regarding the accuracy of Sestamibi -99m Tc while resting for detection of viability, with some studies showing similar uptake forTl and Sestamibi -99m Tc (quantitative assessment) in patients with UA and LV dysfunction. It has also been observed to have satisfactory predictive value for improvement in contractility in the ventricular walls following revascularization, similar to that ofTl.The administration of nitrates before injection of the radiopharmaceutical with the objective of improving resting myocardial flow seems to improve accuracy for detecting myocardial viability. 281
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2):325-429
## Positron emission tomography 282,283
This non-invasive exam is the reference for detecting myocardial viability, as it simultaneously offers information on myocardial perfusion and metabolism. In normal fasting and aerobic metabolism conditions, while resting, long-chain free fatty acids (FFA) represent around 65% to 70% of energy supply to the cardiac muscle, with a lower participation of glucose (15% to 20%),whereas, in post-prandial conditions, glucose becomes the preferred substrate. In the presence of ischemia, the oxidative metabolism of FFA is diminished and glucose also becomes the preferred myocardial substrate. In this manner, even if the energy produced by anaerobic glycolysis is not enough to maintain myocardial contractility, it is vital for the preservation of cellular membrane integrity, which is characteristic of dysfunctional, yet viable myocardium. Some positron emitters, such as fluorine-18, labeling a glucose analogue or fluorodeoxyglucose (FDG), may be used to evaluate viable (or hibernating) myocardium, which is defined as metabolically active tissue, in the presence of a coinciding perfusion defect. FDG-18 F penetrates the cells of the myocardium by the same transport mechanism as glucose and, following phosphorylation to FDG-6-P, remains in the intracellular medium in proportion to the rate of glycolysis, reflecting the The combination of perfusion and metabolism imaging via PET has a sensitivity of 88% and a specificity of 74% for myocardial viability.Some differences exist for patients with diabetes, for whom the preferred form of viability evaluation is withTl or agents bound to 99m Tc. It is also important to remember that the radioisotope fluorine-18 or 18 F is produced in a cyclotron, consisting of the bombardment of enriched water labeled with oxygen-18 or 18 O and decaying via positron emission, with an energy range of 511 keV. Its half-life is 110 minutes, allowing for the best spatial resolution among radiotracers used for PET.
When using PET for joint analysis of metabolism with FDG-F and perfusion (positron emitters are not available for this in clinical practice in Brazil), an excellent predictive value for functional recovery has been observed. Measurements of MBF are typically performed with rubidium-82 ( 82 Rb) or ammonia labeled with nitrogen-13 ( 13 NH 3 ). Based on the concept of hibernating myocardium, segments with reduced perfusion, but with preserved FDG uptake (known as mismatches), are classified as viable, with functional improvements following adequate revascularization. However, when perfusion and FDG uptake are diminished or apparently absent (matches), this reflects an absence of viability (areas of fibrosis), which do not show improvements after revascularization. Finally, the combined approach to blood flow-FDG mismatches has been widely document as a predictor of post-revascularization regional improvements in motility, as well as improvements in symptoms of HF, exercise capacity, and prognosis. The PET and Recovery after Revascularization (PARR-2) study,which is still the only randomized prospective study to evaluate the benefits of results of a management strategy assisted by PET in patients with severe LV dysfunction, evaluated 430 randomized individuals for viability study with PET or conventional treatment without the use of PET. Results of primary analysis after 12 months of follow-up have showed a tendency toward improved results in the FDG-assisted PET, which was not statistically significant. On the other hand, post-hoc analysis, including only patients who adhered to the management strategy recommended based on the findings of FDG PET, showed significant improvements in mortality with the PET-assisted approach, when compared to standard care. Di Carli et al.demonstrated that small areas of viable myocardium (more than 5%), identified by PET, stratified patients into subgroups of high-risk of cardiac events in a year. Equally, comparative studies on viability between PET and SPECT withTl demonstrated agreement of results in 80% of cases. In contrast, a recent multicenter prospective randomized study, known as the Surgical Treatment for Ischemic Heart Failure (STICH) study,was unable to show benefits regarding mortality between patients randomized into revascularization surgery (CABG), in comparison with optimized medical therapy (OMT), in primary intention-totreat analysis, for patients with dilated cardiomyopathy (LVEF ≤ 35%) of ischemic etiology (the first of 2 tested hypotheses, involving 99 centers in 22 countries).
SPECT and/or Doppler echocardiography, associated with a low dose of dobutamine, were used to characterize viability, based on established methodological criteria. Of the 1,212 patients included for evaluation, 601 underwent the aforementioned viability studies, comparing 298 receiving medical therapy and surgical revascularization (CABG Group) to 303 patients with OMT. Of the total of 478 patients with viable myocardium, the outcome of death occurred in 178 (37%), in contrast with 58 (51%) of deaths in 114 patients without viability (hazard ratio: 0.64; 95% CI: 0.48-0.86; p = 0.003). However, after adjusting for other baseline variables, the association with mortality was not significant (p = 0.21). There was significant crossover between the 2 groups and the analysis in question was in favor of better results with CABG.
In spite of these negative findings, recognizing biases in critical analysis of the results in this occasion, it is understood that, in the real world, faced with current evidence,viability study may be of assistance when choosing the best treatment in selected populations, leading to better prognosis in evolution.
## New technologies and future perspectives for nuclear cardiology in studying ischemic heart disease
Established experience and extensive documentation, which has been accumulated over the past decades, have demonstrated that MPS has satisfactory sensitivity and specificity, emphasizing good NPV for ruling out obstructive CAD. Analysis of 32 studies has shown that SPECT has a sensitivity of 87% and a specificity of 73% for detecting significant angiographic lesions (stenosis > 50%).Some limitations to the conventional technique have been observed, such as restricted spatial resolution, reduced counting rates, and attenuation of artifacts. Anger gamma cameras with sodium iodide crystals and photomultipliers, which transform emitted gamma photons into light or scintillation, also have limited temporal resolution in comparison with other imaging methods, such as PET, and they require higher doses of radiotracers, besides to carry out exams with longer image acquisition times. On the other hand, the innumerous advantages of the nuclear method include: a) the utilization of radioisotopes that do not alter the biological properties of the organism being studied; b) high radioactive labeling with a minimal amount of chemical substances, faithfully representing physiology and cellular biochemistry; c) minimal toxicity; d) pixel (smallest component of a digital image) values of myocardial images are directly proportional to parameters inherent in cardiovascular physiology, such as perfusion, function, metabolism, and innervation, attributes which are not shared by other modalities, such as angio-CT, cardiac resonance, and echocardiography; e) another aspect which stands out is the superior contrast resolution for detecting perfusion abnormalities, differentiating normal and hypoperfusion myocardium with great accuracy, facilitating visual and quantitative image analysis. 29,293
Evolution of hardware: As exposure to radiation and its long-term deleterious effects have become important concerns on the part of regulatory authorities and scientific societies, new technologies have been introduced to reduce doses of radiotracers in nuclear exams while maintaining image quality and diagnostic accuracy. In this context, new equipment with CZT detectors arose in the first decade of 2000. Differently from traditional Anger gamma cameras, gamma radiation is directly converted to electric pulses upon contact with the CZT detectors, increasing energy resolution and dispensing with photomultipliers, which makes the detectors much finer and lighter. They are also distinct from older conventional cameras in terms of better spatial and energy resolution and the ability to distinguish dispersed radiation, in addition to being more sensitive for detection of emitted photons.Duvall et al.have shown the viability of a reduced-dose protocol and of reduced doses in a study carried out with a dedicated CZT gamma camera (Discovery NM 530c, GE Healthcare), using 5 mCi of 99m Tc as a resting dose and 15 mCi of 99m Tc as stress dose to label sestamibi or tetrofosmin. There was a significant reduction in exposure to radiation in relation to anterior SPECT protocols, and image quality and accuracy for diagnosing CAD were maintained. Gimelli et al.have also evaluated the viability of a stress-resting protocol with a reduced dose, used a CZT camera in a cohort of 137 patients referred for evaluation of CAD, with subsequent coronary cineangiography. Accuracy for identifying coronary lesions was not affected by reduced radioisotope dosage, and high sensitivity and specificity values were obtained. Hindorf et al.showed that the ideal patient position should be established when performing myocardial exams with CZT gamma cameras.
In addition to evaluating diagnostic accuracy, it has become important to evaluate prognostic value of new imaging protocols using CZT cameras. Oldan et al.compared prognostic value between CZT and conventional gamma cameras, observing that prognostic information provided by CZT technology, regarding the outcome composed of all-case mortality and non-fatal AMI, was similar to that provided by traditional equipment (Anger camera). The same dose, however, was administered to both gamma-camera groups. This fact limited the study's ability to evaluate prognostic value with reduced-dose protocols, as previously described.
Brazilian researchers 301 compared the prognostic values of an ultrafast low-dose protocol with a CZT camera and a traditional protocol with a conventional gamma camera with sodium iodide crystals. By means of a propensity score, 2 groups with equal numbers of patients and similar baseline characteristics were compared. The average dose of radiation in the first group (which underwent the exam with a conventional camera) was estimated at 9.5 mSv, whereas the CZT group had an average exposure dose of around 6 mSv. This dose was lower than the effective average SPECT
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2): doses mentioned in previous studies. It was confirmed that the CZT camera protocol showed similar prognostic results when compared to those obtained with traditional SPECT cameras, emphasizing that patients with MPS on CZT had a lower events rate than those who underwent MPS with traditional gamma cameras.
Evolution of software: Filtered back-projection (FBP) is a traditional reconstruction algorithm in LV imaging, which has was used in many SPECT gamma cameras over time. It considers that the radiation emitting object, in this case the heart, is at the same distance from all detectors and that the photons are also uniformly detected at all angles. This supposition, however, leads to a large number of image artifacts, which may be caused by breast attenuation and loss of counting density at higher distance from the heart, for example. FBP, thus, presents limitations that lead to the development of new iterative reconstruction images, which allow for the correction of these inherent artifacts.New algorithms have been developed, the most widely used of which is known as ordered subset expectation maximization (OSEM). This iterative reconstruction technique is based on estimated projection of the object studied, with additional comparison between the acquired and estimated projections of the object. The projection of proportion is generated, containing the differences between real and estimated projections of the object. These differences are used to modify initial estimation, and every cycle in this chain is called an iteration. Iterations are carried out until a projection more similar to the real object has been achieved. Iterative reconstruction allows for correction of image artifacts, such as dispersion, attenuation, and noise suppression during the reconstruction process, in order to improve image quality and resolution.DePuey et al.described the use of OSEM for processing exams with different acquisition periods (7 to 15 minutes) performed with a dual-head gamma camera with high resolution collimators. It was demonstrated that, notwithstanding lower time, image quality was maintained or even improved by the use of these reconstruction methods. Additionally, in a Brazilian study, Lima et al.analyzed prognostic accuracy of a new reconstruction algorithm, "Evolution for Cardiac TM," with reduced dose and acquisition time in a dedicated gamma camera (Ventri, GE Healthcare), with an average dosimetry of 6.2 ± 0.3 mSv. The 2,958 patients who underwent exams were followed for approximately 3 years, and their results demonstrated a very low rate of major events (death or infarction), when imaging was normal in comparison with the group with abnormal imaging exams.
New perspectives: MPS may have some imaging limitations in patients with multivessel CAD, due to loss of comparative perfusion parameters between different areas of the myocardium, considering that image generation is based on relative uptake of coronary flow labeled with radiopharmaceuticals between the walls of the LV, as described in the introduction to these Guidelines. Given this situation, quantification of absolute coronary flow and coronary flow reserve (CFR) has arisen as an important alternative for diagnostic and prognostic evaluation of these patients. Falcão et al.demonstrated that evaluation of flow reserve via PET assists in the detection of CAD in patients who have left bundle branch blocks. Patients with apparently normal perfusion and abnormal CFR have higher annual rates of cardiac death, non-fatal myocardial infarction, late revascularization, and hospitalization due to cardiac causes than patients with normal perfusion and normal CFR (6.3% versus 1.4%; p < 0.05).Ziadi et al.have expanded these results in a prospective study involving 704 patients who underwent injection with rubidium-82 ( 82 Rb) for PET, with the objective of comparing results in patients with reduced or normal CFR and patients with normal or abnormal perfusion exams. Reduced CFR was an independent predictor of major events, including cardiac death and myocardial infarction, adding prognostic value to the perfusion results. Murthy et al.studied the predictive power of CFR in 2,783 consecutive patients, observing a 5.6fold increase in the risk of cardiac death in patients with lower CFR values, compared to patients with higher values. This variable showed incremental prognostic value in comparison to relative analysis of perfusion and LVEF. The prognostic value of myocardial flow reserve (MFR) as a variable goes beyond CAD. This has been demonstrated in patients with ischemic and non-ischemic cardiomyopathy,hypertrophic cardiomyopathy,and post-cardiac transplant.The measure of coronary flow reserve using PET is quite accurate, but as it is expensive, it is not widely available in clinical practice, especially in Brazil. However, as SPECT technology is an easily accessible tool, studies show the possibility of acquiring dynamic images and quantifying MFR with this method, with some limitations, however, when using traditional gamma cameras, including limited temporal resolution.With the advent of CZT cameras, it has become viable to quantify CFR using this technology.
Wells et al.developed a pig model for measuring absolute myocardial blood flow and flow reserve, using three different radioisotopes, namely,Tl, Tetrofosmin-99m Tc and Sestamibi-99m Tc. Following in this research area, Bouallègue et al.obtained CFR in 23 patients with known three-vessel disease using a CZT gamma camera, successfully obtaining good correlation with angiographic findings. New discoveries related to dynamic SPECT image acquisition with measurements of CFR are opening new and exciting research fields that will allow for different applications of SPECT to the extent that their results are better validated.
## Strategies for reducing exposure to radiation
Ionizing radiation refers to radiation with enough energy to "ionize" atoms and molecules during its interaction with matter, in this case, with elements in the human body. Depending on the type and level of energy used, on the duration of exposure, and on the dose absorbed, damage to the organism may occur. Professionals involved in medical exams or therapies that make use of ionizing radiation should be familiar with the basics of what is known as the "as low as reasonably achievable" (ALARA) principle. This stipulates that an individual's exposure to radiation must be minimized, regardless of reason for exposure. In relation to Avoid shine through. This phenomenon occurs in perfusion studies with 99m Tc (one-day protocol, resting and stress phases) when the dose of the second injection is less than 3 times the first dose, and the residual activity in this step may interfere with interpretation of images corresponding to the second injection. This situation may result in a non-diagnostic study, making new investigations necessary and thus increasing the patient's total received dosage.
nuclear imaging, this means obtaining the principal exam information, most commonly MPS, using the minimum amount of radiation necessary to maintain diagnostic quality. This involves not only the choice of radiotracer, but also the best technique and the best protocol that may be adjusted to minimize radiation exposure.
Furthermore, 2 other important principles guide the application of ionizing radiation for medical imaging: "justification" and "optimization." Justification signifies that a study should be well indicated and justified as adequate, in following with appropriate criteria, as described in these guidelines. The best way to minimize a patient's exposure to radiation is not to recommend an exam that is not appropriately indicated. This situation, however, is often beyond the control of the doctor responsible for performing the exam and should be understood by the referring doctor, who should have a basic grasp on the scientific literature. It is important to emphasize that the risk of a patient dying due to cardiovascular disease (the leading cause of death in Brazil), without undergoing a well indicated exam, is much higher than any eventual risk owing to radiation exposure. The risks of a patient with suspected coronary disease who has an appropriate indication for an exam are not theoretical, but rather real, and they are higher than the risks resulting from radiation use. The other principle which demands our attention is optimization, which represents adjustments to protocols, including the use of the best technological resources available (modern software and hardware) to perform an exam. This task is the responsibility of a multiprofessional team, made up of physicians, supervising nurses, nursing technicians, radiology technologists, biomedical specialists, biologists trained to manipulate radioactive material, professionals with training in radiopharmacy, and a team of medical physicists. The risks of deleterious effects of radiation involving patients, provided that the multiprofessional team uses the best technique and consistently observes the principles of justification and optimization, are minimal, and they are, at times, the fruit of theoretical elaboration with no consolidated practical base.
The INCAPS Nuclear Cardiology Protocols Cross-Sectional Study (INCAPS), an important, recently conducted international study coordinated by the International Atomic Energy Agency (IAEA), involving 65 countries, including Brazil, verified that radiation exposure may be different when comparing patients living in different countries, given the diversity of implemented protocols in nuclear cardiology practice worldwide.Innumerous opportunities have been found to improve the application of nuclear cardiology comprehensively worldwide, basically using the principle of optimization. It has generally been identified that with simple, low-cost orientations, such as adjusting dose to BMI, it is possible to reduce the administered dose of radiation and patient exposure significantly. Latin America is an example,where there are opportunities to improve protocols. It has been recommended that the majority of patients undergoing MPS have a maximum estimated radiation exposure of 9 mSv. This goal is feasible to reach when applying the recommendations listed in, which are strategies supported by the IAEA.In the Brazilian centers that participated in the INCAPS study, average doses were observed to vary between 8.4 and 17.8 mSv, thus demonstrating the possibility of optimizing protocols in the country, which has been undertaken since the publication of INCAPS.
## Reducing radiation using new technologies, image quality, and reliability of findings
Given that exposure to high doses is a source of concern, considering the possibility of biological effects of ionizing radiation, which are known as deterministic (those which occur above certain limits of absorbed dose in a determined tissue, including skin erythema, loss of hair, and, possibly, direct cardiac toxicity) and stochastic (those whose radiation causes damage that may lead to malignancy which is generally long-term),is directly converted into an electric pulse when it comes into contact with CZT detectors, increasing energy resolution and dispensing with photomultipliers, which makes the detectors much finer, lighter, and more sensible to photon detection. Protocols have suggested that it is possible to combine faster exams with lower dosimetry. Owing to high costs, they are still not widely used in Brazil, where there are few more than a dozen gamma cameras with this new technology , which has already begun to contribute relevant publications to the international scenario.One of the limitations, known as the "Achilles heel" of myocardial perfusion image interpretation is the attenuation which gamma rays undergo when they pass through tissues before reaching the detector. The problem lies in the fact that attenuation may simulate myocardial perfusion defects, and their recognition as cases of "false-positive" results greatly depends on the observer's experience. These defects occur more frequently in the inferior wall in men (especially in patients with abdominal obesity), and they are described as diaphragmatic attenuation. In women, they are most commonly found in the anterior wall, due to attenuation caused by breast tissue. These imaging defects are more common in obese patients, for which reason they require higher injected doses. When the defects found are tenuous, when they occur in a similar way during resting and stress, and when they are accompanied by thickness in the walls of LV without abnormalities, the myocardial perfusion study may frequently be interpreted as normal, thus sparing the patient other investigations, both those that involve radiation and those that do not, and minimizing costs. Another way to lower the attenuation artifacts is to apply specific machines with other sources of radiation, such as an x-ray emitting tomograph, which calculates tissue attenuation factors and applies attenuation correction to the photons emitted by the radioactive tracer, reducing the effects of attenuation by means of software. This equipment, however, adds costs to the exam, and it is difficult in terms of financial viability. Even in the USA, which is the country with the highest volume of myocardial scintigraphy studies, it is estimated that only 20% of medical services routinely apply this method. Finally, another method, which is widely applied in practice to resolve apparent defects in uptake generated by attenuation of gamma photons when they penetrate tissue, is to acquire images in the prone and supine positions , especially during the stress phase, which significantly reduces the artifacts described. Some services have routinely implemented this practice, even considering the increased gamma camera utilization time with a new image acquisition series.
With respect to performing stress exam alone in order to reduce radiation by avoiding the resting dose, the following should be considered:
1. It is possible for the observing doctor to succeed in interpreting a study as "absence of ischemia," based only on stress imaging, thus avoiding the resting injection. In order to do this, the observer must be confident that the image is perfectly normal and free of any perfusion defects, including "attenuation artifacts," which are generally recognized by comparing stress and resting images. The alternative is described above, routinely applying attenuation correction, but this would involve increased costs.
## 2.
Another situation, which is not frequent, but which may occur, is when the patient has homogenous tracer distribution in the LV and apparently normal perfusion, but with an observed transient increase or dilation in the same cavity during the stress phase, when compared to resting images (transient ischemic dilation). The following may, additionally, be observed: a) drop in LVEF following stress, compared to resting; and/or b) increased uptake in the RV (generally not visualized) during the phase corresponding to stress, in comparison with resting; these are markers of poor prognosis, even in the presence of perfusion which is apparently "normal" owing to homogenous distribution. In these situations, the patient is exceptionally identified as high-risk based on other findings which are not solely related to tracer distribution in the LV during stress. This analysis and these findings are only possible when comparing resting and stress images. In summary, the doctor interpreting the images should be sure that the stress exam is perfectly normal, in order to dispense with resting image acquisition. Whenever possible, nuclear cardiology should always be performed using exercise as a preferential form of stress instead of pharmacological tests, which serve as alternatives only in patients who are unable to exercise efficiently.
In the presence of severe multivessel coronary disease (involving three arteries) and apparent relative homogeneous radiopharmaceutical distribution during stress, it is extremely rare not to observe other high-risk findings during stress testing, in addition to deterioration of LV function induced by stress itself (ischemic myocardial stunning).
In summary, in this section, various ways to reduce radiation exposure in patients undergoing nuclear cardiology exams have been covered. By means of relatively simple adjustments to protocols, injected doses may be optimized, guaranteeing image quality and, most of all, reliability of findings in an exam which is of great clinical importance to orient patient management.
## Evaluation of cardiac sympathetic activity by scintigraphy with 123 i-mibg
# Introduction
Autonomic cardiac innervation plays a fundamental role on cardiac performance by regulating myocardial blood flow, HR, and myocardial contractility. In several cardiac diseases, cardiac neuronal function is altered and frequently associated with worse evolution. Dysregulation of the autonomic cardiac nervous system increases the risk of potentially lethal arrhythmias and may be a marker of poor prognosis. Scintigraphy imaging of distribution and cardiac neuronal function facilitates the comprehension of the physiopathology of various diseases that affect the heart and may guide treatment, with consequent improvements to clinical results.The autonomic cardiac nervous system encompasses sympathetic and parasympathetic innervation, with its norepinephrine (NE) and acetylcholine neurotransmitters, respectively. These work in equilibrium, and they exert stimulating effects, via adrenergic receptors, and inhibitory effects, via muscarinic receptors, both of which are responsible for electrophysiological and hemodynamic adaptations in the cardiovascular system, in response to bodily demands.In this way, sympathetic stimuli are controlled by cerebral regulatory centers that integrate signals coming from other parts of the brain and receptors in the body. Efferent signals follow descending pathways in the spinal cord and make synapses with preganglionic fibers that emerge at levels T1 to L3. In this sequence, they establish synapses with the paravertebral stellate ganglion and innervate the RV, in addition to the anterior and lateral regions of the LV. In the heart, sympathetic nerves follow the coronary arteries in the subepicardium and then penetrate the myocardium.Parasympathetic fibers are scarce in number in comparison with sympathetic fibers, and they originate in the marrow, following the vagus nerve. They begin in the epicardium, crossing the atrioventricular groove and penetrating the myocardium. They are located in the subendocardium, predominantly innervating the atria, but they are less dense in the ventricles, with the exception of the inferior wall. They greatly control the function of sinoatrial and atrioventricular nodes.
## Cardiac scintigraphy with 123 i-mibg
Metaiodobenzylguanidine (MIBG) is a molecule with a structure similar to that of NE, obtained by means of modifications to the molecular structure of guanethidine (a false neurotransmitter, also an NE analogue), which acts selectively on sympathetic nerves, without, however, being metabolized by monoamine oxidase or catechol-Omethyltransferase or exercising a stimulating effect, as NE does. For the objective of diagnosis, MIBG is labeled with iodine-123, forming the radiotracer MIBG-123 I, 322-325 demonstrating a good correlation between myocardial uptake of MIBG-123 I and NE content in cardiac tissue.After the radiopharmaceutical is injected via intravenous administration, it spreads throughout synaptic space, and is taken up, concentrated, and stored in presynaptic nerve endings in a manner similar to that of NE. MIBG-123 I is retained and localized in cardiac sympathetic nerve endings with scintigraphy images obtained by a conventional gamma camera.The radioisotope iodine-123 predominantly emits gamma photons with an energy of 159 keV and a physical half-life of 13.2 hours, making image acquisition easy and well tolerated. MIBG-123 I is widely used in Europe and Japan, and it has recently been approved for cardiac use in the USA.In Brazil, this technique is available in some centers. Cardiac scintigraphy with MIBG-123 I directly evaluates global and regional sympathetic function of the heart, including uptake, reuptake, storage, and NE release processes in presynaptic nerve endings.Intravenous injection of MIBG-123 I is administered while resting, at least 30 minutes after oral administration of potassium iodide syrup or an iodine-containing solution, in order to block and protect the thyroid. Medications that may potentially interfere with catecholamine uptake, such as antidepressants, and some calcium channel blockers should be suspended for at least 24 hours before administration of the radiopharmaceutical. On the other hand, betablockers, angiotensin converting enzyme inhibitors (ACEI), and/ or angiotensin receptor blockers (ARB) do not need to be discontinued.Normal HMR values vary from 1.9 to 2.8 with an approximate average of 2.2 ± 0.3 in late images, with results ≥ 1.6 considered predictive of lower risks.HMR reflects the density of receptors and, probably, depicts the integrity of presynaptic nerve endings and of the uptake 1 receptor. This elevated index indicates a predominant localization of the radiotracer in the myocardium, which is expected in normal hearts, to the extent that the finding of reduced HMR indicates lower myocardial uptake of MIBG-123 I, translating as reduced density of cardiac adrenergic receptors. Late HMR combines information on neuronal function of uptake and the release of storage vesicles in cardiac nerve endings.show images of patients with normal and altered HMR, respectively.
Myocardial washout rate (WR) of MIBG-123 I is also an important measure of cardiac sympathetic innervation. WR is calculated as the difference in myocardial uptake between the early and late phases and is determined by the percentage of reduction in uptake between these steps, reflecting the amount of catecholamines released in the cardiac synaptic cleft. Cardiac sympathetic hyperactivity is associated with reduced retention of MIBG-123 I in late images (reduced late HMR) and increased WR. Normal WR control values are 10% ± 9%.Higher values are predictive of worse prognosis,although there are several methods for determining this ratio in the literature. Intra-and inter-observer variability of these measurements is less than 5%.
## Clinical applications of cardiac scintigraphy with mibg-123 i
Imaging studies of cardiac adrenergic activity may be useful in several clinical scenarios, including: HF, ventricular arrhythmias (associated with HR and primary arrhythmias), ischemic heart disease, DM, patients undergoing cardiotoxic chemotherapy, pre-and post-cardiac transplant, in early images (15 minutes after injection) and late imaging (4 hours after injection) and the myocardial washout rate (WR) of MIBG-123 I.
## Heart failure
In this condition, altered cardiac adrenergic innervation is strongly correlated with mortality, and reduced cardiac uptake of MIBG-123 I (late HMR) confers independent and additional long-term prognostic value to other established markers, such as LVEF and B-natriuretic peptide (BNP).Some studies have demonstrated that abnormalities in cardiac uptake of MIBG-123 I may be predictive of increased risk of ventricular arrhythmia and sudden cardiac death,with attempts to standardize the procedure for the sake of routine clinical application.Cardiac scintigraphy with MIBG-123 I has been approved for use in clinical practice in cardiology since 1992 in Japan,and it is considered a class I indication for evaluation of prognosis and severity of HF, with level of evidence B.Studies with higher numbers of patients have recently been published in Europe and the USA. The AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF)multicenter, prospective, international study involving the use of MIBG-123 I in HF independently validated the prognostic value of cardiac scintigraphy with MIBG-123 I for the evaluation of patients with chronic HF.They included 961 patients with HF, NYHA HF functional class II-III, and LVEF ≤ 35%, undergoing cardiac scintigraphy with MIBG-123 I, followed for an average of 17 months. Approximately 25% of patients (n = 237) had cardiac events, with approximately 70% of the first events being progression of chronic HF; 20% potentially lethal arrhythmic events (sustained VT > 30 seconds, heart arrest with cardiac arrest with resuscitation and appropriate ICD firing; and approximately 10% cardiac death; with 22% of patients presenting multiple events. Lower risks of the compound outcome were observed in patients with HMR ≥ 1.60 versus HMR < 1.60 (38%; hazard ratio: 0.40; p < 0.001) with a highly significant risk ratio for each individual component of the primary compound outcome evaluated. It is worth highlighting that total mortality over 2 years was around 5 times higher (16.1% versus 3.0%) in patients with late HMR < 1.60 compared to those with HMR ≥ 1.60, respectively.Considering this information, the FDA has approved MIBG-123 I (AdreView R ), in 2013, for evaluation of cardiac sympathetic innervation in patients with New York Heart Association (NYHA) HF class II-III and LVEF < 35%.In addition to prognostic evaluation of HF,other applications which stand out include the following: evaluation of therapeutic response to medication;indication and evaluation of response to cardiac resynchronization therapy (CRT); 342 indication for implant and explant of mechanical left ventricular assist device,and implantable cardioverter defibrillator (ICD); and evaluation of reinnervation following cardiac transplant.Late HMR of MIBG-123 I in patients with severe chronic HF, in accordance with traditional classification criteria (LVEF, BNP, functional class), may help reclassify patients into a category of lower risk for events. Patients with late HMR ≥ 1.6 (even with very low LVEF and elevated BNP) have a low probability of severe cardiac events during a period of up to 2 years. This information may lead to changes in treatment.This marker may, also, help refine indication criteria for high-cost invasive therapies for HF, such as CRTand ICD implant.A Brazilian study carried out by Nishioka et al.has shown that HMR was the only independent predictor of therapy response. Patients with HMR < 1.36 had a lower chance of benefitting from CRT, suggesting that these patients with rather elevated cardiac sympathetic activity have terminal HF.The autonomic nervous system plays an important role in cardiac arrhythmias. Scintigraphy with MIBG-123 I has the potential to select patients for ICD implant more accurately, in addition to identifying those at higher risks of sudden cardiac death, who would not be selected in accordance with current guidelines. Arora et al.,in a pilot study of 17 patients with advanced chronic HF and ICD, divided patients into groups according to the presence or absence of previous ICD firing. In cases with late HMR of MIBG-123 I < 1.54, they observed a higher frequency of ICD firing and a positive predictive value of 71%, at the same time that increased HMR was observed to have a NPV of 83%.
The etiology of HF is frequently classified as ischemic (I) and non-ischemic (NI). Although the physiopathology and the initial lesion are different, investigation studies have suggested that, as the disease progresses, autonomic cardiac abnormalities are characteristic and common, regardless of etiology. Cardiac scintigraphy with MIBG-123 I thus continues to be a strong prognostic marker. Wakabayashi et al.showed that, for both groups, late HMR was the strongest independent predictive factor for sudden cardiac death, although the cutoff points for HMR index values were different, namely 1.50 for ischemic cardiomyopathy and 2.02 for non-ischemic cardiomyopathy. For patients with LVEF < 40% and late HMR lower than the identified cutoff values, the rate of cardiac death was higher in the ischemic group (18.2% annually) than in the non-ischemic group (11.9% annually).
## Ventricular arrhythmia
Sudden cardiac death continues to be one of the leading causes of death worldwide. Scarring and/or nonrevascularized/ischemic myocardium provide important substrates for the occurrence of potentially lethal ventricular arrhythmias.Furthermore, the presence of clinical HF increases the risk of ventricular arrhythmia. The sympathetic nervous system is an important trigger of major arrhythmic events by means of global cardiac adrenergic hyperactivity and heterogeneity of regional myocardial sympathetic activity.Evaluation of the autonomic nervous system via myocardial scintigraphy (MS) with MIBG-123 I may be useful in diverse clinical situations. The presence of denervated yet viable myocardium and the magnitude of denervation are potential markers of an individual's susceptibility to triggering of severe arrhythmias. Several studies have demonstrated the ability of scintigraphy with MIBG-123 I to identify patients at higher risks of developing spontaneous ventricular tachyarrhythmia, appropriate ICD shock,and sudden cardiac death.When analyzing the possibilities of scintigraphy imaging results, the finding of a mismatch between perfusion and myocardial innervation characterizes a scenario of higher risk for ventricular arrhythmia.The denervated regions respond to sympathetic stimuli differently than normal myocardium. This electrophysiological heterogeneity may serve as a substrate for VT and ventricular fibrillation (VF). In the same manner, tomography images (SPECT) of cardiac scintigraphy with MIBG-123 I are useful for recognizing increased arrhythmogenicity. A prospective study of 50 patients with antecedents of myocardial infarction who underwent SPECT imaging with MIBG-123 I and perfusion SPECT perfusion with Tetrofosmin-99m Tc showed, via multivariate analysis, that a late MIBG-123 I SPECT defect score of ≥ 37 was the only parameter capable of differentiating the group of patients who presented VT induced by electrophysiological testing, with a sensitivity of 77% and a specificity of 75%.There were no significant differences in late HMR and the mismatch scores obtained by subtraction of perfusion and sympathetic innervation between the groups with positive and negative induced VT.Moreover, the Prediction of Arrhythmic Events with Positron Emission Tomography (PAREPET) study evaluated quantification of denervated myocardium in 204 patients with ischemic heart disease (LVEF ≤ 35%), by means of PET imaging with 11 C-metahydroxyephedrine (HED-11 C), labeled with carbon-11. Perfusion and myocardial viability have also been characterized with 13 N-ammonia and 18 F-fluordeoxyglucose, respectively. The primary study objective was to observe the occurrence of sudden cardiac death, defined as arrhythmic death or ICD firing due to VF or VT > 240 beats/minute. After 4.1 years of follow-up, sudden cardiac death of 16.2% was registered. The quantification of infarction volume and LVEF were not factors predictive of sudden cardiac death. However, patients with higher volumes of denervated myocardium (33 ± 10% versus 26 ± 11% of the LV; p = 0.001) showed sudden arrhythmic death more frequently. The authors of this study concluded that, in ischemic cardiomyopathy, sympathetic denervation evaluated by HED-11 C PET predicts sudden arrhythmic death regardless of LVEF and infarction volume. This information may improve identification of patients who will most likely benefit from ICD implant.One of the most peculiar aspects of the natural history of chronic Chagas cardiomyopathy is the occurrence of severe ventricular arrhythmia in individuals with preserved LV global systolic function which may evolve to sudden death during early phases of the disease.In 43 patients with chronic Chagas cardiopathy and LVEF ≥ 35%, the correlation between extent of sympathetic denervation, myocardial fibrosis, and severity of ventricular arrhythmias was investigated. Patients were divided into 3 groups, according to the presence of sustained VT, non-sustained VT, and the absence of VT on 24-hour Holter. Sympathetic denervation was evaluated via SPECT imaging with MIBG-123 I and myocardial fibrosis via SPECT with 99m Tc-sestamibi. The sums of perfusion scores (quantity of fibrosis) were similar in the 3 groups. The summed difference score between MIBG-123 I and Sestamibi-99m Tc, which evaluated the extension of denervated yet viable myocardium, was significantly larger in the group with sustained VT on Holter (score of 20.0 ± 8.0), when compared to the group without VT (2.0 ± 5.0; p < 0.0001) and NSVT (11.0 ± 8.0; p < 0.05).
In conclusion, the occurrence of ventricular arrhythmias with different degrees of severity is quantitatively correlated with the extension of cardiac sympathetic denervation, but not with the extension of fibrosis, suggesting that myocardial sympathetic denervation plays a role in the generation of ventricular arrhythmia related to chronic Chagas cardiopathy.Sympathetic denervation may also occur in patients with stable angina in the absence of infarction. Cardiac scintigraphy with MIBG-123 I may show inervation defects in these cases, in the absence of perfusion defects. Sympathetic nervous fibers are more susceptible to oxygen privation than cardiomyocytes and the occurrence of myocardial ischemia may thus lead to transient sympathetic denervation.The fact that recovery of inervation may be a slower process also makes it possible to use myocardial scintigraphy with MIBG-123 I as a marker of ischemic memory in patients whose chest pain has resolved few hours or days prior.
Regional alterations of cardiac sympathetic activity may also be seen in primary arrhythmic conditions, in the absence of CAD,in Brugada syndrome,in hypertrophic cardiomyopathy,and in arrhythmogenic RV dysplasia.These findings in patients with primary arrhythmias support the potential use of cardiac scintigraphy with MIBG-123 I for identifying patients at a risk of sudden cardiac death, who may benefit from ICD implant.
## Cardiotoxicity due to chemotherapy
Over the past decades, there have been great advances in cancer diagnosis and treatment, offering oncology patients reduced mortality, increased survival, and better quality of life. On the other hand, progress in oncological treatment results in higher exposure to the cardiotoxic effects of chemotherapy. Screening for the occurrence of cardiotoxicity (CTX) is highly recommended before, during, and after the completion of chemotherapy. Several methods and diagnostic indexes have been suggested for the detection of CTX and therapeutic strategy planning. Although serial measure of LVEF by conventional echocardiogram is the most utilized strategy for monitoring myocardial damage, it does not appear to be sensitive enough to detect patients with risks of developing significant CTX in early phases of chemotherapy administration.The potential use of cardiac adrenergic imaging for monitoring the cardiotoxic effects of chemotherapy has been debated.There is evidence that reduced cardiac uptake of MIBG-123 I precedes ejection fraction deterioration. 371
## Update
## Update of the brazilian guideline on nuclear cardiology -2020
Arq Bras Cardiol. 2020; 114(2): A recent study has shown that, following 1 year of treatment with anthracyclines, late HMR was the strongest parameter of scintigraphy with MIBG-123 I. This index correlates with conventional echocardiography variables and global indexes of radial and longitudinal strain, in addition to doses of galectin-3 in patients with breast cancer treated with anthracyclines. Altered late HMR was a predictor of abnormality in the global radial strain index on ECG.Cardiac scintigraphy with MIBG-123 I was performed in 20 women with breast cancer and normal LVEF who had undergone treatment with anthracycline derivatives, associated and not associated with trastuzumab. It was observed that anthracycline use with trastuzumab promoted higher frequency and intensity of cardiac adrenergic hyperactivity.Carrió et al.identified abnormal MIBG-123 I uptake in patients who used anthracyclines, where HMR of MIBG-123 I decreased as the cumulative dose of this medication increased.The degree of cardiac uptake of MIBG-123 I may thus be an early marker of CTX. However, multicenter studies with higher case numbers and standardized exam protocols comparing the evaluation of cardiac sympathetic activity with MIBG-123 I before and after treatment need to be carried out in order to clarify these findings further.
## Cardiac autonomic dysfunction in diabetes mellitus (dm)
In patients with DM, there is evidence of cardiac denervation in the absence of clinical manifestations.Diabetic autonomic neuropathy has been implied to be a cause of sudden cardiac death, with or without associated myocardial ischemia. Patients with DM and reduced HMR of MIBG-123 I have an increased risk for clinical progression of HF.It is, however, not yet clear whether cardiac adrenergic imaging may improve clinical outcome in patients with diabetes.
## Cardiac transplant
Cardiac scintigraphy with MIBG-123 I may be useful for evaluation of reinnervation in transplanted hearts. It identifies ventricular sympathetic reinnervation,which slowly develops from the cardiac base several months following surgery, and it is observed in 40% of patients 1 year following transplant.Even though the clinical implications and the mechanisms of cardiac reinnervation have yet to be completely made clear, restoration of cardiac sympathetic innervation probably increases physical capacity, due to improved HR and contractile function during exercise in patients with heart transplants.Evaluation of the process of cardiac reinnervation via scintigraphy with MIBG-123 I seems to be useful for outpatient treatment of patients with heart transplants for the prescription of appropriate exercises, evaluation of the effect of physical training, and prediction of long-term survival.
## Takotsubo syndrome
Takotsubo syndrome, also known as neurogenic cardiomyopathy, stress-induced cardiomyopathy, or broken heart syndrome,is characterized by transient left ventricular dysfunction, electrocardiographic alterations similar to those present in AMI, and minimal alterations in cardiac enzymes in the absence of obstructive CAD. It was described in 1991 in Japan 375 and denominated "Takotsubo" owing to the similarity of the morphological aspect which the LV assumes to a type of trap used to capture octopuses in Japan (round in the bottom and narrow in the upper part). It has recently been recognized as a new entity within the spectrum of acute coronary syndromes.Its real frequency is unknown, but it is estimated that it represents 1% to 2% of cases that present at the emergency room with acute coronary syndrome.It generally affects post-menopausal women (95% of cases occur in women between the ages of 60 and 80), and it is rarely (< 3%) seen in women under the age of 50 or in men. In up to 80% of cases, the syndrome is associated with previous events which produced strong physical or emotional stress, such as separations, financial loss, conflicts, loss of a loved one, illness of a loved one, severe disease, surgery, etc. In some cases, however, no preceding physical or emotional stress may be identified.
Several physiopathological mechanisms have been proposed as participants in generating the syndrome, such as occult atherosclerotic disease, multiple coronary spasms, endothelial dysfunction, and microvascular disease. Nevertheless, the most accepted hypothesis is an excess of sympathetic stimulation, with elevated circulating catecholamines causing dynamic obstruction of LV outflow and resulting in short periods of ischemia and ventricular "stunning."In fact, excessive sympathetic activity with pronounced plasma elevation of catecholamines has been found in almost 75% of patients with Takotsubo syndrome.The reason why Takotsubo syndrome occurs much more frequently in women after menopause is unknown. Several explanations have been proposed, such as the influence of sexual hormones on the sympathetic neurohumoral axisand coronary vasoreactivity;higher vulnerability of women to myocardial stunning, mediated by the sympathetic system;and alterations in endothelial function following menopause, in response to reduced estrogen levels.Clinical presentation is characterized by intense, acute chest pain (similar to that of infarction), dyspnea, ischemic ST-segment alterations (ST-segment elevation and/or inversion of T waves and pathological Q waves), mild increase in cardiac enzymes, and segmental systolic dysfunction in the apex and middle third of the LV, with base hyperkinesis, in the absence of obstructive epicardial coronary disease.
The most accepted criteria for diagnosis are currently those proposed by the Mayo Clinic in 2008:- Transient hypokinesis, akinesis, or dyskinesis in LV midsegments, with or without apical involvement.
- Regional abnormalities that extend beyond epicardial vascular distribution, often with a precipitating factor.
- Absence of CAD or evidence of acute plaque rupture.
- New ECG abnormalities (ST-segment elevation and/or T-wave inversion) or mild elevation in cardiac troponin (disproportional to the degree of LV dysfunction).
- Absence of pheochromocytoma and myocarditis.
## Update
Update of the Brazilian Guideline on Nuclear Cardiology -2020
Arq Bras Cardiol. 2020; 114 (2): Evaluation via myocardial scintigraphy with MIBG-123 I shows defects in the uptake of MIBG generally in the apex, with normal myocardial perfusion observed on perfusion scintigraphy with Sestamibi-99m Tc. Semiquantitative analysis has also demonstrated reduced HMR and increased washout of MIBG-123 I. Abnormalities on myocardial scintigraphy with MIBG-123 I may be detected hours to days following ischemic injury.For this reason, alterations observed on myocardial scintigraphy with MIBG-123 I suggest a physiopathological explanation for this syndrome.Prognosis of affected patients is generally favorable. In the vast majority of cases, the LV dysfunction is transient, and complete recovery commonly occurs in around 8 weeks.
In rare cases, dysfunction may be accentuated, evolving to cardiogenic shock, ventricular arrhythmia, and death (< 1% intra-hospital mortality).
## Final considerations
The diagnostic and prognostic potential for evaluating the autonomic nervous system with nuclear cardiology is great. A growing amount of evidence has shown that cardiac scintigraphy with MIBG-123 I may assist in selection of patients for more sophisticated HR treatments, such as CRT, as well as new medical approaches, and ICD implants for primary prevention. It is also a valuable tool for cardiovascular risk stratification (potentially lethal ventricular arrhythmias, progression of HF, and cardiac death). Due to the high sensitivity of autonomic nervous system fibers to ischemic injury and delayed recovery, myocardial scintigraphy with MIBG-123 I is also useful as an ischemic memory marker or for the recognition of Takotsubo syndrome. Greater clinical experience with this method will, however, be necessary, with the aim of improving positive and negative predictive values, for the sake of greater differentiation of patients with low and high risks, thus contributing to more effective use of medical resources. Japan is the only country where the utility of this imaging technique has been characterized in guidelines. Data related to cost-effectiveness are still limited, and low availability in clinical practice make it difficult to use on a large scale.
14. New Applications of Nuclear Cardiology
# Introduction
The applications of nuclear cardiology go beyond MPS for ischemic heart disease. Some of the indications which will be discussed are not relatively recent in the literature, but they are still little utilized within our context. In comparison to conventional investigation methods, new non-invasive methods of nuclear medicine in cardiology have the potential to improve early detection of affected myocardium, allowing for quantification of disease activity, orienting therapeutic interventions, and monitoring success of treatment.
## Endocarditis
Early diagnosis of infectious endocarditis (IE) continues to be challenging. The pathology should, essentially, be suspected in the presence of fever of unknown origin, especially in association with laboratory signs of infection, anemia, microscopic hematuria, or manifestations of septic embolism. The modified Duke criteria, which are considered a reference, include clinical, microbiological, and echocardiography findings, resulting in a general sensitivity around 80%.Some limitations, however, stand out, especially in patients with prosthetic valves (PV) and cardiac implantable electronic devices (CIED),implying inadequate classification of up to 24% of patients with proven IE.Advanced imaging techniques for early, sensitive diagnosis of IE are, in fact, valuable tools in clinical practice. The combination of both evaluation of myocardial metabolism of glucose via PET/CT using a glucose analogue labeled with 18 F, fluorodeoxyglucose (FDG) (FDG-18 F -PET/CT), and modified Duke criteria resulted in increased sensitivity, without large alterations in specificity.Although FDG-18 F -PET/CT is not reliable for evaluation of native valve endocarditis,it may accurately diagnose endocarditis in valve prostheses and its systemic complications.In recognition of its utility, FDG-18 F -PET/CT was included in the European Society of Cardiology Guidelines, in 2015, as a diagnostic criterion (class of recommendation IIb) for IE in patients with valve prostheses.One option for further improving FDG-18 F -PET/CT imaging is the incorporation of angio-CT (PET/angio-CT), resulting in sensitivity, specificity, positive predictive value, and negative predictive values of 91%, 91%, 93%, and 88%, respectively.As a more specific alternative to FDG-18 F -PET/CT, guidelines on IE include scintigraphy using marked leukocytes with SPECT/CT imaging. SPECT/CT is the combination of nuclear medicine tomography imaging (SPECT) and anatomical imaging via CT, greatly increasing diagnostic accuracy. However, notwithstanding the proven value of this technique for detecting endocarditis, its widespread application is compromised due to limited sensitivity and the difficulty of locating inflammatory foci, but the very high specificity of scintigraphy with marked leukocytes for infection, when using SPECT/CT imaging, may be particularly useful in cases where diagnosis remains uncertain following echocardiography and FDG-18 F -PET/CT, especially in patients who have undergone cardiac surgery over the past 2 months.As an additional possibility, the simultaneous combination of scintigraphy with marked leukocytes and MPS, acquired to improve localization of infectious points in relation to the valve plane defined by perfusion. Limitations to performing SPECT/CT with marked leukocytes are: the need for a specific structure with laminar flow, the manipulation of blood components, procedure duration, and inferior spatial resolution in relation to PET/CT.Furthermore, new bacteria-specific tracers have become available, such as carbohydrates, which are metabolized exclusively by bacteria or antibodies directed against components of the bacterial cell membrane. For example, the protein component of the pilin structure of Enterococcus faecalis is being developed.This recent study has demonstrated the superior quality of images and another possibility for differentiating between infectious and inflammatory causes of endocarditis.
CIED have been increasingly used over recent years,with elevated rates of infection (1% to 3%), and they are associated with 1-year mortality over 10%.Doppler echocardiography is the first line imaging method for evaluation of suspected CIED infection, but its use is limited for investigating infection in extra-cardiac leads and device pockets. Both FDG-18 F -PET/ CT and SPECT/CT scintigraphy with marked leukocytes have demonstrated additional value for diagnosis of infections related to CIED or pacemaker. FDG-18 F -PET/CT has been shown to be especially useful for diagnosing device pocket infections, but it is less reliable for diagnosing infections in the metallic device.The presence of a focal hotspot is considered the best criterion for infection,. It is worth noting that exam accuracy depends on patient preparation and post-implant interval, which is the case with applications involving FDG-18 F. Mild FDG-F uptake has been reported to be nonspecific in patients with CIED or pacemaker with no suspicion of acute-phase infection (≤ 2 months) following cardiac surgery.Moreover, attenuation correction artifacts due to metallic implants should be avoided by means of close evaluation of images without attenuation correction.
Both FDG-18 F -PET/CT and scintigraphy with marked leukocytes via SPECT/CT seem to be beneficial in diagnosing infections related to ventricular assist devices (VAD).FDG-18 F -PET/CT is especially sensitive to infection in these devices. In a small retrospective study, sensitivity to VAD infection was 100%, and specificity was 80%. Furthermore, in 85% of cases, PET imaging had an impact on clinical management of patients.The role of FDG-18 F -PET/CT in investigating extracardiac complications of infection was also studied. In a retrospective analysis of patients with suspected CIED infection, the performance of full body PET also identified septic embolism or infection disseminated into other sites in 28% of cases.These results were confirmed in a prospective study on known device endocarditis.In this cohort, FDG-18 F -PET/CT found septic embolism in 10 patients (29%), including 7 cases of spondylodiscitis, 4 of which were not clinically visible and which resulted in significant modifications to therapy.
Guided myocardial biopsy may be another application of FDG-18 F -PET/CT, as shown in other diseases.Furthermore, MR and PET/CT seem to be complementary in nature.Investigation of the incremental value of PET/MR, a new integrated imaging modality, may have great potential for diagnosing endocarditis.
## Myocarditis
The most common causes of myocarditis are viral infections. Other causes include other types of infections, autoimmune disorders, or drug interactions. Clinical manifestations of myocarditis are highly variable, ranging from subclinical disease to sudden death. This spectrum also reflects the extent to which this histological disease's severity, etiology, and stage of clinical presentation may vary. Inflammation of the myocardium may be focal or diffused, involving any of the cardiac chambers. Endomyocardial biopsy is currently the gold standard for diagnosis, but it has a low sensitivity (20-30%) and significant associated risk.MR is considered the imaging method of reference for non-invasive diagnosis of myocarditis, given that it allows for detection of several characteristics such as inflammatory hyperemia and edema, necrosis, and myocardial scarring, alterations in ventricular size and geometry, regional and global abnormalities in the movement of walls, and identification of pericardial effusion.MR criteria for diagnosis of myocarditis have been summarized in what are known as the Lake Louise Criteria.MR, however, has limitations that are particularly evident in chronic myocarditis, with low diagnostic precision (50% accuracy). 423 Using FDG-18 F -PET/CT, following adequate patient preparation with a carbohydrate-free diet, it is possible to visualize acute inflammation suggestive of active myocarditis. PET imaging may help distinguish active and chronic forms of the disease, following established working protocols.In a prospective study of 65 patients with suspected myocarditis, FDG-18 F -PET was in agreement with MR findings.MR and FDG-18 F -PET/CT seem to be complementary in nature.For this reason, cardiac PET/ MR has potential as a diagnostic tool for myocarditis and a new field of research.
## Update
## Pericarditis
There are multiple causes of acute or chronic pericardial inflammation, including infections (viral, bacterial, or fungal), myocardial infarction, trauma, malign diseases (primary pericardial neoplasm, pericardial metastases, or paraneoplastic syndrome), autoimmune or inflammatory diseases, and metabolic disorders (uremia). Pericarditis may also be iatrogenic, as a collateral effect of medication. Radiotherapy or idiopathic causes are other possible origins. Although its etiology is variable, the pericardium's response to different causes is not specific. Inflammation of pericardial layers and increased production of pericardial fluids are the most common, and they often manifest as chest pain. In the same manner, Doppler echocardiography stands out as a priority for diagnosis and therapeutic follow-up of pericarditis, externalizing findings such as pericardial effusion and thickness. Generally, CT and MR also allow for evaluation of pericardial effusion and thickness, allowing for better differentiation of pericardium and pericardial fluid.The use of FDG-18 F -PET/CT in pericarditis is generally complementary, and it demonstrates the ability to detect inflammatory tissue, even in the absence of obvious anatomical changes.Non-infectious inflammatory pericarditis shows mild to moderate FDG-18 F -PET uptake in the pericardium, with diffuse or focal uptake pattern. The literature is still scarce on the utility of FDG-18 F -PET/CT for differential diagnosis of the underlying causes of this pathology. Some studies relate the possibility of differentiating infectious/inflammatory pericardial disease and neoplastic/metastatic disease, given that malignity, generally, presents intense metabolic activity.Constrictive or effusive pericarditis, an uncommon complication of chemotherapy, may also present pericardial uptake of FDG-18 F, with mild intensity and wide distribution.Only a few case reports are available in the literature, and larger studies are still necessary to determine the accuracy of FDG-18 F -PET/ CT for pericarditis.
## Cardiac sarcoidosis
Sarcoidosis is a granulomatous disease whose etiology is unknown. It most commonly affects the lymphatic ganglia and the lungs, but it may involve any system of organs.The heart is frequently affected,and this represents one of the main causes of death due to this pathology in Japan and the USA.Due to its multifocal aspect and the irregular manner in which sarcoidosis affects the myocardium, the sensitivity of endomyocardial biopsy is extremely low (20% to 30%).In comparison with MR, the advantages of FDG-18 F -PET/CT include the value of functional metabolic information, the detection of active inflammation, the potential for identifying cardiac and extracardiac involvementof sarcoidosis, and the possibility of performing imaging in patients with CIED or renal insufficiency. In order to evaluate extracardiac involvement, it is important to perform full-body imaging.
Sarcoidosis normally manifests as an irregular focal uptake pattern. FDG-18 F -PET/CT has demonstrated that it detects active cardiac and extracardiac forms reliably, with sensitivity between 81% and 89% and specificity between 78% and 82%, respectively.It is necessary to pay attention to the patient preparation required for image acquisition in these cases. It is essential for the patient's diet to be low in carbohydrates and rich in fat the day before the exam and for the patient to be in fasting conditions in order to guarantee that there is no physiological uptake in the myocardium.
FDG-18 F -PET/CT may often be combined with MPS synchronized with ECG, with the objective of ruling out CAD or even identifying resting perfusion defects suggestive of inflammation-induced tissue damage.In addition to this, FDG-18 F -PET/CT in combination with perfusion imaging has shown evidence of prognostic capability in patients with sarcoidosis,orienting myocardial biopsy,and demonstrating valor for predicting response and monitoring therapy. 444
## Cardiac amyloidosis
The CA is a rare form of cardiomyopathy. Frequently subdiagnosed, it is characterized by extracellular deposition of fibrils, composed of varied serum protein subunits, which have low molecular weight. Although more than 30 different amyloid proteins have been described, the 2 that most frequently infiltrate the heart are: light chain immunoglobulin (AL) and transthyretin (TTR). The AL and TTR forms possess different clinical courses, prognoses, and distinct forms of treatment. In the AL form, fibrils are composed of light-chain immunoglobulins and produced by a population of plasma cell clones located in the bone marrow. In the TTR form, deposits are made up of anomalous monomers or dimers of the hepatic tetrameric protein whose origin may be related to genetic mutations of familial origin (mutated TTR or [mTTR]) or the wild type, formerly known as the senile type (sTTR). More than 100 known mutations are related to mTTR and to autosomal dominant inheritance, which may affect individuals in any age group, especially middle-aged men. The most common manifestation of CA is HF with preserved ejection fraction. In its final stage, it is present as restrictive cardiomyopathy, implying very poor prognosis. Definitive diagnosis requires amyloid deposits on endomyocardial biopsy or, in patients with suggestive cardiac findings, amyloid deposits on histological exams of other tissues (e.g., abdominal fat, rectum, or kidneys).Echocardiography is the initial non-invasive exam of choice for diagnosing CA, but its specificity is limited.However, complementary sequence with MR, which has satisfactory sensitivity, may suggest a pattern of cardiomyopathy due to amyloid deposition, except in patients with moderate to severe kidney disease.
It has been reported that scintigraphy with intravenous administration of bisphosphonate radiotracers labeled with 99m-technetium (Pyrophosphate-99m Tc is the most used in Brazil) localizes cardiac amyloid deposition. It is considered sensitive and highly specific for TTR CA, identifying the disease early at onset.One hypothesis for the binding of these bone markers to amyloid fibers is related to the higher quantity of calcium present in TTR protein, in relation to AL. In a recent multicenter study which included 1,217 patients with suspected CA, the combination of moderate to accentuated increase in myocardial uptake of the radiotracer and the absence of specific monoclonal protein in blood serum or urine, had specificity and positive predictive value of 100% for the TTR form of CA. However, scintigraphy with bisphosphonate radiotracers does not reliably detect other types of CA, and it cannot be used quantitatively for therapeutic monitoring.The intensity of the concentration of Pyrophosphate-99m Tc in the cardiac area is correlated to the amyloid subtype. Degree of concentration is compared to bone uptake in the ribcage, considering the following: degree 3, greater uptake than the ribs; degree 2, equal to the intensity of concentration in the ribs; degree 1, lower concentration than in the ribs; and degree zero, no significant cardiac tracer concentration. Severely increased concentration (degrees 2 and 3)is strongly associated with TTR CA, to the extent that some authors suggest dispensing cardiac biopsy in these situations. Less intense increased concentration (degree 1) and absence of increased concentration suggest the AL form, when there is clinical suspicion. Semiquantitative analysis of radiotracer uptake should also be performed. 449 A potential bone radiotracer for PET amyloid imaging is sodium fluoride labeled with 18 F, or Sodium fluoride-18 F. It has been described in single case series, whereas another study identified no increase in uptake of this tracer with TTR CA,indicating the need for further studies to investigate the potential value of PET/CT with Sodium fluoride-18 F for CA.
A small amount of available data has demonstrated the limited application of FDG-18 F -PET/CT for evaluation of CA.Up to the present moment, the most promising alternatives include other specific amyloid markers, such as the Pittsburgh B compound labeled with carbon-11 (PIB-11 C),as well as other compounds labeled with 18 F, such as Florbetapir 457,458 and Florbetaben.All studies have reported promising results for diagnosis of CA, given that PIB-11 C presents uptake in AC. It has additionally been demonstrated that PIB-11 C has lower uptake in patients who have been treated with chemotherapy, in comparison with patients still undergoing treatment. Thus, PIB-11 C -PET has the potential to be used for therapeutic monitoring of patients with light-chain CA as a marker of disease activity.
## Final considerations
New applications of nuclear medicine in cardiologyrepresent an important area which is little explored in our context. They have the capability to detect functional alterations in these pathologies, indicating whether a disease is or active or not and assisting in therapeutic monitoring.
Cardiologists' knowledge of these applications will be essential to their proper use and to the dissemination of these diagnostic methods.
## Update
Update of the Brazilian Guideline on Nuclear Cardiology -2020
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http://www.scielo.br/pdf/abc/v114n2/0066-782X-abc-114-02-0325.pdf
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Hospital do Coração (HCor),1 São Paulo, SP – Brazil Universidade Estadual de Campinas (Unicamp),2 Campinas, SP – Brazil Sociedade Brasileira de Medicina Nuclear (SBMN),3 São Paulo, SP – Brazil Quanta Diagnóstico e Terapia,4 Curitiba, PR – Brazil Hospital das Clínicas da Universidade Federal de Pernambuco,5 Recife, PE – Brazil Hospital Moinhos de Vento,6 Porto Alegre, RS – Brazil Clínica Cardionuclear,7 Porto Alegre, RS – Brazil Universidade Federal do Rio de Janeiro (UFRJ),8 Rio de Janeiro, RJ – Brazil Fonte Imagem Medicina Diagnóstica,9 Rio de Janeiro, RJ – Brazil Clínica de Diagnóstico por Imagem (CDPI), Grupo DASA,10 Rio de Janeiro, RJ – Brazil Instituto do Coração (Incor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP),11 São Paulo, SP – Brazil Cardiologia Nuclear de Curitiba (CNC),12 Curitiba, PR – Brazil Diagnose – Centro de Diagnóstico por Imagem,13 Maceió, AL – Brazil Universidade federal Fluminense (UFF),14 Rio de Janeiro, RJ – Brazil
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afa9a7c2b297cddcdced08eb2d7a6af78fcce659
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pubmed
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Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - Part II*
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Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - Part II*
The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In this second part, the following clinical questions were answered: 1) which patients with primary cutaneous melanoma benefit from sentinel lymph node biopsy? 2) Follow-up with body mapping is indicated for which patients? 3) Is preventive excision of acral nevi beneficious to patients? 4) Is preventive excision of giant congenital nevi beneficious to patients? 5) How should stages 0 and I primary cutaneous melanoma patients be followed?
# Introduction
Cutaneous melanoma (CM) is one of the most potentially dangerous forms accounting for approximately 90% of deaths of skin cancers. The dermatologist is in the forefront of diagnosis and treatment of CM. It is his/her duty to keep updated on best practices in diagnosis, treatment and disease monitoring to be able to diagnose, treat and council patients in the best way. The last Brazilian guidelines on CM were published in 2002. [bib_ref] Melanoma cutâneo -Abordagem da lesão primária, Tovo [/bib_ref] Over 10 years have passed and during this period important advances in the area occurred, with greater relevance to diagnostic techniques. Although some concepts have not changed, it is necessary to update the standards of practice on this important health problem.
These guidelines are intended for diagnostic and therapeutic approach and follow-up of patients with suspected or confirmed diagnoses of primary CM (PCM) with no clinical nor histological evidence of metastatic disease (stages 0, I and II). They do not include ocular nor mucosal melanoma. some cases, as well as reduce morbidity of radical lymphadenectomy that many patients had to undergo. With increased use and outcome of studies devoted to the subject, it was concluded that SLNB does not interfere with survival, but is essential for staging patients with melanoma as well as for regional control (level of evidence A). There are two main advantages in precisely staging the disease: to determine which patients should receive adjuvant therapy and to provide accurate information to the patient about his disease.
A recent study, Multicenter Sentinel Lymph Node Trial-1 (MSLT-1), showed no increase in melanoma-specific survival among patients with PCM with Breslow thickness ranging from 1.2 to 3.5 mm submitted or not to SLNB. [bib_ref] Final trial report of sentinel-node biopsy versus nodal observation in melanoma, Morton [/bib_ref] It was found, however, an increase in disease-free interval for both melanoma patients with intermediate thickness and for patients with thick melanomas (Breslow thickness >3.5 mm). [bib_ref] Final trial report of sentinel-node biopsy versus nodal observation in melanoma, Morton [/bib_ref] This study also demonstrated that SLNB is a procedure that properly stages and provides loco regional control, i.e., avoids extensive lymphonodal recurrences, which result in poorer quality of life (level of evidence A).
SLNB is also useful for determining which patients may benefit from adjuvant therapy. Adjuvant treatment with pegylated interferon for patients with clinical examination or SLNB-evidenced lymph nodes was evaluated in a prospective, randomized study. [bib_ref] Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage..., Eggermont [/bib_ref] In this initial study there was no improvement in survival with adjuvant therapy. In further data analysis, however, it was observed that patients with SLN compromised by micrometastases and ulcerated primary tumor benefited from adjuvant treatment (level of evidence B). [bib_ref] Long term results of the randomized phase III trial EORTC 18991 of..., Eggermont [/bib_ref] For patients with thin melanomas (Breslow thickness <1.00 mm) positivity levels obtained when performing SLNB are too low to justify indication of the procedure. In cases with thickness ranging from 0.75 mm to 1.00 mm, positivity is 6%. [bib_ref] Role of sentinela lymph node biopsy in patients with thin melanoma, Andtbacka [/bib_ref] In another study, patients with Breslow thickness ranging from 0.75 mm to 1.00 mm demonstrated 13% positivity when ulceration or mitosis were present, or 5% when these factors were absent. For the group as a whole, positivity was 8%. [bib_ref] Sentinel node biopsy is indicated for thin melanomas ≥0,76 mm, Han [/bib_ref] Thus, SLNB can be indicated in rare cases of thin melanoma associated with ulceration and/or lymph vascular invasion (level of evidence B).
There is benefit in using SLNB for melanoma with mitotic index >1 and Breslow thickness > 0.75 mm. For smaller depths, even when mitosis are present, SLNB positivity is <5%, making SLNB indication questionable (level of evidence B). [bib_ref] Sentinel node biopsy is indicated for thin melanomas ≥0,76 mm, Han [/bib_ref] For thick melanomas (≥3.5 mm) MSLT-1 study showed benefit in disease-free time and loco regional control (level of evidence B). [bib_ref] Final trial report of sentinel-node biopsy versus nodal observation in melanoma, Morton [/bib_ref] Recent studies show that presence of regression alone is not indicative for performing SLNB, since no statistical difference was found when comparing cases with or without regression. [bib_ref] Sentinel node biopsy is indicated for thin melanomas ≥0,76 mm, Han [/bib_ref] [bib_ref] National Comprehensive Cancer Network (NCCN). Melanoma, version 2.2013: featured updates to the..., Coit [/bib_ref] The same occurs regarding Clark level [bib_ref] National Comprehensive Cancer Network (NCCN). Melanoma, version 2.2013: featured updates to the..., Coit [/bib_ref] [bib_ref] Factors predictive of status of sentinel lymph nodes in melanoma patients from..., White [/bib_ref] (level of evidence B).
## Recommendations:
- SLNB is indicated for patients with PCM with thickness ≥1.00 mm, without palpable lymph nodes (grade of recommendation B). - SLNB is indicated for patients with PCM with thickness <1.00 mm when ulceration and/or lymph vascular invasion are present (grade of recommendation B). - SLNB is indicated for patients with PCM with thickness between ≥0.75 mm and <1.00 mm that present one or more mitosis per field (grade of recommendation B). - SLNB is indicated for patients with PCM with thickness ≥4.00 mm, for regional control (grade of recommendation B).
## 2) follow-up with body mapping is indicated for which patients?
Prior to discussion it is essential to clarify the difference between body mapping (BM) and follow-up with BM. BM is the name given to the combination of total body photographic documentation with digital dermoscopy of nevi. [bib_ref] Benefits of total body photography and digital dermatoscopy ("two-step method of digital..., Salerni [/bib_ref] It is indicated for melanoma early diagnosis, and it is based on evaluation of dermoscopic features of the patient's nevi. [bib_ref] Results from an observational trial: digital epiluminescence microscopy follow-up of atypical nevi..., Haenssle [/bib_ref] [bib_ref] Characterization of 1152 lesions excised over 10 years using total-body photography and..., Salerni [/bib_ref] When used as an isolated test, performed on a single occasion, it works just as a sole dermatoscopic examination, missing one of its major uses: the dynamic observation of the lesions. "Follow-up with BM" is based on the fact that benign lesions tend to remain stable over time, in contrast to the expected evolution in melanomas. [bib_ref] Monitoring patients with multiple nevi, Puig [/bib_ref] In addition, follow-up with BM also allows early detection of new lesions, not identified in previous exams. [bib_ref] Incidence of new and changed nevi and melanomas detected using baseline images..., Banky [/bib_ref] [bib_ref] Follow-up of melanocytic skin lesions with digital epiluminescence microscopy: patterns of modifications..., Kittler [/bib_ref] [bib_ref] Identification of clinically featureless incipient melanoma using sequential dermoscopy imaging, Kittler [/bib_ref] Isolated BM, not aimed at follow-up, is frequently used in Brazil as a diagnostic test to replace/ complement dermoscopic examination usually performed during dermatological consultations. This indication is far from ideal, but is justified in situations where dermoscopy of the entire body surface cannot be performed (level of evidence D).
High-quality publications established parameters for indicating and performing follow-up with BM. [bib_ref] Benefits of total body photography and digital dermatoscopy ("two-step method of digital..., Salerni [/bib_ref] [bib_ref] Results from an observational trial: digital epiluminescence microscopy follow-up of atypical nevi..., Haenssle [/bib_ref] [bib_ref] Characterization of 1152 lesions excised over 10 years using total-body photography and..., Salerni [/bib_ref] [bib_ref] Monitoring patients with multiple nevi, Puig [/bib_ref] [bib_ref] Incidence of new and changed nevi and melanomas detected using baseline images..., Banky [/bib_ref] [bib_ref] Follow-up of melanocytic skin lesions with digital epiluminescence microscopy: patterns of modifications..., Kittler [/bib_ref] [bib_ref] Identification of clinically featureless incipient melanoma using sequential dermoscopy imaging, Kittler [/bib_ref] [bib_ref] Evidence-based dermoscopy, Menzies [/bib_ref] [bib_ref] A clinicodermoscopic approach for skin cancer screening: recommendations involving a survey of..., Argenziano [/bib_ref] [bib_ref] Changes observed in slow-growing melanomas during long term dermoscopic monitoring, Terushkin [/bib_ref] [bib_ref] Metaanalysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on..., Salerni [/bib_ref] [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] Advances in dermoscopy for detecting melanocytic lesions, Gulia [/bib_ref] [bib_ref] Dermoscopy of patients with multiple nevi: improved management recommendations using a comparative..., Argenziano [/bib_ref] Based on epidemiological studies, it was determined that patients who benefit from follow-up with BM are those who are at increased melanoma risk (level of evidence A). [bib_ref] A clinicodermoscopic approach for skin cancer screening: recommendations involving a survey of..., Argenziano [/bib_ref] [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] Definition of increased melanoma risk is variable. Different studies on the subject mention individual risk factors. The most accepted ones are described in table 3. [bib_ref] Identification of clinically featureless incipient melanoma using sequential dermoscopy imaging, Kittler [/bib_ref] [bib_ref] Evidence-based dermoscopy, Menzies [/bib_ref] [bib_ref] A clinicodermoscopic approach for skin cancer screening: recommendations involving a survey of..., Argenziano [/bib_ref] [bib_ref] Changes observed in slow-growing melanomas during long term dermoscopic monitoring, Terushkin [/bib_ref] [bib_ref] Metaanalysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on..., Salerni [/bib_ref] [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] Advances in dermoscopy for detecting melanocytic lesions, Gulia [/bib_ref] [bib_ref] Dermoscopy of patients with multiple nevi: improved management recommendations using a comparative..., Argenziano [/bib_ref] [bib_ref] Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals, Rhodes [/bib_ref] [bib_ref] Risk prediction models for incident primary cutaneous melanoma: a systematic review, Vuong [/bib_ref] [bib_ref] Public education and cancer of the skin. What do people need to..., Rhodes [/bib_ref] [bib_ref] Metaanalysis of risk factors for cutaneous melanoma, III: family history, actinic damage..., Gandini [/bib_ref] [bib_ref] Metaanalysis of risk factors for cutaneous melanoma, II: sun exposure, Gandini [/bib_ref] [bib_ref] Impact of dermoscopy on the management of high-risk patients from melanoma families:..., Gandini [/bib_ref] [bib_ref] High risk of malignant melanoma in melanoma-prone families with dysplastic nevi, Greene [/bib_ref] [bib_ref] Risk of cutaneous malignant melanoma in patients with "classic" atypical-mole syndrome. A..., Marghoob [/bib_ref] Indication of follow-up with BM for individuals with moderate to high risk is justified by the greater efficiency of this type of monitoring, which is demonstrated by the lower ratio between excised benign nevi during follow-up of these patients (15:1), compared to 79:1 in low-risk (with no risk factors for melanoma), patients. For low-risk patients follow-up with BM is not indicated because it reduces the specificity of the diagnosis and results in a greater number of unnecessarily excised benign lesions (level of evidence B) [bib_ref] Long term dermoscopic follow-up of melanocytic naevi: clinical outcome and patient compliance, Schiffner [/bib_ref] [bib_ref] Selection of patients for long term surveillance with digital dermoscopy by assessment..., Haenssle [/bib_ref] [bib_ref] Availability of digital dermoscopy in daily practice dramatically reduces the number of..., Tromme [/bib_ref] [bib_ref] Impact of dermoscopy and short term sequential digital dermoscopy imaging for the..., Menzies [/bib_ref] Dermoscopic follow-up of isolated lesions (which is different from a BM) with short term revaluation, however, can be used for low-risk patients who have few lesions with some dermoscopic atypia without initial clinical and dermoscopic criteria for melanoma (level of evidence A). In such cases, excision should also be considered as a potentially beneficial alternative to follow-up (level of evidence B). [bib_ref] A clinicodermoscopic approach for skin cancer screening: recommendations involving a survey of..., Argenziano [/bib_ref] [bib_ref] Changes observed in slow-growing melanomas during long term dermoscopic monitoring, Terushkin [/bib_ref] [bib_ref] Metaanalysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on..., Salerni [/bib_ref] [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] Advances in dermoscopy for detecting melanocytic lesions, Gulia [/bib_ref] [bib_ref] Dermoscopy of patients with multiple nevi: improved management recommendations using a comparative..., Argenziano [/bib_ref] [bib_ref] Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals, Rhodes [/bib_ref] [bib_ref] Risk prediction models for incident primary cutaneous melanoma: a systematic review, Vuong [/bib_ref] [bib_ref] Public education and cancer of the skin. What do people need to..., Rhodes [/bib_ref] [bib_ref] Metaanalysis of risk factors for cutaneous melanoma, III: family history, actinic damage..., Gandini [/bib_ref] [bib_ref] Metaanalysis of risk factors for cutaneous melanoma, II: sun exposure, Gandini [/bib_ref] [bib_ref] Impact of dermoscopy on the management of high-risk patients from melanoma families:..., Gandini [/bib_ref] [bib_ref] High risk of malignant melanoma in melanoma-prone families with dysplastic nevi, Greene [/bib_ref] [bib_ref] Risk of cutaneous malignant melanoma in patients with "classic" atypical-mole syndrome. A..., Marghoob [/bib_ref] [bib_ref] Long term dermoscopic follow-up of melanocytic naevi: clinical outcome and patient compliance, Schiffner [/bib_ref] [bib_ref] Selection of patients for long term surveillance with digital dermoscopy by assessment..., Haenssle [/bib_ref] Iatrogenic risk factors, such as immunosuppression or use of vemurafenib, should also be considered when indicating follow-up with BM (level of evidence B). [bib_ref] Melanoma Patients under Vemurafenib: Prospective Follow-Up of Melanocytic Lesions by Digital Dermoscopy, Perier-Muzet [/bib_ref] In addition to defining which patients benefit from follow-up with BM, optimal follow-up regimen was also studied. Two regimens (short and long term follow-up), which have different indications and objectives, are the most accepted. While short term BM follow up is intended to reevaluate few lesions with some degree of suspicion, long term BM follow-up is indicated for multiple unsuspected lesions in individuals with multiple nevi. [bib_ref] Monitoring patients with multiple nevi, Puig [/bib_ref] [bib_ref] A clinicodermoscopic approach for skin cancer screening: recommendations involving a survey of..., Argenziano [/bib_ref] When suspicious lesions at an early BM are identified, a revaluation must be re-schedule within 2 to 4 months in order to detect short term dermoscopic changes. This type of monitoring is more precise in identifyng featureless melanomas than the long term BM follow up. It also increases patient adherence [bib_ref] Dermoscopic monitoring of melanocytic skin lesions: clinical outcome and patient compliance vary..., Argenziano [/bib_ref] [bib_ref] Assessment of the optimal interval for and sensitivity of short term sequential..., Altamura [/bib_ref] (level of evidence A). Patients undergoing short term follow-up with BM where no suspicious lesion was detected should be re-assessed every 6-12 months (level of evidence A). [bib_ref] Benefits of total body photography and digital dermatoscopy ("two-step method of digital..., Salerni [/bib_ref] [bib_ref] Monitoring patients with multiple nevi, Puig [/bib_ref] [bib_ref] Changes observed in slow-growing melanomas during long term dermoscopic monitoring, Terushkin [/bib_ref] [bib_ref] Metaanalysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on..., Salerni [/bib_ref] The combination of short and long term follow-up with BM is indicated because it allows deteciont of a higher proportion of thin and in situ melanomas than that expected in the general population (level of evidence A). [bib_ref] Monitoring patients with multiple nevi, Puig [/bib_ref] [bib_ref] A clinicodermoscopic approach for skin cancer screening: recommendations involving a survey of..., Argenziano [/bib_ref] [bib_ref] Metaanalysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on..., Salerni [/bib_ref] A recent meta-analysis demonstrated a greater melanoma detection probability with longer follow-up. [bib_ref] Metaanalysis of digital dermoscopy follow-up of melanocytic skin lesions: a study on..., Salerni [/bib_ref] This fact justifies permanent monitoring, with no expectations of discharge (level of evidence B). [bib_ref] Monitoring patients with multiple nevi, Puig [/bib_ref] It should be kept in mind that follow-up with BM complements but does not replace clinical and dermoscopic examination of the entire skin surface. High-risk patients followed with BM should also be examined completely periodically by the dermatologist 13 (level of evidence A).
## Recommendations:
- Follow-up with BM has benefits for patients with increased risk for melanoma (see text) (grade of recommendation A).
Main benefits are: Fewer excisions of benign lesions, without loss of sensitivity (grade of recommendation A).
Allows diagnosis of thinner melanomas than those diagnosed in individuals not subjected to such follow-up (grade of recommendation A).
- Follow-up with BM is not indicated for low-risk individuals because it reduces diagnostic specificity and results in a greater number of benign lesions unnecessarily excised (grade of recommendation B). - Isolated suspicious lesions without specific criteria for melanoma, identified in low-risk individuals, can be followed with short term BM, which increases sensitivity for diagnosis of featureless melanoma (grade of recommendation A).
## 3) is preventive excision of acral nevi beneficious to patients?
Acral melanocytic nevi (AMN) often cause concern because it is widely accepted that they would have a higher risk of malignant transformation than those located elsewhere. It is also known that AMN frequently present cytological and architectural atypia, with atypical junctional proliferation on histology. [bib_ref] Histopathological features of acral melanocytic nevi in children: study of 21 cases, Evans [/bib_ref] There are no retrospective nor prospective studies indicating the frequency and types of AMN that undergo malignant tranformation. AMN are far from uncommon and acral melanoma (AM) is less common than other types of melanoma. [bib_ref] Report of survey of the palms, soles, and genitalia of 10,000 young..., Cullen [/bib_ref] The opinion among authors ranges from "only remove pigmentary lesions that present irregular shape or color", to "excise every nevus of palmo-plantar region", based on the questionable role of trauma in the development of melanoma in this region. [bib_ref] Guidelines for removal of acral and mucosal nevi, Gorelick [/bib_ref] Relation between presence of AMN and melanoma development in palmo-plantar region is controversial. Rokuhara et al [bib_ref] Number of acquired melanocytic nevi in patients with melanoma and control subjects..., Rokuhara [/bib_ref] suggest that this relation is not significant (level of evidence A). Koguchi et al showed that AMN prevalence in patients who have had plantar AM is not greater than the control group (level of evidence A). [bib_ref] The prevalence of melanocytic nevi on the soles in the japanese population, Kogushi-Nishi [/bib_ref] Green et al reported that patients with AM have a large numbers of nevi, including acrally located nevi (level of evidence A). [bib_ref] A case-control study of melanomas of the soles and palms (Australia and..., Green [/bib_ref] It is a common belief that risk of developing AM is greater in African-Americans and Asians. There are publications demonstrating a lower prevalence of AMN in Caucasians compared with African-Americans. Palicka et al found palmar or plantar nevi in 42% of African-Americans versus 23% of Caucasians (level of evidence B). [bib_ref] Acral Melanocytic Nevi. Prevalence and distribution of gross morphologic features in White..., Palicka [/bib_ref] Furthermore, while CM incidence in all sites is significantly higher in Caucasians (level of evidence A) incidence in acral regions is similar between Caucasians and African-Americans 48,49 (level of evidence B). AM, as a percentage of all melanoma cases, has been reported in 60% to 75% of African-American, 43% to 49% in Asians, and 5 to 7% in Caucasians. [bib_ref] Melanoma in black South Africans, Hudson [/bib_ref] -52 CM 5-year survival rate is worse in African-Americans compared with Caucasians, but when stratified by stage, prognosis is similar in any race, suggesting that diagnosis in African-Americans tends to be made at more advanced stages. [bib_ref] Plantar melanoma: is the incidence of melanoma of the sole of the..., Stevens [/bib_ref] Few case-control studies are available regarding AM risk factors, which are suspected to differ from those associated with CM of other sites. UV radiation is thought to play an insignificant role among AM. Green et al [bib_ref] A case-control study of melanomas of the soles and palms (Australia and..., Green [/bib_ref] Wong et al [bib_ref] Acral lentiginoua melanoma (including in situ melanoma) arising in association with naevocellular..., Wong [/bib_ref] and Phan et al 55 showed 10-27% histological contiguity between AM and junctional and dermal MN. The authors discuss that these values should demonstrate a downward bias, since AM is usually diagnosed in advanced stages and might destroy the associated nevi (level of evidence B). Furthermore, recent studies suggest that AM can also occur de novo.
Dermoscopy shows different pigment distribution in AMN and in situ AM, indicating that these lesions arise from different portions of the epidermis and, therefore, would develop independently 56,57 (level of evidence B). Additionally, a genetic mechanism was proposed for the development of de novo AM, which includes KIT mutation and cyclin D1 gene amplification rather than the previously described BRAF mutation, suggesting that AM did not originate from a nevus [bib_ref] Molecular pathogenesis of malignant melanoma: a different perspective from the studies of..., Takata [/bib_ref] (level of evidence B).
Some authors consider nevi on the genitalia and perianal region as acrally located. As it happens with AMN, preventive removal of nevi in genital and perianal region is common. This is justified by the difficulty in monitoring the lesion, due to the intimate location and reluctance in accepting examination. Hunt et al 59 performed a retrospective study in children with genital nevi and concluded that preventive biopsy is not necessary in the absence of clinical and dermatoscopic suspicion. The authors found no association between genital nevi and risk factors for melanoma,such as large number of nevi or family history of melanoma (level of evidence B). Gleason et al 60 performed a clinicopathologic analysis of 56 nevi located on female genitalia and, despite the more frequent presence of histologic features of atypia than in other locations, they followed a benign course (level of evidence B).
## Recommendations
- No studies evaluating the relationship between removal of AMN and benefits for the patient were found. - There are reports of histologic contiguity between pre-existing AM and AMN. The possibility of AM occuring de novo makes it un-necessary to biopsy every AMN (grade of recommendation B). - Recommendation for preventive resection of AMN on the genitalia and perianal region should follow the same approach of melanoma cases located in other sites, i.e., removal of lesions with clinical or dermatoscopic suspicion (grade of recommendation C).
## 4) is preventive excision of congenital melanocytic nevi (cmn) beneficious to patients?
The concern with CMN is justified by the risk of malignant transformation that it may present. It is known that the risk is proportional to the dimensions of the CMN, what makes the classification of lesions according to size to assume practical importance. The most accepted classification is the one that considers the largest diameter reached by CMN in adulthood: small <1.5 cm; medium = 1.5-19.9 cm; and giant >20.0 cm. [bib_ref] Congenital nevocytic nevi and malignant melanomas, Kopf [/bib_ref] Considering that nevus growth is proportional to the child's body, it can be estimated that a nevus on the head or the body of a newborn of >9 cm and >6 cm, respectively, will be giant in adulthood. [bib_ref] Neurocutaneous melanosis, Makkar [/bib_ref] [bib_ref] Congenital Melanocytic Nevi: Treatment Modalities and Management Options, Marghoob [/bib_ref] The risk of malignant transformation was overestimated for some time. Giant CMN (G-CMN) present a probable risk throughout life of <5% 64-66 (level of evidence B). On the contrary small or medium CMN (S/M-CMN) present a low risk of melanoma development, close to that observed for general population 67,68 (level of evidence C). Thus, malignization risk, even for G-CMN, is not so high to make prophylactic excision of these lesions mandatory and dogmatic.
Classically, melanoma risk in G-CMN is referred as higher in the first years of life, when monitoring should be more rigorous. In 55% of patients with G-CMN who develop melanoma, tumor appears in the first five years of life and 70% before puberty [bib_ref] Melanoma risk in congenital melanocytic naevi: a systematic review, Krengel [/bib_ref] [bib_ref] A study of large congenital melanocytic nevi and associated malignant melanomas: review..., Dedavid [/bib_ref] (level of evidence B). Evidences in the literature are insufficient for safe, consensual recommendation, either for preventive removal of these lesions, or for expectant management (level of evidence A). [bib_ref] Recent Data on the Risk of Malignancy in Congenital Melanocytic Nevi: The..., Hernández [/bib_ref] [bib_ref] Current Management Approaches for Congenital Melanocytic Nevi, Krengel [/bib_ref] [bib_ref] Congenital melanocytic nevi: Where are we now? Part I. Clinical presentation, epidemiology,..., Alikhan [/bib_ref] [bib_ref] Congenital melanocytic nevi: Where are we now? Part II. Treatment options and..., Ibrahimi [/bib_ref] [bib_ref] Large congenital melanocytic nevi: Therapeutic management and melanoma risk. A systematic review, Vourc'h-Jourdain [/bib_ref] [bib_ref] Large Congenital Melanocytic Nevi: Associated Risks and Management Considerations, Slutsky [/bib_ref] [bib_ref] Risk of melanoma arising in large congenital melanocytic nevi: a systematic review, Watt [/bib_ref] Studies about S/M-CMN are much more scarce and full of methodological challenges, also leading to inaccurate risk of melanoma, but close to the risk of the general population. In these cases the risk is apparently higher after puberty, since S/M-CMN associated melanoma tends to occur commonly in adulthood 75 (level of evidence C). Furthermore, melanoma tends to be more superficial, (origin at the dermo-epidermal junction), which may facilitate its detection, and occurs preferably at the periphery of nevus (level of evidence C). [bib_ref] Congenital melanocytic nevi-when to worry and how to treat: Facts and controversies, Price [/bib_ref] [bib_ref] Giant Congenital Melanocytic Nevi, Arneja [/bib_ref] G-CMN associated melanoma can have a deeper origin in the skin (dermis), presenting as a tumor or nodule. The presence of these, especially if firm, hard-ened and adherent, with fast growth history, associated or not with adenopathy, should be observed with caution. If that is the case, performing a biopsy should be considered. Neuroid tumors, such as neurofibromas and schwannomas, common in G-CMN, generally present elastic and movable consistency. Palpation of skin and lymph node chain is an essential step of the physical examination of these patients.
Apparently, G-CMN lesions that carry increased risk of malignancy are those located in the axis (trunk, head/neck), especially the large ones (>40 cm) with numerous satellite lesions. [bib_ref] Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients..., Marghoob [/bib_ref] Approximatively 75% of G-CMN associated melanomas occur in nevi with "bathing suit" distribution. [bib_ref] Risk of melanoma arising in large congenital melanocytic nevi: a systematic review, Watt [/bib_ref] Moreover, nevus restricted to limbs present reduced risk of malignancy, as well as those in individuals with few satellite lesions. The malignant transformation of satellites lesions (found in 80% of patients with G-CMN) is improbable. Clinical significance of satellite lesions is to translate increased risk of neurological involvement (Neurocutaneous melanosis -NCM) and melanoma, when present in large numbers (>50).
Paradoxically, G-CMN lesions with higher risk of melanoma, which removal could theoretically be beneficial, are difficult to excise, either because of nevus dimension, which can compromise a significant area of the tegument, or because nevus cells are located deeper into the skin, sometimes reaching the muscular fascia.
It must be remembered that melanoma risk is not limited to the skin or nevi, but may also occur in extra-cutaneous sites, especially in the central nervous system. In such case, it is refered to as neuro-cutaneous melanosis (NCM), defined as melanocytic proliferation of benign or malignant lesions in the leptomeninges, most commonly associated with G-CMN. Thus, complete removal of G-CMN does not stop the risk of melanoma, because it is unfeasible to remove all nevus cells in extra-cutaneous sites.
Management of CMN should be individualized and discussed with the patient and family, considering, in addition to melanoma risk, other aspects such as age, location of the nevus, size and depth, clinical appearence (especially color and surface), personal and family risk of melanoma, aesthetic impact and patient's desire or not to remove the nevus (level of evidence B). [bib_ref] Congenital Melanocytic Nevi: Treatment Modalities and Management Options, Marghoob [/bib_ref] [bib_ref] Recent Data on the Risk of Malignancy in Congenital Melanocytic Nevi: The..., Hernández [/bib_ref] [bib_ref] Controversias en el nevus congénito, Paradela [/bib_ref] [bib_ref] Congenital melanocytic naevi, Kovalyshyn [/bib_ref] [bib_ref] Congenital melanocytic nevi: Where are we now? Part II. Treatment options and..., Ibrahimi [/bib_ref]
## Recommendations a) small or medium cmn
- There is no dogmatic approach. As well as melanoma risk, factors such as age, location (especially in difficult self-examination areas), size, clinical and dermoscopic appearance of the nevus, history of modification, presence of other risk factors for melanoma, aesthetic impact and patient desire must be taken into consideration (grade of recommendation A). - When surgical excision is the option, it is should preferably be performed from 7-8 years until puberty, when the child already collaborates with the procedure under local anesthesia (grade of recommendation C). - Photographic monitoring and digital dermoscopic evaluation (especially of smaller nevi) are very useful in the clinical management of these patients (grade of recommendation C).
## B) giant cmn
- G-CMN removal, when desired and feasible, must be early, since the risk of melanoma is apparently greater in childhood (grade of recommendation B). - When indicated, intervention should be performed after the first six months of life due to the risk of anesthetic complications in this age group (grade of recommendation C). - Although the risk is apparently higher in childhood and adolescence, it is advisable to keep track during adulthood, because the risk remains throughout life (grade of recommendation B). - Patients with NCM do not benefit from excision of the nevus (grade of recommendation B). - The approach of the G-CMN should be multidisciplinary (dermatologists, pediatricians, plastic surgeons, neurologists and psychologists, among other professionals) and individualized for each patient (grade of recommendation B). - Histologic interpretation of G-CMN associated nodes (especially in children <1 year) should be performed by experienced dermatopathologists since they often simulate melanoma (grade of recommendation B).
## 5) how should stages 0 and i primary cutaneous melanoma patients be followed?
The potential aggressiveness of CM justifies the follow-up of patients after completion of necessary therapeutic measures. The main objectives of follow-up are two: to reduce morbidity and mortality through early detection of disease progression and to search for new primary lesions. Every patient diagnosed with CM should be staged according to the recommendations of the American Joint Committee on Cancer (7th edition) (level of evidence A). [bib_ref] Final version of 2009 AJCC melanoma staging and classification, Balch [/bib_ref] In stage I are included patients with invasive melanoma and Breslow thickness <1.0 mm (T1), as well as patients with melanomas and Breslow thickness 1,1 mm to 2.0 mm, but not exhibiting ulceration or positive mitotic index (T2a). Stage 0 corresponds to patients with in situ melanoma .
Patients diagnosed with stage I PCM have less chance of relapse compared with more advanced stages. Patients with T1 and T2 tumors present 10-year survival rates of 92% and 80%, respectively. For stage 0 patients the survival rate is almost 100%. [bib_ref] Final version of 2009 AJCC melanoma staging and classification, Balch [/bib_ref] Soon after diagnosis a careful history should be taken (clinical history and physical examination), followed by guidance on melanoma and its potential consequences. Furthermore, an adequate level of understanding on the aspects of the disease must be acquired by patients and a constant dialogue, accessible and understandable to their level of knowledge, must be offered during the period of follow-up, clarifying issues related to the disease. Appropriate orientation regarding the possibility of relapse or appearance of new primary lesions, social issues and primary preventive care for individuals and their families should also be given. (level of evidence D). [bib_ref] American Academy of Dermatology. Guidelines of care for the management of primary..., Bichakjian [/bib_ref] [bib_ref] Comparison of melanoma guidelines in the U, Fong [/bib_ref] [bib_ref] Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma, Pflugfelder [/bib_ref] Patients with stage II PCM should conduct periodic clinical examination, consisting of general skin assessment and palpation of lymph nodes. There is no consensus on the frequency of this assessment. Recommendations are that it should be performed 2-4 times a year during the first 5 years after diagnosis and once a year until completing 10 years of follow-up. Frequency may depend on factors such as presence of multiple primary melanomas (MPM), atypical nevi, family history, patient anxiety and ability to recognize recurrences or new lesions (evidence level D). [bib_ref] National Comprehensive Cancer Network (NCCN). Melanoma, version 2.2013: featured updates to the..., Coit [/bib_ref] [bib_ref] Comparison of melanoma guidelines in the U, Fong [/bib_ref] [bib_ref] Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma, Pflugfelder [/bib_ref] [bib_ref] Costeffectiveness of surveillance of stage I melanoma. A retrospective appraisal based on..., Bassères [/bib_ref] In more than half of patients with relapses, lesions are detected by the patients themselves, thus they should be taught to perform self-examination of the skin and lymphatic chains in search of suspicious lesions (level of evidence C). [bib_ref] Comparison of melanoma guidelines in the U, Fong [/bib_ref] [bib_ref] Follow-up in patients with localised primary cutaneous melanoma, Francken [/bib_ref] [bib_ref] Methods of detection of first recurrence in patients with stage I/II primary..., Dalal [/bib_ref] [bib_ref] Efficacy of skin self-examination practices for early melanoma detection, Pollitt [/bib_ref] Patients in stage 0 apparently do not require periodic clinical examination, since disease progression is unlikely (level of evidence C). [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] Methods of detection of first recurrence in patients with stage I/II primary..., Dalal [/bib_ref] The possibility of MPM must be taken into consideration for such patients, therefore stage 0 PCM patients should receive information and perform self-examination of the skin and general examination of skin annually (level of evidence D).
Although some authors indicate laboratory tests (especially serum lactate dehydrogenase and alkaline phosphatase), the majority suggests that such exams should not be performed routinely in patients in stage I (level of evidence C). [bib_ref] National Comprehensive Cancer Network (NCCN). Melanoma, version 2.2013: featured updates to the..., Coit [/bib_ref] [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] American Academy of Dermatology. Guidelines of care for the management of primary..., Bichakjian [/bib_ref] [bib_ref] Comparison of melanoma guidelines in the U, Fong [/bib_ref] [bib_ref] Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma, Pflugfelder [/bib_ref] [bib_ref] The prognostic value of serum S100B in patients with cutaneous melanoma: a..., Mocellin [/bib_ref] S100 serum levels was observed as a potential predictor of advanced disease in patients with CM. Patients with stage I to III can present it as a progression marker. In places where S100serum levels is available, the recommendation is to use it. Patients with stage 0 do not need to perform additional tests (level of evidence C). [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] Methods of detection of first recurrence in patients with stage I/II primary..., Dalal [/bib_ref] [bib_ref] The prognostic value of serum S100B in patients with cutaneous melanoma: a..., Mocellin [/bib_ref] [bib_ref] Prognostic significance of serum S100B protein in high-risk surgically resected melanoma patients..., Tarhini [/bib_ref] There is little evidence of benefits in performing imaging exams for stage I PCM patients. Chest X-ray appears not to provide benefits when performed in routine. It may identify false-positive lesions, presenting low possibility of detection of lesions with surgical potential to modify survival, besides not being able to diagnose early lung metastases. Sometimes it causes anxiety in patients. Patients with stage 0 do not require imaging (level of evidence C). [bib_ref] Surveillance after surgical treatment of melanoma: futility of routine chest radiography, Brown [/bib_ref] [bib_ref] Costs of the detection of metastases and follow-up examinations in cutaneous melanoma, Leiter [/bib_ref] [bib_ref] The role of surveillance chest X-rays in the follow-up of high-risk melanoma..., Morton [/bib_ref] [bib_ref] Early detection of asymptomatic pulmonary melanoma metastases by routine chest radiographs is..., Tsao [/bib_ref] Abdominal ultrasound (US) is also not routinely recommended for asymptomatic stage I PCM patients. Cost-effectiveness is low for metastases detection in this group of patients (level of evidence C). [bib_ref] Prognostic significance of serum S100B protein in high-risk surgically resected melanoma patients..., Tarhini [/bib_ref] [bib_ref] Surveillance after surgical treatment of melanoma: futility of routine chest radiography, Brown [/bib_ref] [bib_ref] Costs of the detection of metastases and follow-up examinations in cutaneous melanoma, Leiter [/bib_ref] [bib_ref] The role of surveillance chest X-rays in the follow-up of high-risk melanoma..., Morton [/bib_ref] Axillary and inguinal US-proven lymph-nodes, in some studies, to be superior to palpation in the detection of metastases. Thus, its use may be indicated for this group of patients, especially those with Ib or thicker tumors, always considering the cost-effectiveness and availability of the method, as well as the ability of professionals to perform it (level of evidence C). [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] Methods of detection of first recurrence in patients with stage I/II primary..., Dalal [/bib_ref] [bib_ref] Ultrasonogra¬phy or palpation for detection of melanoma nodal invasion: a meta-analysis, Bafounta [/bib_ref] [bib_ref] Ultrasound examination of regional lymph nodes significantly improves early detection of locoregional..., Blum [/bib_ref] [bib_ref] Is ultrasound lymph node examination superior to clinical examination in melanoma follow-up?..., Machet [/bib_ref] [bib_ref] The impact of ultrasound scanning in the staging and follow-up of patients..., Rossi [/bib_ref] CT scan also presents little benefit for patients with thin CM, adding significant rates of radiation exposure 98 (level of evidence C). It´s use should be restricted for patients with suspicion of recurrence based on clinical and/or imaging examination conducted with a less accurate method (level of Evidence D).
PET scan seems to have higher resolution to detect suspicious lesions, but given the low probability of disease progression in stages 0 and I, the vast majority of tests conducted in patients with early CM are normal, and false positives may occur; thus this examination is not recommended on a routine basis 99 (level of evidence C).
Finally, most authors suggest that complementary and imaging tests should be performed only in patients with stage I PCM who are symptomatic and present suspicion of tumor recurrence on physical examination (level of evidence D). [bib_ref] National Comprehensive Cancer Network (NCCN). Melanoma, version 2.2013: featured updates to the..., Coit [/bib_ref] [bib_ref] Revised U.K. guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] [bib_ref] American Academy of Dermatology. Guidelines of care for the management of primary..., Bichakjian [/bib_ref] [bib_ref] Comparison of melanoma guidelines in the U, Fong [/bib_ref] [bib_ref] Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma, Pflugfelder [/bib_ref] Recommendations:
- All patients diagnosed with melanoma should be evaluated clinically and staged according to the AJCC TNM system (grade of recommendation A). - Stage 0 melanoma patients do not need follow-up with laboratory or imaging tests (grade of recommendation C). - Stage II melanoma patients should perform clinical evaluation of the skin and lymph nodes regularly (2-4 times a year) in the first 5 years after diagnosis of melanoma and once a year until completing 10 years of follow-up (grade of recommendation D). - Laboratory and imaging tests should be performed only for patients with stage I mela-noma who present symptomatic or suspicion of disease recurrence, according to the physician's choice and tests availability (grade of recommendation C). - US of lymph node chains (level of evidence C) and dosage of S100 serum levels may be valid, even in asymptomatic patients, if they present stage Ib or higher, and according to the availability and accessibility of the method (grade of recommendation C).
At the end of the presentation of this second part of the Brazilian guidelines on melanoma, it is very important to highlight that these guidelines are not intended to restrain medical practice, but make it more homogeneous, reducing uncertainty/disagreement of good practice standards. By establishing standards, in addition to reducing the differences in care, it is also possible to provide options based on evidence, allowing the physician to make decisions about treatment or diagnostic methods, reducing the strain on patients, doctors and health system. These guidelines reflect the best scientific information published on the subject until the date of its preparation. Nevertheless, these data must be interpreted carefully, since the results of future studies could lead to changes in recommendations. In some cases, these guidelines should not be followed, always keeping in mind the patient's well being as well as other special circumstances. It is also important to remember that it is out of the scope of these guidelines to discuss aspects of prevention of skin cancers, such as use of sunscreen and other measures, which should be discussed in a specific article.q
[table] Table 1: Syntax of descriptors used to research each question and number of selected articles [/table]
[table] Table 2: Grade of recommendation and level of evidence A: Experimental or observational studies of higher consistency. B: Experimental or observational studies of lower consistency. C: Case reports/ uncontrolled studies. D: Opinion without critical evaluation, based on consensus, physiological studies or animal models. [/table]
[table] Table 3: Risk factors most associated with melanoma development [/table]
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http://www.scielo.br/pdf/abd/v91n1/0365-0596-abd-91-01-0049.pdf
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The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In this second part, the following clinical questions were answered: 1) which patients with primary cutaneous melanoma benefit from sentinel lymph node biopsy? 2) Follow-up with body mapping is indicated for which patients? 3) Is preventive excision of acral nevi beneficious to patients? 4) Is preventive excision of giant congenital nevi beneficious to patients? 5) How should stages 0 and I primary cutaneous melanoma patients be followed?
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23f1654fd05a7f366b45bb5e882900c7c7ae7964
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pubmed
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WSES-AAST guidelines: management of inflammatory bowel disease in the emergency setting
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WSES-AAST guidelines: management of inflammatory bowel disease in the emergency setting
Background: Despite the current therapeutic options for the treatment of inflammatory bowel disease, surgery is still frequently required in the emergency setting, although the number of cases performed seems to have decreased in recent years. The World Society of Emergency Surgery decided to debate in a consensus conference of experts, the main pertinent issues around the management of inflammatory bowel disease in the emergent situation, with the need to provide focused guidelines for acute care and emergency surgeons.Method: A group of experienced surgeons and gastroenterologists were nominated to develop the topics assigned and answer the questions addressed by the Steering Committee of the project. Each expert followed a precise analysis and grading of the studies selected for review. Statements and recommendations were discussed and voted at the Consensus Conference of the 6th World Society of Emergency Surgery held in Nijmegen (The Netherlands) in June 2019. Conclusions: Complicated inflammatory bowel disease requires a multidisciplinary approach because of the complexity of this patient group and disease spectrum in the emergency setting, with the aim of obtaining safe surgery with good functional outcomes and a decreasing stoma rate where appropriate.
# Background
Inflammatory bowel disease (IBD) encompasses a group of chronic inflammatory disorders comprising most commonly of ulcerative colitis (UC) and Crohn's disease (CD). The incidence of IBD appears to be rising in recent decades. Ng et al.reported that the highest prevalence values were in Europe (UC 505 per 100 000 in Norway; CD 322 per 100 000 in Germany) and North America (UC 286 per 100 000 in the USA; CD 319 per 100 000 in Canada). The prevalence of IBD exceeded 0.3% in North America, Oceania, and many countries in Europe. Overall, the majority of studies on CD and UC report stable or decreasing incidence of IBD in North America and Europe. Since 1990, the incidence has been rising in newly industrialized countries in Africa, Asia, and South America, including Brazil. The overall incidence of UC in Europe, North America, and Oceania is independent of gender. In CD, less consistent findings have been reported, with some cohorts suggesting a female predominance in the incidence of CD and others failing to find any gender difference. Differences in gender-specific incidence exist, with a female predominance in CD in western populations and a male predominance in eastern studies. No gender differences were found in UC.
IBD typically manifests in the 2nd or 3rd decade of life. Although their pathogenesis is still unclear, it is hypothesized that chronic intestinal inflammation originates from an overly aggressive mucosal immune response against luminal bacteria in genetically susceptible subjects.
CD is characterized by transmural inflammation that can occur in the entire gastrointestinal (GI) tract and common localizations include the terminal ileum and colon. Due to the transmural inflammation, complications may present such as abscesses and fistulas.
In contrast, UC demonstrates mucosal inflammation and typically starts distally in the rectum, showing progression towards the more proximal colon. The disease will mostly be limited to the colon and ileal involvement is rare (backwash ileitis).
Diagnosis of IBD is generally made by assessment of symptoms, biochemical markers, and colonoscopy combined with radiology and histology. The different phenotypes of IBD share common clinical features but may have a heterogeneous presentation which includes abdominal pain, vomiting, diarrhea, rectal bleeding, weight loss, and anemia. Extra-intestinal manifestations such as arthritis, skin disorders, and uveitis may also be present.
IBD is chronic and potentially disabling, frequently leading to hospitalizations, lower quality of life and inability to work, with a substantial socio-economic impact.
IBD management aims to achieve induction of remission, followed by maintenance therapy to prevent recurrent disease flares. IBD therapy is tailored and the choice of the treatment regimen depends on several factors including the type, distribution, and disease severity, as well as co-morbidity and patient preferences. Generally, depending on the level of severity, most patients with CD and to a lesser extent those with UC will require immunosuppression to control intestinal inflammation. Conventional immunosuppressive therapies include azathioprine, 6mercaptopurine, methotrexate, and 6-thioguanine. These therapies may be necessary for many years, particularly given the incurable nature of CD.
In case of insufficient response to immunosuppressive treatment, or in case of intolerance, biologics are the next line of therapy in a step-up approach. Different mechanisms are currently available. Anti-TNF such as infliximab, adalimumab, and golimumab are available and usually the first biologic that is prescribed due to the lower costs since the introduction of biosimilars and good effectiveness/safety profile. Next line biologicals include vedolizumab (anti-integrin), preventing leukocyte homing to the gut, and ustekinumab for CD blocking the interleukin 12/23 pathway. Recently, tofacitinib was approved for the treatment of UC, which is a JAK inhibitor and belongs to the group of small molecules.
Despite the current therapeutic arsenal for the treatment of IBD, surgery is still frequently required although the number of cases performed seems to have decreased in recent years. It is reported that the risk of first CD surgery after 10 years of disease decreased from 44 to 21% in the last 2 decades in the UK, with the risk of a second resection decreasing from 40 to 17%. This is likely due to the introduction of anti-TNF therapy, as well as improved multidisciplinary IBD management aiding this development.
Similarly, colectomy rates in UC decreased in a prospective Swiss cohort and the 5-, 10-, 15-, and 20-year cumulative colectomy rates after diagnosis were 4.1%, 6.4%, 10.4%, and 14.4%, respectively. Interestingly, the vast majority of colectomies took place within the first 10 years since diagnosis.
The improved outcomes for patients with CD are further reflected in recent studies. For example, the population-based cohort of South-Limburg (The Netherlands) showed that hospitalization rate reduced from 65.9% to 44.2% and the surgery rate from 42.9 to 17.4% at 5 years, respectively (both P<0.01). However, patients with CD still show progression towards a complicated phenotype. This is characterized by the formation of stenosis (stricturing phenotype) or abscess/fistula (penetrating phenotype). In contrast, patients who do not progress over time towards these phenotypes are considered "inflammatory phenotype." The latter study showed that the rate of progression towards penetrating or stricturing phenotype was around 21% in the 1990s and this rate did not change until 2011 when 2 different time cohorts were analyzed. In contrast, the rate of immunosuppression increased from 30 to 70%, and biologic use from 3 to 41%.
Thus, despite improved IBD management and decreasing surgical rates, patients with complicated IBD continue to present with acute complications requiring admission for emergency care. This is in part explained by the progression towards a complicated phenotype (structuring or penetrating phenotype). Secondly, patients have more therapeutic options and continue to be treated with available biologics. When failure of biologic therapy occurs, patients are usually more refractory and prone to requiring hospitalization and surgery. Toxic colitis with or without megacolon, massive hemorrhage, free perforation, an acute abscess (either intraabdominal or perianal) with sepsis, and intestinal obstruction are examples of acute surgical emergencies.
CD can present with acute complications requiring emergency surgery in approximately 6-16% of cases. In acute severe UC, intravenous corticosteroids remain the cornerstone of medical therapy but about 30% of patients do not respond to corticosteroids. After failing 3-5 days of corticosteroids, patients should be considered for second line medical therapy in the form of cyclosporine or anti-TNF therapy, as well as consideration and counselling for colectomy.
Complicated IBD requires a multidisciplinary approach because of the complexity of this group of patients. The management of IBD is very well established in the elective setting but is still unclear in the urgent/ emergency setting with a lot of grey areas and a highly variable quality of management in the lack of established consensus and guidelines that could lead to poor overall and functional outcomes.
The World Society of Emergency Surgery (WSES) decided to debate in a consensus conference of experts in the fields, the main issues pertinent to the management of IBD in the emergent situation, with the need to provide a focused guide for acute care and emergency surgeons.
# Materials and methods
During the 2018 WSES congress, the Scientific Board of the WSES expressed the necessity to address the lack of guidelines about the management of IBD in the emergency setting, to improve outcomes, decreasing morbidity, and mortality correlated to the emergency treatment of these chronic and complex diseases. "Crohn", "Ulcerative colitis", "abdominal pain", "emergency", "biochemical", "laboratory", "markers", "investigation"; "test"; "metabolic panel"
Initial assessment and Diagnosis Q.2: In patients with a suspected complicated IBD, which are the appropriate imaging studies that should be performed in the emergency setting?
"Crohn"; "Ulcerative colitis"; "emergency"; "radiology"; "computed tomography"; magnetic resonance"; ultrasonography"; "peritonitis"; abscess"; "occlusion"
Non operative management and preoperative assessment Q.3: Which is the role of interventional radiology in the management of intra-abdominal abscesses related to Crohn's disease in the emergency setting?
"Crohn"; "abscess"; "stricture"; "drainage"; "antibiotics"; "surgery"; "emergency"; "ulcerative colitis"
Preoperative management Q.4: In patients presenting with complications related to IBD, what is the appropriate medical treatment and nutritional support? -The role of medical treatment and management of specific IBD drugs -The role of nutritional support "Crohn"; "Ulcerative Colitis"; Nutritional support"; "immunosuppression"; "steroids"; "biologics"; "medical treatment" antibiotics"; "emergency"; "preoperative"; "postoperative"; "surgery" "Crohn"; "ulcerative colitis"; "toxic megacolon"; "upper gastrointestinal bleeding";"peritonitis"; "perforation"; "occlusion"; "obstruction";"emergency"; "surgery"; "indications";"radiolology";"angio-embolisation"; "computed tomography";"angiography", "lower gastrointestinal bleeding", "non operative management"
Surgical management Q.6: Which surgical approach is recommended for complicated IBD in the emergency setting?
"Acute severe ulcerative colitis"; "intestinal bleeding"; "hemorrage";"Crohn"; "anastomosis"; "laparoscopy"; "open"; "non operative management"; peritonitis"; "occlusion"; "perforation"; "toxic megacolon"; minimally invasive tecnique"; "emergency";"damage control";"open abdomen"
Surgical management Q.7: How to manage perianal sepsis in the emergency setting?
"perianal"; "abscess"; "fistula"; "sepsis";"antimicrobial"; "medical treatment"; "surgery";"emergency", "Crohn"
A group of experienced surgeons and gastroenterologists were nominated to develop the topics assigned and answer the questions addressed by the Steering Committee (SC) of the project. The main topics debated are summarised in the. The scientific coordinator of the WSES IBD Guidelines supervised each step of literature searching, study selection, and the final presentation of evidence.
Each expert followed the PRISMA methodologyin the selection of papers to consider for review, and articles selected were included in the final analysis. Pediatric patients were excluded. The study group developed a focused draft and a variable number of statements. Each statement was evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE).
The provisional statements and the supporting literature were reviewed and discussed with the WSES scientific coordinator by email and modified if necessary. The final data and contributions were presented at the 2019 WSES Congress at Nijmegen.
The WSES scientific coordinator of the project revised the statements, wrote the recommendations based on Consensus conference comments/suggestions, and wrote the final draft. It was submitted to all authors for evaluation and approval. All the comments and pertinent suggestions were considered in the final manuscript. Complicated IBD is defined as summarized in. Statements and recommendations are summarized in.
Clinicians and surgeons should be aware that these guidelines should be considered as an adjunctive tool for decision and management but they do not substitute for the clinical judgment for individual patients.
# Results
Q.1: In patients with suspected complicated IBD, which are the appropriate biochemical investigations that should be performed?
[formula] Statement 1.1 [/formula]
In clinical practice, the diagnosis of CD and UC is based on a set of modalities including clinical, biochemical, endoscopic, radiological, and histological diagnostics rather than a single reference standard (QoE low C).
# Statement 1.2
In assessing an acute abdomen in patients with IBD, laboratory tests including full blood count, electrolytes, liver enzymes, inflammatory biomarkers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and serum albumin and pre-albumin (to assess nutritional status and degree of inflammation) are mandatory (QoE moderate B).
# Statement 1.3
In case of a suspected IBD flare, infectious causes should be ruled out, especially Clostridium difficile and Cytomegalovirus (QoE low C).
## Recommendation
We recommend assessing Crohn's disease or ulcerative colitis disease activity in the urgent clinical situation by performing the following laboratory tests: a full blood count, including hemoglobin, leukocyte count, and platelet count; serum C-reactive protein level, erythrocyte sedimentation rate; serum electrolytes; liver enzymes level; serum albumin; renal function; and fecal calprotectin level, when it is possible. It is mandatory to exclude any infectious diseases by performing blood-, stool cultures, and toxin test for Clostridium difficile (strong recommendation based on a moderate level of evidence 1B).
## Summary of evidence and discussion
In assessing a patient with acute abdominal pain in the emergency room, the main laboratory tests requested are full blood count (20.1%), electrolytes (19.1%), cardiac enzymes (19.0%), and liver function tests (11.5%).
In differentiating the cause underlying acute abdominal pain, the diagnostic accuracy values of C-reactive protein (CRP) and white blood cell count (WBC) can be elevated.
IBD disease activity will usually impact laboratory tests results with anemia, leukocytosis, thrombocytosis, elevated liver enzymes, hypoalbuminemia, and increased inflammatory markers. In addition, therapies may cause abnormalities in liver enzymes, leukocytes, and kidney function. Consequently, for patients with IBD admitted to the emergency room for evaluation, laboratory tests should always include full blood count with differential, comprehensive metabolic panel, liver enzymes, and lipase.
CRP and fecal calprotectin (FC) are the most widely used biomarkers for IBD evaluation. CRP is the inflammatory marker of choice as it is more sensitive than erythrocyte sedimentation rate (ESR) for the evaluation of acute abdominal pain in patients with IBD, and correlates better with endoscopic disease activity in CD rather than in UC. It should be noted that a normal Sigmoidoscopy allows intra-luminal assessment of distal IBD disease activity, bleeding source identification and biopsies in an acute setting, when it is available (QoE C).
# Statement 2.7
In stable patients presenting with signs of gastrointestinal haemorrhage, computed tomography angiography should be considered to localise the bleeding site before angio-embolisation or surgery, especially when endoscopic assessment is not available (QoE C)
## Recommendations 2
We recommend investigating the acute abdomen in IBD patients with IV contrast-enhanced computed tomography scan in the emergency setting, to exclude the presence of intestinal perforation, stenosis, bleeding and abscesses and to help guide decision making for immediate surgery or initial conservative management (Strong recommendation based on low level evidence 1C Percutaneous drainage of abscesses > 3 cm could avoid immediate surgery and should be used as a bridging procedure before elective surgery to reduce the need for stoma creation and limit intestinal resection in malnourished and high risk patients (QoE C).
# Statement 3.4
Surgery should be considered in the case of failure of percutaneous drainage and in patients with signs of septic shock (QoE C). Statement 3.5 Surgery should be considered for patients with enteric fistulae and if clinical evidence of sepsis persists despite the initial treatment plan (QoE C).
## Recommendations 3
We recommend performing radiological percutaneous drainage of intra-abdominal abscesses > 3 cm related to Crohn's disease associated with early empiric administration of antibiotics, to adapt these as soon as possible to microbiological cultures results. The antimicrobial therapy should be reevaluated according to patient's clinical and biochemical features (Strong recommendation based on a low level evidence 1C). We recommend administering an early empiric antimicrobial therapy in stable patients presenting with abscess < 3 cm, with close clinical and biochemical monitoring (Strong recommendation based on a low level evidence 1C).
## Q.4:
In patients presenting with complications related to IBD, what is the appropriate medical treatment and nutritional support?
a) The role of medical treatment and management of specific IBD drugs
[formula] Statement 4.1 [/formula]
The optimal management of IBD patients presenting with acute abdominal pain is multidisciplinary, involving a gastroenterologist and an acute care surgeon (QoE C).
# Statement 4.2
All IBD patients presenting with an acute abdomen should receive adequate volume of intravenous fluids, low-molecular-weight heparin for thromboprophylaxis and electrolyte abnormalities and anaemia should be corrected (QoE C). The initial medical treatment for severe active UC is intravenous corticosteroids, in case of hemodynamic stability of the patient (QoE A).
# Statement 4.6
The response to intravenous steroids should be best assessed by the third day (QoE C).
# Statement 4.7
In non-responder hemodynamically stable patients, medical rescue therapy including infliximab in combination with a thiopurine, or ciclosporin should be considered in a multidisciplinary approach (QoE B).
# Statement 4.8
Infliximab should be considered if anti-inflammatory therapy for penetrating ileocecal Crohn's disease is required, following adequate resolution of intra-abdominal abscesses in a multidisciplinary approach (QoE C). Statement 4.9
Preoperative treatments with immunomodulators associated with anti-TNF-α agents and steroids are risk factors for intra-abdominal sepsis in patients requiring emergency resectional surgery (QoE B) Statement 4.10 In complex perianal fistulizing disease infliximab or adalimumab can be used as first line therapy in combination with azathioprine following adequate surgical drainage if indicated. A combination of ciprofloxacin and anti-TNF improves short term outcomes (QoE A).
b) The role of nutritional support
# Statement 4.11
Preoperative nutritional support is mandatory in severely undernourished patients (QoE A) Statement 4.12 Total Parenteral nutrition should be reserved for nutritionally deficient IBD patients unable to tolerate enteral nutrition and when the enteral route is contraindicated, in critically ill patients presenting with signs of shock, intestinal ischemia, high output fistula, and/or severe intestinal haemorrhage (QoE B) Statement 4.13 Total parenteral nutrition is the mode of choice when emergency surgery is needed for complicated IBD (QoE A)
## Recommendations 4
We recommend evaluating medical treatment in IBD patients presenting with acute abdominal pain and disease activity in a multidisciplinary approach (Strong recommendation based on low level evidence 1C). We recommend not routinely administrating antibiotics in IBD patients but only in the presence of superinfection, intra-abdominal abscesses, and sepsis (Strong recommendation based on high level evidence1A) We recommend administering antibiotics according to the epidemiology and resistance of the setting in a duration that depends on the patient's clinical and biolchemical findings. Antifungals should be reserved for high risk patients such as those with bowel perforation and recent steroid treatment. (Strong recommendation based on high level evidence 1A)
We recommend administering as soon as possible venous thromboembolism prophylaxis with LMWH for the high risk of thrombotic events related to complicated IBD and the emergency setting (Strong recommendation based on high level evidence 1A) We recommend weaning off steroids (wean preoperatively, ideally 4 weeks) and stopping immunomodulators associated with anti-TNF-α agents before surgery, as soon as possible to decrease the risk of postoperative complications, in accordance with a gastroenterologist (Strong recommendation based on moderate level evidence 1B) Computed tomography angiography should be performed in patients with ongoing bleeding who are hemodynamically stable after resuscitation (QoE C).
[formula] Statement 5.3.4 [/formula]
Surgical treatment is recommended in patients with life-threatening bleeding and persistent hemodynamic instability and in patients with acute severe ulcerative colitis non-responders to medical treatment presenting with a massive colorectal haemorrhage (QoE B). Statement 5.3.5 Significant recurrent gastrointestinal bleeding could be an indication for urgent surgery (QoE C).
## Recommendations 5.3
We recommend performing immediate surgery in unstable patients presenting with hemorrhagic shock, and non responders to resuscitation. An intra-operative ileoscopy, if available, could be useful in localising the bleeding source in patients with Crohn's disease. In patients presenting with acute severe ulcerative colitis and refractory haemorrhage, non responders to medical treatment, the surgical treatment of choice is a subtotal colectomy with ileostomy, if skills are present (Strong recommendation based on low level evidence 1C). We suggest evaluating hemodynamically stable IBD patients presenting with a gastrointestinal bleeding at first with a sigmoidoscopy and an esophagogastroduodenoscopy (Weak recommendation based on low level evidence 2C)
## 4) free perforation
Recommendation 5.We recommend performing surgical exploration in the presence of radiological signs of pneumoperitoneum and free fluid within the peritoneal cavity in acutely unwell patients presenting with complicated Crohn's disease or acute severe ulcerative colitis (Strong recommendation based on low level evidence 1C) If the patient presenting with gastrointestinal bleeding in Crohn's disease is haemodynamically stable and endoscopic and/or interventional radiology measures have been unsuccessful, then a surgical exploration in a laparoscopic (multi-port or in single incision) approach is recommended.
[formula] (QoE C) Statement 6.2.3 [/formula]
If the patient presenting with gastrointestinal bleeding in Crohn's disease is haemodynamically unstable and endoscopic and/or interventional radiology procedures have been unsuccessful, then a surgical exploration in an open approach is recommended to reduce operating time (QoE C).
c) Free perforation and purulent/faecal peritonitis Statement 6.2.4 A laparoscopic approach with resection, lavage and stoma is suggested in hemodynamically stable patients presenting with perforation and peritonitis in Crohn's disease, to avoid complications associated with anastomotic leak (QoE C) Statement 6.2.5 If there is haemodynamic stability and only localised contamination, an anastomosis may be considered but other factors will also need to be considered (QoE C) Statement 6.2.6 If evidence of severe sepsis/septic shock, damage control surgery may be considered, with resection, stapled off bowel ends and temporary closure (laparostomy) with return to theatre in 24-48 h for a second look, washout and consideration of stoma vs anastomosis (QoE C). There is insufficient evidence to recommend SILS or robotic surgery in the emergency setting (QoE C).
3) Anastomotic considerations in emergency surgery for Crohn's Disease Statement 6.3.1 If a patient in the emergency setting has 2 or more risk factors for anastomotic complications, then a stoma should be formed following resection.
(QoE C)
CRP does not rule out CD disease activity; therefore, the results should be interpreted with caution given the low sensitivity of this test. The sensitivity of CRP ranges from 70 to 100% in the differential diagnosis between CD versus irritable bowel syndrome and ranges from 50 to 60% in UC. Levels of CRP are higher in active CD than in UC.
ESR determination monitors satisfactorily the acutephase response of IBD after the first 24 h. In contrast, during the first 24 h, the CRP is a better indicator of the acute phase. The ESR, compared with CRP, reaches the highest point less quickly, and it decreases more slowly and has a lesser degree of change.
Previous studies assessing the best monitoring of medical treatment measured prospectively some laboratory parameters such as full blood count, CRP, ESR, alfa1 antitrypsin, and orosomucoid in CD patients every 6 weeks after recent weaning of steroidsand showed that the best predictor of short-term relapse is the combination of CRP and ESR. Patients with CRP > 20 mg/L and ESR > 15 mm had an eight-fold increased risk of relapse with a negative predictive value of 97%, suggesting that normal CRP and ESR could almost exclude relapse in the next 6 weeks.
Anti-inflammatory or immunosuppressive drugs do not affect CRP production. Therefore, changes of CRPSummary of statements and recommendations (Continued)
[formula] Statement 6.3.2 [/formula]
If a decision to anastomose has been made, there is no evidence to suggest that one type of anastomosis (stapled vs hand sewn) is superior to the other in terms of complication rates or recurrence, and the decision can be left to surgeon preference (QoE C).
## Recommendations 6
We recommend performing a surgical exploration by laparotomy in a hemodynamically unstable patient presenting with complications related to IBD such as perforation and severe peritonitis, massive intestinal bleeding, obstruction, toxic megacolon, severe colitis non responder to medical treatment, taking in to consideration damage control surgery principles with or without an open abdomen (Strong recommendation based on low level evidence 1C). We recommend performing a laparoscopic approach in hemodynamically stable patients presenting with complications related to IBD, when skills are available, in order to decrease morbidity and length of hospital stay (Strong recommendation based on low level evidence 1C). We recommend performing a subtotal colectomy with ileostomy in patients presenting with acute severe refractory colitis, and massive colorectal bleeding non responders to medical treatment, in a laparoscopic or open approach according to patient's hemodynamic stability and surgeon's skill (Strong recommendation based on low level evidence 1C). We suggest considering an (stapled or hand sewn) anastomosis in hemodynamically stable patients with Crohn's disease who have good preexisting nutritional status and who are taking no steroids or other immunosuppression and presenting with no bowel vascular compromise and only localised peritonitis. A defunctioning stoma should also be considered in the emergency setting. An assessment of the rectum should be made at the time of abscess drainage, to assess for signs of proctitis. (QoE C)
## Recommendation 7
We recommend performing adequate surgical drainage of perianal abscess in Crohn's disease without searching for an associated fistula (Strong recommendation based on low level evidence 1C) concentrations during treatment occur only as a result of the effect of the drug on the inflammation or disorder.
In addition, in assessing acute severe UC, defining the population by Truelove Witts criteria (summarized inis essential. The Truelove-Witts criteria combine frequency of bloody stools (⩾6 per day) with at least one marker of systemic toxicity such as pulse rate >90 bpm, temperature >37.8°C, hemoglobin <10.5 g/dl, and/or an ESR >30 mm/h. In patients with UC, the risk of progression to the second-line therapy is directly dependent on the number of variables present on admission, with a 50% risk for colectomy when three or more additional criteria are present. After 3 days of intensive treatment (hydrocortisone and/or cyclosporine/anti-TNF) patients with frequent stools (> 8/day), or 3-8 stools/day and CRP > 45 mg/L, should be identified and reviewed jointly by a gastroenterologist and surgeon as most of them will need to undergo colectomy.
Thrombocytosis correlates well with IBD disease severity, and, interestingly, it may persist even after bowel resection in some patients with IBD. The mean platelet volume has been proposed as a potential marker of clinical disease activity, being inversely proportional to the levels of CRP and ESR. The cause of the reduction in platelet volume in clinically active UC is unknown, but it may be a direct result of the thrombopoiesis disorder often observed in the early phases of systemic inflammatory progression. The platelets also relate to the increased incidence of thromboembolic phenomena in CD and UC. Some studies report that spontaneous platelet aggregation is observed in more than 30% of patients with IBD.
The number of white blood cells (WBC) increases during the acute phase response, and it is influenced by immunosuppressive drugs utilized in IBD, such as glucocorticoids (increased WBC) or azathioprine and 6mercaptopurine (decreased WBC).
Serum albumin is a negative acute phase marker and decreased levels may be found during inflammation.
Fecal calprotectin (FC) is a granulocyte-derived protein measured in the stool and is a non-invasive, cheap, and extensively studied biomarker used in IBD which correlates with clinical and endoscopic disease activity. A cutoff of 30 μg/g had 100% sensitivity in discriminating active CD from irritable bowel syndrome in the study of Tibble and colleaguesThe correlation with disease activity is less robust for disease localised to the terminal ileum (versus distal colonic disease), with likelihood of false negative results in case of proximal disease. Most hospitals will not have an immediate assay ready for same-day results, so this can limit the application of this marker in an emergency setting.
In a patient with diarrhoea, stool cultures should be obtained. In particular, fever and sudden onset of symptoms may direct the differential diagnosis towards an infection. In the latter setting, bacterial stool culture or PCR, and especially C. difficile toxin, must be considered. IBD patients are at increased risk for C difficile and subsequent hospitalization and colectomy. In addition, corticosteroids seem to be an independent risk factor for presenting with infectious colitis. Depending on the clinical setting, PCR for viral and parasitic agents may be considered. For example, IBD patients receiving immunosuppression are more prone to CMV colitis, which can be measured in serum and biopsies. Blood cultures are mandatory.
Clinical evaluation and laboratory tests are useful to stratify IBD patients in to low and high risk of complicated disease.
Khoury et al.developed a diagnostic clinical score to predict the presence of an intra-abdominal abscess in CD patients presenting with acute abdominal pain in the ED. This score included 5 parameters that were significantly associated with abscess formation, such as ileocolonic location of the disease, perianal CD, neutrophilto-lymphocyte ratio, and CRP level, whereas the current use of corticosteroids was negatively associated with abscess formation. Q.2: In patients with a suspected complicated IBD, which are the appropriate imaging studies that should be performed in the emergency setting? Statement 2.1
Cross-sectional imaging (computed tomography, magnetic resonance imaging, ultrasonography) is recommended to detect strictures and extra-luminal IBD complications including fistulae and abscesses (QoE C).
# Statement 2.2
Computed tomography and magnetic resonance imaging are the most sensitive and specific imaging tests for detecting abscesses and stenosis in IBD (QoE B). Contrast-enhanced computed tomography is the key study in the emergency setting in assessing IBD extraluminal complications such as abscesse and fistulae, and a source of bleeding in the case of gastro-intestinal haemorrhage (QoE B).
# Statement 2.4
The diagnostic accuracy of magnetic resonance enterography for assessing disease activity and complications related to IBD (including strictures) is similar to CT scan with a decreased ionising radiation exposure (QoE C)
# Statement 2.5
Point of care ultrasonography can have a role in showing free fluid, abscesses, or intestinal distention in the emergency department, particularly when CT scan is not available (QoE C)
# Statement 2.6
Sigmoidoscopy allows intra-luminal assessment of distal IBD disease activity, bleeding source identification, and biopsies in an acute setting, when it is available (QoE C).
# Statement 2.7
In stable patients presenting with signs of gastrointestinal hemorrhage, computed tomography angiography should be considered to localize the bleeding site before angio-embolization or surgery, especially when endoscopic assessment is not available (QoE C)
## Recommendations
We recommend investigating the acute abdomen in IBD patients with IV contrast-enhanced computed tomography scan in the emergency setting, to exclude the presence of intestinal perforation, stenosis, bleeding, and abscesses and to help guide decision making for immediate surgery or initial conservative management (strong recommendation based on low-level evidence 1C). We suggest performing a point of care ultrasonography (if skills are available) when computed tomography scan is not available, in order to assess the presence of free intra-abdominal fluid, intestinal distension, or abscess. The magnetic resonance enterography (if available) is the preferred technique to diagnose strictures, to differentiate fibrotic from inflammatory components and disease activity (weak recommendation based on low-level evidence 2C).
In stable patients presenting with signs of gastrointestinal bleeding, we recommend performing a computed tomography angiography to localize the bleeding site before angio-embolization or surgery (weak recommendation based on low-level evidence 2C).
If computed tomography and ultrasonography are unavailable, we suggest referring stable patients to a hospital where 24/7 emergency imaging is available (weak recommendation based on very low-level evidence 2D)
## Summary of evidence and discussion
An accurate acute abdominal assessment in patients in the emergency room with IBD is crucial to aid an early diagnosis and optimal treatment plan. Symptoms may result from the underlying IBD, or disease complications, but can also reflect a complication of therapy, an infection, or a separate medical problem. Imaging studies are mandatory to assess disease phenotype and complications, in order to facilitate informed decision making.
Usually, a cross-sectional study involving ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI), allows for a full thickness evaluation of the bowel wall and associated abnormalities. The potential benefits of cross-sectional imaging in patients with IB include better inflammation grading, such as identification of mild degree of activity, which may be relevant whenever assessing response to treatment and, of utmost importance, an accurate preoperative detection and grading of fibrosis in stricturing CD, facilitating surgical versus medical therapeutic decisions.
The Truelove-Witts classification for UC and the Montreal classification (summarized into assess CD phenotype are frequently used to stratify IBD patients at admission, and they require laboratory test and abdominal imaging results.
It is fundamental in an emergency to check the IBD disease activity and extent. In CD, the disease behavior can progress towards a penetrating phenotype over time, and in UC, can involve all of the colon.
In the emergency setting, CT should be the first radiological investigation to assess the acute abdomen in this group of patients, especially in the case of a suspected intra-abdominal abscess, perforation, or intestinal obstruction due to stricture(s). Using surgery as a reference standard, CT showed a sensitivity of 85% and a specificity of 88% for the detection of intra-abdominal abscesses.
Moreover, it is useful to stratify patients for immediate surgery or a medical treatment plan in assessing the type of bowel strictures; in fact, inflammatory strictures could benefit from a medical anti-inflammatory treatment, and fibrotic strictures could require endoscopic balloon dilation or surgery.
US showed specificity and sensitivity of 86% and 94% in detecting small bowel inflammation in comparison with MRI sensitivity and specificity that is 74% and 91%, respectively, in expert hands.
A systematic reviewshowed that conventional trans-abdominal US sensitivity for stricture diagnosis ranged from 80 to 100% with specificity rates of 63-75%. The application of small intestinal contrast US demonstrated increased sensitivity rates of 88-98% with specificity rates ranging from 88 to 100%. CT enterography (CTE) sensitivity and specificity were reported to be both 100%. CT enteroclysis, in which the luminal contrast is delivered direct to the small bowel, had a sensitivity of 92% and specificity of 39% reported in one study only. With regard to magnetic resonance imaging enterography (MRE), the sensitivity for stricture detection ranged from 75 to 100% with specificity between 91% and 96%.
In a prospective blinded study, Point of Care US (POCUS) demonstrated that it is an accurate technique in defining disease activity and extent in IBD compared to ileocolonoscopy with the advantage of being non-invasive. It showed a 91% sensitivity and 83% specificity for detecting endoscopically active IBD, correlating with a positive predictive value (PPV) of 89%, a negative predictive value (NPV) of 86%, and a kappa coefficient of 0.74 (88%). POCUS-defined disease extent has a 87% sensitivity and 81% specificity, correlating with a PPV of 85% and NPV of 83% and a kappa coefficient of 0.70 (85%).
Strictures can be assessed reliably by both CT and MRI. Sensitivity was 85% vs 92% and specificity was 100% vs 90%, respectively. In addition, CTE is a modality that can be applied and it will provide a more detailed assessment of the bowel wall. However, the need for large volume oral contrast prohibits its use in the emergency setting.
In a prospective cohort study In clinical practice, MRE is frequently used in the outpatient setting. The lack of radiation and the excellent quality of images are advantages of this technique. This is particularly applied for evaluation of the small bowel and perineum. However, the use in an emergency setting is limited due to the oral contrast, increased study time, costs, and lack of availability.
In stable patients presenting with signs of GI hemorrhage, CT angiography should be considered to localize the bleeding site before angio-embolization or surgery, when an endoscopic evaluation is not possible and the patient is unable to tolerate the bowel preparation. A systematic review showed high sensitivity (85.2%) and high specificity (92.1%) of CT angiography for diagnosing acute gastrointestinal bleeding.
Endoscopy may be of added value as a diagnostic procedure for selected patients with IBD presenting with lower GI-bleeding in an emergency setting. A full colonoscopy is usually not possible given the need for oral bowel preparation prior to the colonoscopy, as well as the inability for oral intake of large volumes. However, a flexible sigmoidoscopy is possible with preparation with an enema. This procedure can aid in establishing the level and location of disease activity in UC and distal colonic CD and to detect preoperatively a source of bleeding. In addition, it can be used to rule out other conditions such as colonic ischemia, infections, and cancer. Finally, biopsies may be obtained for histologic assessment. A sigmoidoscopy will come with insufflation so should therefore not be applied in patients with obstruction or toxic megacolon given the increased risk of intestinal perforation.
Q.3: Which is the role of interventional radiology in the management of intra-abdominal abscesses related to Crohn's disease in the emergency setting? Statement 3.1
Percutaneous drainage associated with antimicrobial treatment should be considered as a first-line treatment in the management of abscesses related to Crohn's disease, in stable patients (QoE C).
# Statement 3.2
Small abscesses (<3 cm) could be treated with intravenous antibiotics with a risk of recurrence, especially if associated with enteric fistula (QoE B)
# Statement 3.3
Percutaneous drainage of abscesses > 3 cm could avoid immediate surgery and should be used as a bridging procedure before elective surgery to reduce the need for stoma creation and limit intestinal resection in malnourished and high-risk patients (QoE C).
# Statement 3.4
Surgery should be considered in the case of failure of percutaneous drainage and in patients with signs of septic shock (QoE C).
# Statement 3.5
Surgery should be considered for patients with enteric fistulae and if clinical evidence of sepsis persists despite the initial treatment plan (QoE C).
## Recommendations
We recommend performing radiological percutaneous drainage of intra-abdominal abscesses >3cm related to Crohn's disease associated with early empiric administration of antibiotics, to adapt these as soon as possible to microbiological culture results. Antimicrobial therapy should be re-evaluated according to patient's clinical and biochemical features (strong recommendation based on a low-level evidence 1C).
We recommend administering an early empiric antimicrobial therapy in stable patients presenting with abscess <3cm, with close clinical and biochemical monitoring (strong recommendation based on a lowlevel evidence 1C).
## Summary of evidence and discussion
Abscess, fistula, bleeding, and stenosis are common complications of CD. Various interventional radiological techniques can be considered as a first-line option for non-operative treatment, with good outcomes. In case of intestinal obstruction for stenosis, bowel dilatation can be performed both with radiological and with endoscopic guidance, in stable patients. Embolization of GIhemorrhage is technically feasible, but it should be limited to strictly selected cases.
Intra-abdominal abscesses in patients with CD typically result from a perforation or penetrating ulcers, and they are an expression of luminal disease activity associated with transmural translocation of bacteria from the diseased bowel to contiguous tissue. Abscesses may be intraperitoneal, retroperitoneal, or intra-mesenteric, most frequently located in the right lower quadrant adjacent to the terminal ileum. In the literature, occurrence rates for intra-abdominal abscesses vary from 10 to 30%. Active IBD warrants medical treatment, but the presence of an abscess contraindicates immunosuppressive medication.
There are several treatment options for intraabdominal abscesses in CD. Previously, the majority of abscesses were treated with operative drainage, but with the improvement of interventional radiological techniques, the use of percutaneous drainage (PD) is increasing, associated with administration of antibiotics.
Success rates for PD in the literature vary from 74 to 100%. There are no RCTs comparing percutaneous and surgical drainage, but two meta-analyses tried to clarify the role of percutaneous drainage, compared to surgical management.
He et al. in 2015aimed to compare clinical outcomes between PD alone and preoperative percutaneous drainage and initial surgery for patients with CD-related spontaneous intra-abdominal abscess, performed a meta-analysis of 9 (non-randomized and retrospective) studies including 513 patients and found a reduction in stoma creation rate and complication rate for patients undergoing pre-operative PD. The reason for these improved outcomes could be related to an improvement in patients' general and nutritional condition prior to definitive surgical intervention and to the control of the infectious source. Moreover, they reported that the risk for recurrent abscess was higher in patients who underwent PD alone than those who underwent initial surgery, highlighting that delayed abdominal surgery is almost inevitable in the majority of the patients presenting with intra-abdominal abscess.
Another meta-analysis, including six studies with a total of 333 patients was performed by Clancy et al. in 2016. They compared the use of PD alone and surgery in the management of patients presenting with a CD-related intra-abdominal abscess and reported an increased incidence of abscess recurrence for patients undergoing only PD, but interestingly, they also found that PD can successfully avoid surgery in 29.3% of patients. In addition, they found no significant difference in the overall complication rate, permanent stoma requirement, or length of stay between patients undergoing percutaneous drainage or immediate surgery. PD (guided by US or CT) appears to be a relatively safe procedure as part of a bridge to surgery technique, but not all abscesses are "drainable" or "accessible." Effectiveness depends on abscess characteristics, such as location, number, size, presence of fistulae, or close proximity to vital structures. Independent risk factors for PD failure are bowel wall thickness, disease length, bowel dilation, and abscess size of greater than 6 cm. Furthermore, multiple percutaneous drainage procedures have been required in 8-20% of patientsand it could increase the risk of complications such as damage to vital structures in close proximity to the abscess or severe hemorrhage.
Complications of PD, for both spontaneous and postsurgical abscesses (not specific to CD), occur in approximately 10% of procedures. Major complications such as sepsis, small bowel fistulae, colon perforation, and death (due to sepsis or hemorrhage) have been described in 5-11% of cases. Minor complications (such as bacteremia or infection at the site of the catheter insertion) occur in approximately 3%.
Feagins et al.suggested that non-drainable abscesses smaller than 3 cm and without evidence of fistula and no steroid therapy are likely to respond to antibiotic therapy alone although with high recurrence rates. In this setting, antibiotics should cover Gram-negative bacteria and anaerobes and it is important to closely observe the clinical condition of the patient in case of any deterioration.
Antibiotic therapy, including a combination of fluoroquinolones or third-generation cephalosporin and metronidazole in patients with CD, should be adapted to the sensitivity of the bacteria (and sometimes fungi) to antibiotics, if PD is performed..
The appropriate duration of antibiotic therapy is unclear. Clinical improvement should be seen within 3-5 days after starting antibiotics and percutaneous drainage, with a decrease in drainage production. If a patient's condition does not improve, re-evaluation and repeat imaging are indicated to determine whether the abscess has been adequately drained. If not, repositioning of the drain or surgical intervention is required.
If sepsis is controlled after adequate PD, CD medication should be started to prevent recurrence. Patients with a concomitant stenosis, an entero-cutaneous fistula or refractory active disease are likely to require surgery, but preoperative PD, if it is feasible, associated with delayed surgery, can decrease the extent of intestinal resection, postoperative septic complications, and potentially reduce stoma rates.
## Q.4: in patients presenting with complications related to ibd, what is the appropriate medical treatment and nutritional support?
a) The role of medical treatment and management of specific IBD drugs The response to intravenous steroids should be best assessed by the third day (QoE C).
# Statement 4.7
In non-responder hemodynamically stable patients, medical rescue therapy including infliximab in combination with a thiopurine or ciclosporin should be considered in a multidisciplinary approach (QoE B).
# Statement 4.12
Total parenteral nutrition should be reserved for nutritionally deficient IBD patients unable to tolerate enteral nutrition and when the enteral route is contraindicated, in critically ill patients presenting with signs of shock, intestinal ischemia, high output fistula, and/or severe intestinal hemorrhage (QoE B).
## Statement 4.13 total parenteral nutrition is the mode of choice when emergency surgery is needed for complicated ibd (qoe a).
Recommendations We recommend evaluating medical treatment in IBD patients presenting with acute abdominal pain and disease activity in a multidisciplinary approach (strong recommendation based on low-level evidence 1C).
We recommend not routinely administrating antibiotics in IBD patients but only in the presence of superinfection, intra-abdominal abscesses, and sepsis (strong recommendation based on high-level evidence 1A)
We recommend administering antibiotics according to the epidemiology and resistance of the setting in a duration that depends on the patient's clinical and biochemical findings. Antifungals should be reserved for highrisk patients such as those with bowel perforation and recent steroid treatment (strong recommendation based on high-level evidence 1A).
We recommend administering as soon as possible venous thromboembolism prophylaxis with LMWH for the high risk of thrombotic events related to complicated IBD and the emergency setting (strong recommendation based on high-level evidence 1A).
We recommend weaning off steroids (wean preoperatively, ideally 4 weeks) and stopping immunomodulators associated with anti-TNF-α agents before surgery, as soon as possible to decrease the risk of postoperative complications, in accordance with a gastroenterologist (strong recommendation based on moderate level evidence 1B).
We recommend administering nutritional support (parenteral or enteral, according to GI function and in conjunction with a dietician/nutrition team) in IBD patients as soon as possible (strong recommendation based on moderate level evidence 1B).
## Summary of evidence and discussion
The management of IBD in an emergency setting is very challenging. Early surgical management is correlated with extended intestinal resection, high stoma rate, and high risk of postoperative complications. Preoperative optimization of the patient, PD, and delayed surgery are associated with decreased risk of complications and length of postoperative stay. Medical treatment should be discussed in a multidisciplinary team. In the management of patients with CD presenting with an intra-abdominal abscess, few studies have addressed medical treatment alone (without percutaneous or surgical drainage) as the primary approach, and all available reports are retrospective or observational studies. According to available data, only abscesses smaller than 3 cm could be treated with antibiotics alone without PD, but it is not clear how to select patients for this therapeutic approach and for how many days to administer antibiotics, with high (37 to 50%) recurrence rates.
Following abscess drainage, the preferred CD medical treatment option is anti-TNF therapy in addition to ongoing antibiotic treatment. There are no randomized studies in the literature to clarify whether percutaneous or surgical drainage should always be followed by a delayed resection, although most case series favor a delayed elective resection.
In case of an ileal stenosis, a delayed resection should be considered and it is preferred to de-escalate corticosteroids prior to surgery in order to reduce the risk of post-operative complications.
The available literature on the use of biologic therapy before urgent surgery with anti-TNF-α agents, antiintegrin therapy, and anti-interleukin therapy is controversial. Biologic agents can induce and maintain clinical remission, heal the mucosa, and change the natural course of the disease, if used in a timely fashion, avoiding disease progression towards stenosis and fistula formation. The PUCCINI trialis based on a high level of evidence due to the strict protocol followed in collecting data prospectively, and its results demonstrated no effect of anti-TNFs on postoperative complications.
Other factors that can affect postoperative complications in intestinal resections in patients with CD are previous use of steroids, impaired nutritional status, and an unfavorable abdominal environment. Usually, most patients with surgical indication in CD are already using biological agents, and more than one of these factors can also be present. Therefore, in malnourished patients, with previous steroids and/or anemia, the surgical approach can be affected.
In conclusion, direct cause-effect relationship of biologics alone leading to increased rates of complications was not demonstrated and different studies results are controversial.
If an urgent surgical exploration is needed, it is extremely important to check concomitant use of steroids, phenotype of the disease, and current nutritional status, in order to establish the surgical plan.
The influence of nutritional status on postoperative morbidity and mortality has been well documented in both retrospective and prospective studies. Poor preoperative nutritional status has been linked consistently to an increase in post-operative complications and poorer surgical outcome.
Malnutrition is an independent risk factor for adverse postoperative outcomes and affects up to 70% of the IBD population. Malnutrition can occur in UC but is a more common problem in CD since CD can affect any part of the GI tract and UC is restricted to the large bowel, which has few direct malabsorptive effects. Nutritional complications occur in 20 to 85% of patients with CD. This specific condition becomes more serious during the active phase of CD, which is associated with decreased food intake, intestinal absorption dysfunction, drug side effects, and active inflammation.
Defining malnutrition is difficult, especially in patients with IBD, and a gold-standard test of malnutrition has not been identified.
The European Society for clinical nutrition and metabolism (ESPEN) reported that serum albumin of <3 g/dl, BMI < 18.5 kg/m 2 , and weight loss > 10-15% within 6 months are the best indicators of severe malnutrition in CD.
Parenteral nutrition should be reserved for nutritionally deficient IBD patients unable to tolerate enteral nutrition and when the enteral route is contraindicated in patients presenting with severe shock, intestinal ischemia, high output fistula, and/or severe intestinal hemorrhage.
Preoperative nutrition supplementation reduces postoperative complications in patients with CD, in particular, enteral nutrition. In a recent meta-analysis (3 prospective and 2 retrospective studies including 1111 CD patients), it was reported that the rate of postoperative complications in the group receiving preoperative nutritional (enteral or total parenteral nutrition) support was 20.0% compared with 61.3% in the group who had standard care without nutritional support [OR=0.26, 95% confidence interval (CI): 0.07-0.99, P<0.001]. Postoperative complications occurred in 15.0% of patients in the group who received preoperative total parenteral nutrition compared with 24.4% in the group who did not (OR=0.65, 95% CI: 0.23-1.88, P=0.43). Postoperative complications occurred in 21.9% in the group who received preoperative enteral nutrition compared with 73.2% in the group that did not received preoperative enteral nutrition (OR=0.09, 95% CI: 0.06-0.13, P<0.001).
Exclusively enteral nutrition is feasible in CD patients presenting with non-radiologically drainable abdominal abscesses. It is associated with a reduction in surgical rate, optimized preoperative condition, and improved postoperative outcomes in this specific group of patients.
Concerning the role of a medical treatment to avoid or postpone surgery, most patients with UC presenting with an ongoing flare in an emergency setting could be treated with intravenous corticosteroids.
In this group of patients, when the checked hemodynamic status is stable, the first step in the diagnostic process includes confirming disease activity with a flexible sigmoidoscopy and ruling out intestinal pathogens including Clostridium difficile and CMV. At this point, it is possible to decide on rescue therapy.
Patients with significant systemic toxicity, as evidenced by severe weight loss, fever, tachycardia, high inflammatory markers, and persisting abdominal pain, should be evaluated for colectomy. If a medical rescue therapy is considered appropriate, IV corticosteroids are administrated. A systematic review of 32 trials of steroid therapy for acute severe colitis, involving 1991 patients from 1974-2006, reported an overall response to steroids of 67% [95% CI 65-69%]. A colectomy was carried out in 29%.
In case of insufficient response to IV corticosteroids, an early (day 3) assessment should take place and subsequent therapy with either infliximab (IFX) (5 mg/kg) or ciclosporin (2 mg/kg/day) should be considered, along with the possibility of surgery. Both medical therapies are potent for inducing remission in this subgroup of patients with comparable outcomes. The open-label CYSIF trial randomized 111 thiopurine-naive patients with severe colitis despite 5 days of IV steroids, to IV ciclosporin 2 mg/kg/day for 8 days followed by 4 mg/kg/day oral therapy, or infliximab 5 mg/kg at weeks 0, 2, and 6. All responders at day 7 received oral azathioprine and tapered steroids from day 8. Approximately 85% patients in both groups responded to treatment by day 7. Treatment failure at day 98 (the primary endpoint) was reported in 60% patients in the ciclosporin arm compared with 54% patients in the IFX arm. The colectomy rate by day 98 in the ciclosporin vs the infliximab group was 18% vs 21% [P = 0.66].
If a surgical procedure is needed, then subsequent steroid withdrawal is mandatory. Antibiotics should not be routinely administered. Controlled trials of oral or IV metronidazole, tobramycin, ciprofloxacin, or vancomycin in acute UC have shown no consistent benefit in addition to conventional therapy. In the treatment of complex peri-anal fistulae due to CD an initial abscess drainage and seton placement, according to the symptoms and complexity of the fistula and anti-TNF treatment including infliximab or adalimumab can reduce fistula drainage and induce fistula closure.
Antibiotics such as a combination of ciprofloxacin and metronidazole can be added to enhance this effect, but this will only aid in improving short-term clinical outcomes. To enhance the effect of anti-TNF in complex fistulizing disease, combination of anti-TNF treatment with thiopurines should be considered.
Zangenberg et al.carried out a systematic review to identify clear recommendations for the preoperative medical management of patients with IBD, in particular those with CD.
The analysis of the literature showed that before elective surgery:
Steroid withdrawal (wean preoperatively, ideally 4 weeks unless an emergency) is recommended while steroid stress dose is not recommended; Thiopurines' administration appears to be safe, but it may be prudent to plan the procedure remotely from the last dose of an anti-TNF agent; Nutritional risk screening is recommended to unveil and correct any malnutrition; Venous thromboprophylaxis prior to surgery is well supported by evidence while extended 4-week prophylaxis needs further research but is likely to be beneficial; Percutaneous us or CT-guided drainage for intraabdominal abscesses is recommended with a considerable risk of recurrence;
Smoking cessation can be beneficial for wound healing, as well as reducing the risk of disease recurrence in CD.
## Recommendations
We suggest evaluating all hemodynamically stable patients presenting with acute severe ulcerative colitis in a multidisciplinary approach with the gastroenterologist to decide on options for initial medical treatment (weak recommendation based on low-level evidence 2C).
We recommend performing emergency surgical exploration in hemodynamically unstable patients, according to damage control principles and in patients with colonic perforation. A Subtotal colectomy with ileostomy in acute severe ulcerative colitis is the surgical treatment of choice in patients presenting massive colorectal haemorrhage or non-responders to medical treatment (strong recommendation based on high-level evidence 1A).
Summary of evidence and discussion According to the diagnostic criteria of Truelove and Witts for UC severity classification, acute severe colitis affects 5 to 15% of patients with UC and is characterized as colitis with bloody stool frequency ≥ 6/day and a tachycardia (>90bpm), or temperature >37.8°C, or anemia (hemoglobin 10.5g/dL), or an elevated ESR (>30mm/h) (only one additional criterion in addition to the bloody stool frequency ≥6/day is needed to define a severe attack). Endoscopic criteria for severe colitis include a hemorrhagic mucosa with deep ulceration, mucosal detachment on the edge of these ulcerations and well-like ulceration, all of which can be assessed at flexible sigmoidoscopy.
There are some controversies regarding the indications for surgery in case of severe acute colitis, and the determination of the correct time for surgery is still a matter of debate. It is well known that the majority with severe acute colitis will respond to medical therapy: in 2007, Turner et al.conducted a systematic review including 32 clinical trials analyzing the response to steroid therapy in severe UC and found that the response rate to steroids is 66% and 34% of patients required colectomy within a short period of time. This study has some limitations, such as the time period of the included studies and the wide heterogeneity among included cohorts of patients, but interestingly found a small reduction in colectomy rates in the studies that reassessed the need for colectomy after 2 weeks of medical therapy versus those who did it within 2 weeks. Furthermore, the introduction of biologic therapy opened new perspectives for salvage therapy in steroid-refractory patients and some studies demonstrated that up to 80% of patients with acute severe colitis resistant to steroid therapy could respond to biologic therapy, thus avoiding an emergent colectomy. Post-operative morbidity is higher after emergency surgery when compared with elective surgery, for both UC and CD, suggesting that the increased use of rescue therapy may contribute to reducing emergency surgical interventions and improve outcome. On the other hand, there is evidence to suggest that both a delay in surgeryand prolonged intravenous immunosuppressive therapy are associated with increased morbidity and mortality following subsequent surgery. Based on these results, it seems reasonable to suggest a tailored approach to the patient with acute severe colitis and an attempt at initial conservative management with bowel rest, parenteral nutrition, parenteral steroids, and broadspectrum antibiotics. The patient must be monitored closely for any signs of progressive deterioration, such as worsening pain or tenderness, progressive leukocytosis, fever, tachycardia, or hypotension. For steroid refractory disease, surgical options or therapeutic alternatives for rescue therapy should be considered early (on or around day 3 of corticosteroid therapy) by a multidisciplinary team that includes both a surgeon and gastroenterologist.
2) Toxic megacolon Statement 5.2.1 In patients presenting with toxic megacolon complicated by perforation, massive bleeding (unstable patients), clinical deterioration, and signs of shock, surgery is mandatory (QoE A). Recommendation We recommend not delaying surgery in critically ill patients presenting with toxic megacolon (strong recommendation based on moderate -level evidence 1C).
Summary of evidence and discussion Toxic megacolon is a rare but severe and potentially fatal complication of colonic inflammation.
Its main characteristics are as follows:
Radiographic evidence of total or segmental colonic distention of > 6 cm Presence of systemic toxicity Inflammatory (or infectious) etiology.
In order to avoid colectomy, medical treatment should be carried out aggressively and in a timely fashion (steroids, fluids, transfusions, etc.) and the correct timing for surgery is still controversial. In fact, while some evidence suggests that the initial medical treatment obviates the need for surgery in about 50% of patients, there is a significant body of literature that highlights how a delay in surgical intervention carries the risk of colonic perforation and abdominal compartment syndrome, thus increasing the mortality rate. For these reasons, management of toxic megacolon requires coordination between medical and surgical services with aggressive attempts at medical therapy and early surgical intervention in the absence of improvement, development of complications, or deterioration. Frequent reevaluations must be performed until the patient's condition has clearly improved or until there is evidence of deterioration, in which case urgent surgery is indicated. Persistent fever after 48-72 h of steroid therapy should raise the possibility of local perforation or abscess. Free perforation, massive hemorrhage, increasing transfusion requirements, increasing signs of toxicity, and progression of colonic dilatation are indications for an urgent operation.
Unlike colonic obstruction, in which cecal dilation with perforation is a concern, the transverse colon is the area of greatest concern in toxic megacolon. Perforation in patients with toxic megacolon is associated with a high mortality rate , regardless of whether the perforation is contained or free. Recommendations We recommend performing immediate surgery in unstable patients presenting with hemorrhagic shock, and non responders to resuscitation. An intraoperative ileoscopy, if available, could be useful in localizing the bleeding source in patients with Crohn's disease. In patients presenting with acute severe ulcerative colitis and refractory hemorrhage, non-responders to medical treatment, the surgical treatment of choice is a subtotal colectomy with ileostomy, if skills are present (strong recommendation based on low-level evidence 1C).
## 3) uncontrolled gastrointestinal bleeding
We suggest evaluating hemodynamically stable IBD patients presenting a gastrointestinal bleeding at first with a sigmoidoscopy and an esophagogastroduodenoscopy (weak recommendation based on low-level evidence 2C).
Summary of evidence and discussion Gastrointestinal bleeding is a common complication in patients with UC or CD and is caused by inflammation/ulceration of the bowel. Usually, the bleeding resolves with medical treatment and rarely it requires an immediate surgical procedure.
Medical treatment includes patients with hemodynamic instability and/or suspected ongoing bleeding receiving intravenous fluid/blood product resuscitation with the goal of normalization of blood pressure and heart rate prior to endoscopic evaluation/ intervention. Packed red blood cells should be transfused to maintain the hemoglobin above 7g/dL. A threshold of 9g/dL should be considered in patients with massive bleeding, significant comorbidities (especially cardiovascular ischemia) or possible delay in receiving therapeutic interventions.
Massive, life-threatening lower gastrointestinal bleeding is uncommon in patients with IBD and occurs in less than 6% of cases. Because of the low incidence of severe hemorrhage in IBD, a limited number of studies are available to guide management.
In IBD patients, bleeding has different features depending on the underlying disease. In UC, the bleeding typically occurs in patients with pancolitis from diffuse areas of mucosal ulceration. In CD, however, the bleeding most often is a result of focal erosion into an intestinal vessel, and this could include the small bowel.
In UC, the endoscopic assessment and treatment of the bleeding source that could be massive because of the diffuse nature of colonic inflammation is rarely possible. In CD, which is often a segmental disease, it is useful to try to localize the source of bleeding preoperatively to avoid surgery or an extensive intestinal resection, even more so severe bleeding in a patient with CD could be due to an associated condition, such as gastritis or peptic ulcer disease, or multiple segments of GI tract could be involved in the bleeding and this could be a diagnostic and therapeutic challenge for the endoscopist, with a high risk of re-bleeding.
The hemodynamic status of the patient presenting with hematemesis or massive melena or bright red rectal bleeding has to be assessed: the patient has to be resuscitated and stabilized, and a nasogastric tube is inserted to protect the airway and decompress the stomach. In a stable patient, a gastroscopy could be required to rule out an upper gastrointestinal bleeding. If a lower gastrointestinal source is suspected then one should consider sigmoidoscopy or colonoscopy.
The clinical significance of performing contrastenhanced CT before colonoscopy has been examined in recent years. In a retrospective study of acute LGIB, Nagata et al. reported that the detection rate for vascular lesions was higher for colonoscopy following CT than for colonoscopy alone (35.7% vs 20.6%, P = 0.01), leading to more endoscopic examinations (34.9% vs 13.4%, P < 0.01).
In patients with IBD who are bleeding, the role of angiography and of angioembolization is not yet clear: the few studies available in the literature are case reports and suggest that angiography/angioembolization could be feasible in stable patients, but further studies are needed to better define outcomes in emergency setting.
The major advantage of angiography and embolization is that it can control severe bleeding without bowel preparation. A systematic review reported that superselective angiographic embolization achieves immediate hemostasis in 40-100% of diverticular bleeding with occasional rebleeding (15%). The disadvantages of angiography and embolization include the requirement for active bleeding and the risk of bowel ischemia and the administration of IV contrast. The rate of bowel ischemia following embolization was 1-4% in recent studies. Angiography localizes the bleeding source in 24-70% of cases. Angiography requires blood loss rates > 0.5 mL/min to localize a bleeding site.
Moreover, CT angiography may be useful as a noninvasive diagnostic tool prior to angiography, because it is more sensitive and identifies bleeding at rates of 0.3 mL/ min. Other methods of localization include the use of a nuclear medicine labeled red cell scans if bleeding is not detected by angiography.
Once the source is known, the decision to perform a surgical urgent procedure depends on bleeding source itself, the hemodynamic condition of the patient and on the availability/feasibility of less invasive therapeutic options (i.e., endoscopy or angiography).
If the patient is unstable, even after significant resuscitation, a surgical exploration is mandatory. In clinical practice, surgery is indicated for patients who demonstrate continued hemorrhage despite resuscitation or have other indications for resection of diseased bowel.
Significant bleeding is a rare event in Crohn's disease, and all common causes of upper and lower gastrointestinal bleeding should be assessed; when a surgical exploration is required, it is recommended to perform an intra-operative ileoscopy to find the source of bleeding if the source has not been identified pre-operatively. All efforts to identify the bleeding source should be made preoperatively.
In case of acute severe ulcerative colitis, the bleeding could involve all the colon mucosa, and the surgical treatment of choice is a subtotal colectomy with ileostomy, to decrease the risk of recurrent bleeding, but it is important to have performed a flexible sigmoidoscopy to make sure there is no significant bleeding source in the rectum.
## 4) free perforation
Recommendation We recommend performing surgical exploration in the presence of radiological signs of pneumoperitoneum and free fluid within the peritoneal cavity in acutely unwell patients presenting with complicated Crohn's disease or acute severe ulcerative colitis (strong recommendation based on low-level evidence 1C).
Summary of evidence and discussion Free peritoneal perforation in inflammatory bowel disease is a rare condition, with few cases reported in the literature. It occurs in 1-3% of Crohn's disease patients as a first manifestation or in the course of the disease, and it is more frequent in severe acute ulcerative colitis. Perforation is considered a serious and potentially life-threatening event and is one of the main indications for emergency surgical intervention. Free perforation is the indication for surgery in up to 16% of the cases of complicated IBD. The site of perforation is usually located in the colon in cases of UC, while patients with CD can present with perforation of either the small or large bowel. Free perforation is an absolute indication for emergency surgery, even though the evidence available in the literature is scarce, but delayed surgery is correlated with high mortality and morbidity in patients with IBD.
## 5) intestinal obstruction
Statement 5.5.1 Surgery is mandatory for symptomatic strictures that do not respond to medical therapy and are not amenable to endoscopic dilatation (QoE C). Recommendation We recommend performing surgery in patients presenting with bowel obstruction because of fibrotic or medically resistant stenosis (strong recommendation based on low-level evidence 1C).
Summary of evidence and discussion Small bowel obstruction is the most common complication requiring elective surgery in CD and affects up to 54% of patients. Strictures complicating CD usually affect the small bowel but could arise anywhere in the GI tract and could be divided into inflammatory or fibrostenotic. It is often difficult to distinguish whether the obstruction is caused primarily by inflammation or fibrostenosis. Patients with inflammatory disease deserve a trial of medications aimed at reducing inflammation. Conversely, patients with symptomatic fibrostenotic disease and obstruction require an interventional approach, either surgical or endoscopic.
Endoscopic balloon dilation has proven successful in the management of primary intestinal strictures or anastomotic strictures in CD. For fibrotic strictures, endoscopic balloon dilation has a technical success rate of 89 to 92%, with 70 to 81% patients experiencing short-term relief of symptoms. Long-term results are less impressive, with 73.5% of patients requiring a repeat dilation and 43% requiring surgical intervention within 2 years.
Endoscopic stricturotomy is an evolving, novel therapy for which only few short-term retrospective studies exist to demonstrate its safety and efficacy compared with endoscopic balloon dilation or ileocolic resection.
Large bowel strictures, especially in UC, should raise high concern for malignancy. When required to perform an emergent colectomy, oncologic principles should be followed. Patients with small bowel stenosis mainly due to inflammation may improve with medical treatment such as steroids. In patients that do not show improvement with medical treatments, suspect stenosis due to fibrosis, and consider radiological investigation with CT or MR enterography and the possibility of endoscopic dilation on the basis of the length and site of the stenosis, the number of stenotic sites, and the presence of ulcers.
Surgery is warranted for small bowel CD stenosis that causes an intestinal obstruction with potential impending perforation, with long or multiple strictures, when the stricture is not endoscopically accessible and when medical and/or endoscopic treatment fails to adequately improve the patient's symptoms or when there is concern about concomitant malignancy. Q.6: Which surgical approach is recommended for complicated IBD in the emergency setting? 1) Emergency surgery for ulcerative colitis Statement 6.1.1 In the setting of free perforation and generalized peritonitis or toxic megacolon, in hemodynamically unstable patient, an open approach is recommended (QoE C). If emergency surgery is indicated, a laparoscopic approach to adhesiolysis and bowel resection is recommended if appropriate expertise exists, with care taken to avoid iatrogenic bowel injury in patients presenting with intestinal obstruction for Crohn's disease (QoE C).
## B) bleeding statement 6.2.2
If the patient presenting with gastrointestinal bleeding in Crohn's disease is hemodynamically stable and endoscopic and/or interventional radiology measures have been unsuccessful, then a surgical exploration in a laparoscopic (multi-port or in single incision) approach is recommended (QoE C).
[formula] Statement 6.2.3 [/formula]
If the patient presenting with gastrointestinal bleeding in Crohn's disease is hemodynamically unstable and endoscopic and/or interventional radiology procedures have been unsuccessful, then a surgical exploration in an open approach is recommended to reduce operating time (QoE C). c) Free perforation and purulent/fecal peritonitis Statement 6.2.4
A laparoscopic approach with resection, lavage and stoma is suggested in hemodynamically stable patients presenting with perforation and peritonitis in Crohn's disease, to avoid complications associated with anastomotic leak (QoE C). Statement 6.2.5 If there is hemodynamic stability and only localized contamination, an anastomosis may be considered but other factors will also need to be considered (QoE C). Statement 6.2.6 If evidence of severe sepsis/septic shock, damage control surgery may be considered, with resection, stapled off bowel ends, and temporary closure (laparostomy) with return to theater in 24-48 h for a second look, washout, and consideration of stoma vs anastomosis (QoE C). There is insufficient evidence to recommend SILS or robotic surgery in the emergency setting (QoE C).
## 3) anastomotic considerations in emergency surgery for crohn's disease
[formula] Statement 6.3.1 [/formula]
If a patient in the emergency setting has 2 or more risk factors for anastomotic complications (such as discussed in the text), then a stoma should be formed following resection (QoE C). Statement 6.3.2 If a decision to anastomose has been made, there is no evidence to suggest that one type of anastomosis (stapled vs hand sewn) is superior to the other in terms of complication rates or recurrence, and the decision can be left to surgeon preference (QoE C).
Recommendations
We recommend performing a surgical exploration by laparotomy in a hemodynamically unstable patient presenting with complications related to IBD such as perforation and severe peritonitis, massive intestinal bleeding, obstruction, toxic megacolon, severe colitis non responder to medical treatment, taking into consideration damage control surgery principles with or without an open abdomen (strong recommendation based on low-level evidence 1C).
We recommend performing a laparoscopic approach in hemodynamically stable patients presenting complications related to IBD, when skills are available, in order to decrease morbidity and length of hospital stay (strong recommendation based on low-level evidence 1C).
We recommend performing a subtotal colectomy with ileostomy in patients presenting with acute severe refracrory colitis, non responders to medical treatment, in a laparoscopic or open approach according to patient's hemodynamic stability (Strong recommendation based on low level evidence 1C). We suggest considering an (stapled or hand sewn) anastomosis in hemodynamically stable patients with Crohn's disease who have good pre-existing nutritional status and who are taking no steroids or other immunosuppression and presenting with no bowel vascular compromise and only localized peritonitis. A defunctioning stoma should also be considered in the emergency setting (weak recommendation based on low-level evidence 2C).
Summary of evidence and discussion Surgical treatment can be particularly challenging when patients with IBD present as an emergency, as they are often much more unwell than when being considered for elective intervention. Moreover, the surgical options may be more limited and there may also be less time for full multidisciplinary involvement in the decision making process, especially in critically ill patients. In addition, many centers will have an emergency surgical on-call rota that is staffed with surgeons whose main specialist elective practice is not in IBD surgery. Therefore, it is necessary to be aware of the principles of emergency operative surgery for patients presenting acutely with the complications or sequelae of UC and CD.
Emergency surgery for Ulcerative colitis The indications for emergency surgery in ulcerative colitis include medically resistant disease, bleeding, toxic megacolon, and perforation. Open and laparoscopic approaches may be considered in the emergency setting, according to availability of trained local expertise.
There is a role for open surgery. An open approach is likely to be favored in the setting of a perforation, where a faster operation is required to allow the patient to have their source control surgery in a timely fashion and to be cared for post-operatively in the ICU as quickly as possible. In addition, toxic megacolon, which is now thankfully uncommon, may prove particularly challenging in terms of handling the bowel laparoscopically without perforation, and so open surgery is again recommended.
Otherwise, laparoscopic surgery has been shown to lead to a reduction in length of stay and infectious complications in the emergency setting. The existing data relate to multiport laparoscopic surgery, and as such, this would be recommended over a single port approach in the emergency setting, with no data available to support the use of a robotic approach.
Emergency surgery for Crohn's disease Indications for emergency abdominal surgery in the setting of Crohn's disease include bowel obstruction, perforation, and bleeding. Management of patients with an intra-abdominal abscess has been dealt with elsewhere in this guideline.
Up to 16% of patients with Crohn's disease will present with a bowel perforation. Management decisions are often complex and will need to be made around mode of surgical access, decision for anastomosis, and if so, using which anastomotic technique. Bowel resection is generally required in the emergency setting, with the requirement for strictureplasty being more common in the elective setting. The type of resection needed will be according to the disease site, and this may be a small bowel resection, ileocecal resection, or colonic resection, generally subtotal colectomy.
In terms of mode of access, for the patient with bowel obstruction due to non-active stricturing disease or adhesions, a laparoscopic approach is preferred, according to local expertise, as there is evidence for reduced length of stay and fewer complications. Great care is needed on establishing pneumoperitoneum, as the bowel will be distended, and as such, an open port insertion technique should be used. Available data relate to multi-port laparoscopic approach, as opposed to single-port, and there are no data to support a robotic approach in this setting.
An open approach remains preferable in the setting of bleeding with hemodynamic instability where endoscopic and interventional radiology techniques have not been successful, and in a patient with a free perforation. When a patient with a free perforation has severe sepsis or septic shock, and associated significant peritoneal contamination, it may be preferable to perform damage limitation surgery in the form of bowel resection with stapled off bowel ends, peritoneal lavage, laparostomy, and rapid return to ICU for on-going care, with a planned second look laparotomy 24-48 h later with further bowel inspection, peritoneal lavage, abdominal closure, and consideration of stoma formation versus anastomosis.
Anastomosis decision making in Crohn's disease in the emergency setting.
In the emergency setting, the decision whether to perform a primary anastomosis following resection for Crohn's disease can be challenging, and there are also considerations of whether a particular anastomotic technique may be preferable if so.
It is imperative to consider the clinical state and presentation of the patient, as well as the indication for surgery, when thinking about whether an anastomosis may be appropriate in the emergency setting. Factors to consider when contemplating anastomosis include the following:
Patient factors: e.g., sepsis, degree of peritoneal contamination (local only vs widespread), hemodynamic stability, need for inotropes, nutrition/albumin, abscess, immunosuppression (e.g., steroids, timing of recent anti-TNF treatment), smoking Disease factors: fistulising/perforating vs stenotic, proximal jejunal vs ileal If a patient has 2 or more risk factors in the emergency setting, then a resection with stoma should be performed, rather than an anastomosis. A stoma following resection may still be an appropriate option when only one risk factor is present. If an anastomosis is performed, consideration should be given to a defunctioning stoma.
If an anastomosis (usually small bowel or ileocolic) is to be performed, then in general, the options to consider will include the configuration (end-to-end vs side-to-side) and material (stapled vs suture) used. Overall, in the specific setting of IBD surgery, there is no evidence for superiority of any one technique over the other in terms of complication rates or recurrence. Therefore, the decision can generally be left to surgeon preference.
If a stapled anastomosis is being performed, consideration should be given to performing this in an isoperistaltic configuration, in order to allow easier neo-terminal ileal intubation at subsequent surveillance colonoscopy.
If there is chronically thickened small bowel in the setting of a long-standing bowel obstruction, consideration should be given to performing a hand-sewn anastomosis as the stapler may not function adequately in this setting where the bowel wall is very thickened and edematous.
Data for the newer Kono-S small bowel anastomotic configuration, which is a hand sewn technique that leads to a wide lumen with mesenteric exclusion, are confined to the elective setting and as such, would not be recommended for emergency cases at present.
In Crohn's colitis, the indications for emergency surgery are as for ulcerative colitis, including medically resistant disease, bleeding, toxic megacolon, and perforation and may also include large bowel obstruction if there is a stricture present. Open and laparoscopic approaches are appropriate in the emergency setting, according to local expertise. Q.7: How to manage perianal sepsis in the emergency setting? Statement 7.1
An acute abscess should be adequately drained under general anesthetic, with no routine requirement for wound packing (QoE C).
# Statement 7.2
No active attempt should be made to find an associated anal fistula at the initial abscess presentation (QoE C).
# Statement 7.3
If an obvious fistula exists (without probing), the fistula should not be laid open and a loose draining seton should be inserted (QoE C).
# Statement 7.4
There is no role for any additional surgical fistula treatment modality in the emergency treatment of Crohn's perianal sepsis (QoE C).
# Statement 7.5
An assessment of the rectum should be made at the time of abscess drainage, to assess for signs of proctitis (QoE C).
## Recommendation
We recommend performing adequate surgical drainage of perianal abscess in Crohn's disease without searching for an associated fistula (strong recommendation based on low-level evidence 1C).
## Summary of evidence and discussion
Around 1 in 3 patients with CD will develop perianal manifestations of the disease, which will include the risk of perianal abscess and fistula. When presenting with an acute perianal or ischiorectal abscess, the main principle of surgical intervention is to perform adequate drainage, and this will likely require a general anesthetic in most cases.
In the acute setting, it can be difficult to find an underlying fistula with significant induration and sepsis present, and so no active attempt should be made to find an associated fistula and minimal tissue disruption/destruction should occur. Over-vigorous attempts to probe for a fistula at emergency surgery may lead to an iatrogenic track and internal opening, which will add great complexity to the on-going management of the patient's perianal disease and greatly increase the risk of nonhealing.
If there is a deep cavity evident, consideration may be given to short-term use of an appropriate drain (e.g., corrugated drain, Malecot catheter). In addition, if there is concern of undrained sepsis, potentially being fed from a supralevator source, then an urgent inpatient MRI scan will be required.
There is no requirement for wound packing following abscess drainage, although its role is currently under investigation in a multicenter randomized controlled trial in the UK. Packing may have a limited role for short-term hemostatic requirements.
If an associated anal fistula is obvious at the time of abscess drainage without any probing, then a loose draining seton should be inserted. The loose draining seton should be low profile and made of a soft material of the surgeons choice, avoiding any bulky knots and avoiding any firm suture material such as nylon. There should be no attempt to lay the fistula open at the same time, in order to minimise tissue disruption and preserve future anal function. This approach will allow subsequent treatment planning with the patient, then being an active participant in the multidisciplinary management decisions required to minimize future symptoms and maximize the chance of potential fistula healing. When sepsis is present, there is no role for attempts at surgical adjuncts to fistula healing, such as fibrin glue, fistula plug, LIFT, advancement flap, VAAFT, FiLac, and stem cells, in the emergency setting.
In order to plan future treatment with the patient and IBD multidisciplinary team, it is essential to know if there is associated active proctitis in association with the perianal sepsis. For this reason, an assessment of the rectal mucosa should be made at the time of abscess drainage, either in the form of rigid or flexible sigmoidoscopy.
# Conclusions
Complicated inflammatory bowel disease requires a multidisciplinary approach because of the complexity of this group of different diseases in the urgent/emergency setting with the aim of obtaining good functional outcomes and to decrease stoma rates where possible.
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Society of swallowing and dysphagia of Japan: Position statement on dysphagia management during the COVID-19 outbreak
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Society of swallowing and dysphagia of Japan: Position statement on dysphagia management during the COVID-19 outbreak
# Introduction
On April 3, 2020, the Society of Swallowing and Dysphagia of Japan (SSDJ) issued an emergency announcement entitled "Emergency statement on dysphagia management during the novel coronavirus outbreak". Shortly thereafter, on April 14, the SSDJ proposed a concrete statement for dysphagia treatment in consideration of the ongoing spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The main routes of transmission of SARS-CoV-2 are physical contact with infected persons and exposure to respiratory droplets. In cases of infection, the nasal cavity and nasopharynx have the highest viral load in the body. Swallowing occurs in the oral cavity and pharynx, which correspond to the sites of viral proliferation. In addition, the possibility of infection by aerosol transmission is also concerning. Dysphagia treatment includes a broad range of clinical assessment and examinations, dysphagia rehabilitation, oral care, nursing care, and surgical treatments, and any of these can lead to the production of droplets and aerosols, as well as contact with viral particles. Recent studies have reported that nosocomial infection, originating from caregiving staff, may occur during meals. Moreover, it should be noted that persons with asymptomatic infections in Japan or other countries can form in-hospital clusters leading to the spread of infection regardless of whether they are healthcare professionals or patients [bib_ref] Epidemiology of Covid-19 in a long-term care facil, Mcmichael [/bib_ref].
Most patients with dysphagia are elderly and have complications, such as heart diseases, diabetes, respiratory diseases, and cerebrovascular diseases. They might be at a higher risk for severe illness from the novel coronavirus disease 2019 . With this taken into consideration, all healthcare professionals involved in dysphagia treatment must be fully briefed in terms of proper infection control measures and must appropriately implement them. The statement herein establishes three regional categories based on the status of SARS-CoV-2 infection. Accordingly, the SSDJ proposes specific infection countermeasures that should be implemented in consideration of 1) the current status of SARS-CoV-2 infection in the region, 2) the patient status of SARS-CoV-2 infection, and 3) whether the examinations or procedures conducted corresponds to aerosol-generating procedures (AGPs), depending on the status of dysphagia treatment. Strain and exhaustion of medical resources both in Japan and overseas is anticipated during the COVID-19 epidemic. The timing of dysphagia rehabilitation and indication for treatment will differ from the usual. Prioritizing the maintenance of medical infrastructure will be paramount in consultation with teams of medical experts at each facility.
This statement is arranged into separate sections providing information and advice considering the COVID-19 outbreak, including "clinical swallowing assessment and examination", "dysphagia rehabilitation", "oral care", "nursing care", "surgical procedure for dysphagia", and "tracheotomy care".
As SSDJ proposed these statements for the purpose of crisis management during the COVID-19 outbreak, based on case series and guidelines from other countries where the spread of COVID-19 occurred earlier, these statements are not an evidence-based clinical practice guideline. Thus, these statements would require later evaluation and revision as needed. It should also be considered that patients could receive appropriate care, but the care may be limited under these circumstances where this statement is widely accepted among healthcare professionals.
## Terminology used in this statement and basic concept of classification
2.1. Regional division by infection status Prefectures are designated as one of the three categories and are managed depending on the status of infection [ * 1,2] 1) Regions where SARS-CoV-2 infection is not endemic (non-endemic regions) : the prefecture where 0-9 patients are currently hospitalized due to COVID-19. 2) Regions in which SARS-CoV-2 infection is endemic (endemic regions) : the prefecture where 10 or more patients are currently hospitalized due to COVID-19. 3) Regions experiencing an epidemic of SARS-CoV-2 infections (epidemic regions) : Regions targeted by a declara-tion of emergency, prefectures in which infection countermeasures or equivalent restrictions are ongoing, or where there is suspicion of infection clusters in the vicinity of a medical facility. * 1. The current number of patients hospitalized due to COVID-19 in the relevant prefecture according to the Ministry of Health, Labour and Welfare (reference materials regarding COVID-19 cases in Japan). The number of "currently hospitalized" patients listed in reports prepared by prefectures in Japan is the current number of patients hospitalized due to COVID-19 (in that prefecture). https://www.mhlw.go.jp/stf/ newpage _ 10651.html. * 2. The website https://www.stopcovid19.jp displays the relevant data for reference purposes, in an easy-to-understand format, as the current number of patients hospitalized due to COVID-19 in each prefecture. SARS-CoV-2 is transmitted primarily through droplets or physical contact with infected persons. However, it has been suggested that the virus can float in air for prolonged periods of time, increasing the risk of infection as a result of adsorption into aerosols (particles of 5 µm or smaller).
## Classification by status of sars-cov-2 infection
Swallowing managements reported to generate aerosols include induction of the gag and coughing reflexes; feeding exercises with a risk of aspiration; suctioning in the oral/nasal cavities, pharynx, and trachea; and endoscopic examination. Infection prevention measures against these AGPs differ depending on the local infection status in patients. For more information, please refer to the respective section.
## Preventative measures against sars-cov-2 infection
and personal protective equipmentPreventive measures by route of infection SARS-CoV-2 has been confirmed to follow two primary routes of infection: droplet infection and infection through physical contact. The possibility of aerosol-based infection has also been suggested. The basic concept of preventive measures focusing on routes of infection can be summarized through the following three points:
- Healthcare workers should wear personal protective equipment (PPE), such as surgical masks, goggles, face/eye shields, and caps, which protect the eyes, nose, and mouth. - Use surgical masks to prevent splashing of fluids from patients. - Pay close attention for potential transmission via aerosols (see below for countermeasures).
## Measures against contact infection
Avoid transmitting virus present on the hands through contact with the mucous membranes of the eyes, nose, and mouth. - Healthcare workers should wear PPE, such as gloves, aprons, gowns, and masks. - Use surgical masks to prevent splashing of fluids from patients. - Maintain a distance of at least 1.5 m.
## Measures against infection by aerosols
Surgical masks may have some effect, but no definite effects have been verified.
2) Recommendations of additional precautions for AGPs
The following precautions are recommended in addition to the use of PPE when engaging in AGPs (strongly recommended for procedures possibly producing large amounts of aerosols):
- Use an N95 mask and always perform a seal check when donning the mask. - Wear eye protection (goggles/face shield).
- Wear clean long-sleeved gowns (sterilization not necessary) and gloves. - Wear a non-permeable apron or gown.
- Perform the AGP in a well-ventilated room.
- Observe hand hygiene before and after contact with patients and surrounding environmental surfaces, as well as after removing PPE.
## Appropriate ppe selection and utilization in dysphagia management [6]
The selection of PPE should be made according to the risk of infection due to the procedure. In this proposal, PPE for dysphagia management is described as follows, according to the purpose. - Nasal/oral protection: N95 mask * or powered air purifying respirator (PAPR) * Before using an N95 mask, conduct a user seal check . - Eye protection: Face shield ± goggles * * Recommend using an anti-fogging agent in advance, when using goggles. - Physical protection: impermeable long-sleeved gowns - Head exposure protection: Wear a surgical cap. Take care to avoid exposing hair after affixing cap.
## 2.6.
Recommendations regarding appropriate PPE based on regional classification, patient status of SARS-CoV-2 infection, and presence of AGPsIn dysphagia management, most examinations and therapies will involve AGPs, and to prevent the spread of nosocomial infection, special precautions to prevent aerosol-based infection, as well as standard precautions, will be necessary. However, it should be noted that the supply of medical resources at medical facilities around the world is limited. The distribution of medical resources at each facility will be coordinated with specialized departments. In case of a shortage of suitable PPE for dysphagia treatment, prior-ity should be given to the maintenance of the medical care infrastructure at each facility (e.g., withholding AGP-related tests and therapies). However, examinations/therapies for unconfirmed cases in endemic regions should not interfere with in-house policies at medical facilities where strict infection control measures, such as strictly limiting external contact, should be followed .
## Wearing and removing ppe
Removal of PPE may inadvertently spread the infection. Conduct training for donning and doffing PPE beforehand. Consideration should also be given to the separation of spaces for the donning and doffing PPE (clean areas/passage areas/semi-contaminated areas/contaminated areas) as much as possible at each facility.
The standard methods for donning and doffing of PPE are described in detail at the following websites (The Research Group of Occupational Infection Control and Prevention in Japan homepage).
- Surgical masks: https://www.safety.jrgoicp.org/ppe-3usage-sugicalmask.html Recommended management of appropriate PPE based on regional classification, infection status, and presence of aerosol generating procedures.
## Confirmed and suspected
## Clinical swallowing assessment and examination for patients with dysphagia
Swallowing assessment in non-epidemic areas or for SARS-CoV-2-negative patients should be conducted with appropriate PPE. The evaluation for patients with suspected or confirmed COVID-19 is not recommended in consideration with the risk of aerosol generation. In this clinical statement, we propose a strategic plan to facilitate safe practice in dys-phagia management for clinical care staff and patients with dysphagia.
If the condition of patients is not serious, non-urgent swallowing assessment should be postponed because clinical swallowing assessment includes many AGPs. Transmission of SARS-CoV-2 to clinical care staff needs to be prevented. When these high-risk procedures cannot be postponed in consideration of the necessity for each patient and the prevalence of COVID-19 in the relevant area, they may be permitted with a minimum number of participants and with proper PPE.
## Medical history, mental and physical examination, and evaluation of oral motor and pharyngeal and laryngeal function
In the current pandemic context, the clinical swallowing assessment without producing aerosols is more preferable compared to AGPs. Dysphagia screening tools, such as the Eating Assessment Tool-10and the Seirei Questionnaire of Swallowing, can be utilized to detect dysphagia. Pharyngeal sensory testing or flexible endoscopic evaluation of swallowing with sensory testing are considered as AGPs, can be incredibly high risk, and require different PPE that do not produce aerosols.
## Simple screening tests for evaluating swallowing function
Screening tests for dysphagia are intended to select the patients who are strongly suspected without videofluorography (VF) and fiberoptic endoscopic evaluation of swallowing (FEES, VE), and include repetitive saliva swallowing test (RSST), cervical auscultation of swallowing, water swallow test, modified water swallow test, and food test. Among them, RSST and cervical auscultation of swallowing can be performed for patients wearing a mask without oral intake, and thus, the risk of aerosol generation is very low. However, some screening tests, such as water swallow test and modified water swallow test, are AGPs .
Considering some procedures such as water swallow test and modified water swallow test may induce coughing, adoption of the highest level of PPE is highly recommended when undertaking these procedures for patients with suspected or confirmed COVID-19. Concerning water swallow test, modified water swallow test (3 mL) overrides the original version of the water swallow test (30 mL). Recommended management of clinical swallowing assessment and examination for patients with dysphagia.
## Confirmed and suspected
Negative and 2-week change to negative after confirmation
## Fiberoptic endoscopic evaluation of swallowing (fees)
The nasopharynx carries a higher viral load than the oropharynx. Thus, FEES has a higher risk of aerosolization from the nasal passage and nasopharynx. FEES can trigger sneezing and/or coughing, leading to aerosolization during the procedure. In light of the pandemic of COVID-19, clinicians need to consider risks related to FEES, and suspension of laryngeal sensory testing and FEES examinations should be seriously considered to minimize aerosol generation.
Possibility of virus attachment to the endoscopy - FEES may elicit sneezing and/or coughing by the stimulation to the nasal mucosa - FEES can trigger sneezing and/or coughing by aspiration during examination and can require suction, which may generate droplets and aerosols. - FEES can induce coughing due to sensory testing.
## Swallowing videofluorography (vf)
VF is also an AGP but is preferable to FEES in the current situation of COVID-19 as it does not involve invasive instrumentation during the procedure, and the administering clinician (otolaryngologists or SLPs) can maintain a greater distance from the patient while the examination is performed. VF may be the safer option in the current climate. In cases where accurate assessment is necessary, we advocate for adoption of VF with high-level PPE to minimize the risk to patients and clinical care staff in consideration of the infectious status of the area. To minimize aerosol generation and scattering when patients aspirate the contrast medium, patients are required to wear a surgical mask during examination.
## Other swallowing evaluations
Other swallowing evaluations include tongue pressure measuring, pharyngeal manometry, and swallowing CT. Considering these are AGPs, these are not positively recommended.
## Swallowing therapy
Healthcare professionals, who provide dysphagia therapy in close patient proximity, can be at high risk of transmitting the COVID-19 virus. Both indirect exercises (non-swallowing exercises) and direct exercises (swallowing exercises) involve direct contact with a patient's oral mucosa and secretions and exposure to droplets/aerosols that can be generated by coughing and sneezing. Furthermore, if a healthcare professional is an asymptomatic or pre-symptomatic carrier of COVID-19, the virus can be transmitted to patients from the healthcare professional through rehabilitation and may cause hospitalacquired infections.
It is strongly advised that standard and additional precautions for AGPs, including use of PPE, hand hygiene, and disinfection of environmental surfaces and equipment, be implemented during swallowing therapy. If PPE, disinfectants, and other materials are in short supply, and adequate infection prevention cannot be achieved, swallowing therapy should be suspended under the COVID-19 outbreak.
## The risk of covid-19 transmission and infection in swallowing therapy
The risk of COVID-19 transmission and infection should be minimized in swallowing therapy. Physicians who order swallowing therapy to healthcare professionals should confirm the patient's current COVID-19 status and carefully assess the urgency of intervention. All healthcare professionals must be updated with the local infection control policies and must maintain a close relationship with the infection control office of their institution.
There are numerous exercises in swallowing therapy. The risk of COVID-19 transmission and infection involved in an exercise would be different depending on the ways the exercise is performed. For example, in a tongue strengthening exercise, a clinician may put his/her fingers into a patient's oral cavity to place a load on muscles. The clinician can avoid direct contact with the patient's oral mucosa/secretions and train the patient regarding the methods of self-tongue strengthen training. Likewise, in respiratory rehabilitation, the risk of infection would be different if a patient forcefully exhales into the air or into a disposable sealed bottle through a tube. Therefore, it was not possible to define the risk of infection involved in all dysphagia exercises in this guidance. Instead, we listed several typical swallowing exercises and presented their potential risk of infection so that healthcare professionals can perform a COVID-19 risk assessment for their patients.
## 1) indirect exercises (non-swallowing exercises) 1 exercises involve low risk of infection
Exercises involve no direct contact to the oral or pharyngeal mucosa and secretions of patients and low probability of aerosol generation.
- A set of exercises that typically includes stretching the neck, tongue, and lip movement - Neck, lip, tongue, cheek, and jaw exercises without contacting the patient's oral cavity - The tongue-holding maneuver - Head-lifting exercises (Shaker exercise) - Electrical stimulation and other therapies Although these exercises are considered to involve low risk of infection, healthcare professionals should use appropriate PPE and maintain a permissible distance from the patient throughout rehabilitation.
## Exercises that require direct contact to the oral or pharyngeal mucosa and secretions or exposure to respiratory droplets
Exercises in which a clinician places his/her fingers to the patient's oral cavity and contacts the mucosa (massaging, stretching, or strengthening of the lip, tongue, cheek, gum, and jaw) 3 Aerosol generating procedures- Exercises that may induce the cough reflex: thermal-tactile stimulation, the K-method, tube-swallowing exercises, balloon exercises, and ice-chip swallows. - Exercises that require forced expiration or voice: coughing, forced expiration or huffing, and voice exercises.
## 2) direct exercises (swallowing exercises)
Direct exercises (swallowing exercises), such as posture adjustment and compensatory swallowing maneuvers, involve a high risk of exposure to the droplets and aerosols produced by patients. During direct exercises, healthcare profes-sionals should select an adequate level of dysphagia diet, patient's posture, and swallowing maneuvers so that the patient does not cough or clear the throat and avoid generating the droplets or aerosol during dysphagia rehabilitation.
## 3) strategies to reduce infection risk
To reduce the risk of infection during swallowing training, the following measures are recommended.
- Educate patients with cough etiquette and hand hygiene - Always ventilate the therapy rooms - Disinfect the environmental surfaces and therapy equipment after each use - Maintain a sufficient distance between healthcare professionals and a patient - Avoid facing the patient, and provide the therapy from the patient's back or side - Consider using a mirror or a tablet to give instructions and feedback to patients - Provide a self-training program to the patient - When showing a patient how to perform an exercise, do not take off the mask, but show a model using pictures or movies - Minimize the length of one session or frequency of rehabilitation - If an AGP is inevitable, perform it at the end of the session [fig_ref] Table 3: Recommended management of swallowing therapy [/fig_ref] shows the PPE standard categorized by the regional and patient's infection statuses. PPE usage should be followed according to the guidance of each institution. Maintaining medical services should be prioritized over dysphagia rehabilitation during the COVID-19 outbreak. In epidemic areas, a newly admitted patient and a patient who had stayed at the hospital longer than two weeks without presenting any clinical symptoms would have different levels of risk of having a COVID-19 infection. In addition, in an area where clusters have been occurring, the likelihood of a newly admitted patient to be COVID-19 positive would increase.
## Infection prevention
Healthcare professionals should learn techniques to take off the PPE without contacting the contaminated surfaces of PPE after therapy to protect themselves from infection.
## Swallowing therapy for patients with covid-19
Swallowing therapy for patients with active COVID-19 should only be carried out when essential with special precautions.
## Oral care
Especially for dysphagic patients, oral hygiene is necessary because aspiration of oropharyngeal flora into the lung may cause aspiration pneumonia. However, we must be thoroughly cautious to avoid spreading the virus through oral care during the COVID-10 outbreak.
Oral care can involve a visible spray that contains saliva and microorganisms. From the study of spattering during oral care using an adenosine triphosphate (ATP) monitoring system [bib_ref] Investigation of spattering and intraoral environment during oral care of patients, Uematsu [/bib_ref] , large amounts of ATP, which denotes the presence of organic material and living cells, were detected on the surface of the care giver's wrist, face shield, and apron. The study also confirmed any oral care including using toothbrush, sponge brush, suction, and wipe with gauze cause spattering and showed higher amount of splash and spatter when a toothbrush, sponge brush, and suction or bed elevation was used during the care or when the procedure took more than 5 min. Although there are currently no data available to assess the risk of SARS-CoV-2 transmission during dental practice, a cough may be induced when cleaning solution or saliva penetrate into the pharynx, consequently spreading airborne infectious agents. When care givers provide oral care, they must be aware that it is an AGP and ensure appropriate preventive measures according to the degree of regional spread. If the patients can care for themselves, it would be better to encourage selfcare considering their circumstance.
## Precautions and proper ppe for oral care depending on region and infection status ( table 4 )
In endemic and epidemic regions, provide oral care only after you have assessed the patients and considered both the risk to the patient of deferring care and the risk of disease transmission associated with providing care. If possible, pro-vide shorter time care and care for the highest need. If PPE and supplies are limited, consider deferring. [bib_ref] Epidemiology of Covid-19 in a long-term care facil, Mcmichael [/bib_ref] As the patients may choke on water during rinsing, it is recommended to wipe oral mucosa with wet tissue for oral use, wet gauze, or swab after mechanical cleaning. Among water rinsing, wiping with wet tissue for oral use, and wiping with sponge brush, wiping with wet tissue is the most effective method to decrease bacteria on the tongue, palate, or gingivobuccal fold [bib_ref] Comparisons of methods eliminating contaminants after oral care. -Preliminary study in healthy..., Ikeda [/bib_ref].
## General consideration in oral care
2 Denture cleaning of patients with suspected or confirmed COVID-19.
To avoid the spread of the microorganisms from the denture, disinfect the denture before washing with water. After cleaning, rinse the denture with enough water to eliminate the chemical agents. It would be recommended to sink the denture for 30 min into 0.05-0.5% of sodium hypochlorite aqueous solution or ethanol for disinfection or wiping the denture with gauze saturating with it. The spray on the denture may cause airborne infectious agents. For dentures with metal clasps or metal bases, rust-preventive additive sodium hypochlorite aqueous solution should be used.
3) Consideration for reducing the aerosol generation during oral care 1 Tooth brushing with water-based mouth moisturizer As a substitute for tooth paste, teeth should be brushed with water-based mouth moisturizer, which can contribute to preventing the spread of dental plaque by retaining it in the mouth .Extraoral vacuum system If the environment allows, use of extraoral vacuum system would help capture aerosols that escape outside the mouth and minimize droplets.Mouth rinse before procedures Chlorhexidine, which is commonly used as mouth rinse in dental practice, may not be effective in killing SARS-CoV-2 [bib_ref] Transmission routes of 2019-nCov and controls in dental practice, Peng [/bib_ref]. The virus is vulnerable to oxidation. Mouth rinsing with 0.2% povidone or 1% hydrogen peroxide is recommended to reduce the oral microbes, including potential COVID-19 carriers [bib_ref] Transmission routes of 2019-nCov and controls in dental practice, Peng [/bib_ref].
## Surgery for swallowing disorders
Surgeries for Swallowing Disorders are divided into three groups according to the purpose. 1) "Surgeries for improving swallowing function", 2) "aspiration prevention surgeries", which can prevent complete aspiration by separating the floodway from the airway, and 3) "tracheostomy" for securing the airway and the suction route of respiratory secretions.
"Surgeries for improving swallowing function" include pharyngoplasty, cricopharyngeal myotomy, laryngeal suspension, laryngoplasty (injection medialization), and infrahyoid myotomy. Each procedure can be combined with other procedures depending on the swallowing function of patients with dysphagia. However, these surgeries should be postponed during the COVID-19 pandemic because they require postoperative rehabilitation for a comparatively long time. We have to consider the possible risks of spreading SARS-CoV2 infection.
"Aspiration prevention surgery" can be postponed by performing a preceding tracheostomy. However, it can be allowed in some cases according to the regional situations of the coronavirus infection. Even in regions where COVID-19 is spreading, considering the background of the intractable diseases, recurrence of aspiration pneumonia, and carriers of multidrug-resistant bacteria, in some cases, the surgery can be performed, only if the comprehensive merits are estimated to be high.
"Tracheostomy" is a surgical procedure which opens a direct airway into the trachea from the neck. A tracheostomy tube is placed to maintain the airway and suck thick mucus and secretions from the trachea and lower airway. Tracheostomy should not be positively performed on patients suspected and confirmed for COVID-19. Tracheostomy for patients confirmed as being COVID negative is not restricted if needed. Regarding the strategy for tracheostomy, please see the Guide for tracheostomy from the Oto-Rhino-Laryngology Society of Japan. [fig_ref] Table 5: Recommended management of surgeries for patients with swallowing disorders [/fig_ref] shows how to manage surgeries for patients with swallowing disorders during the COVID-19 outbreak.
## Tracheostomy care
At the stage of COVID-19 outbreak, points to note regarding tracheostomy care including suctioning of tracheostomy tube are as follows.
Given that tracheostomy is a high-risk procedure that can generate aerosols, to protect the staff members that are involved in tracheostomy care, it is essential that staff wear appropriate PPE prior to any intervention. There is no other choice of wearing available PPE as an alternative countermeasure for viral infection, when the stock of appropriate PPE is insufficient.
It is recommended that clinicians consider that any critically ill patient recovering from COVID-19 pneumonitis is considered high risk of infection to staff during tracheostomy insertion. Be careful not to generate aerosols during tracheostomy care as follows.
- Tracheostomy procedures such as dressing, cuff care, tube care, and heat moisture exchanger change are considered high risk for staff as aerosols can be generated. - When suctioning to remove respiratory secretions, pay attention not to cause coughing. - Closed suction systems should be used.
- A simple face mask may be applied over the face of patients if the cuff is deflated to minimize droplet spread from the patient. - Use of double lumen tracheostomy tube is recommended for patients with COVID-19, and to reduce the frequency of changing tracheostomy tube, only inner tube change may be permitted. - After withdrawing mechanical ventilation, a heat moisture exchanger should be put on a tracheostomy tube. Be sure to prevent the heat moisture exchanger from being detached from the tube. - Tracheostomy tube change can be delayed until the patient is confirmed as COVID-19 negative or COVID-19 symptoms improve. However, an individual assessment must be made for each patient. - Avoid use of fenestrated tubes for patients with suspected and confirmed COVID-19 to reduce the aerosol risks to staff. Cuffed non-fenestrated tubes should to be used until the patient is confirmed as COVID-19 negative. - Not changing the tracheostomy tube and dressings can be allowed, unless obvious signs of infection or problems.
In view of the change in the domestic and oversea situations, tracheostomy tubes can be in a short supply. You should check the stock status of tracheostomy tubes in the medical facilities and in the country. Subsequent planned tube changes can be postponed unless signs of infection or problems such as bleeding or severe granulation are observed.
## Nursing care
Nurses provide various forms of care to patients with dysphagia, such as oral care, and indirect/direct swallowing exercises as dysphagia therapy, meal support, and oral or tracheal suctioning. Patients with dysphagia often have multiple
## As usual
As usual As usual * suggested priority for COVID-19 testing.
## Table 6
Recommended management of meal support and suctioning.
## Confirmed and suspected
Negative and 2-week change to negative after confirmation underlying conditions, which are more likely to become severe in conjunction with infection by SARS-CoV-2. With the ongoing spread of SARS-CoV-2 infection, there is a possibility that infections will be transmitted between healthcare workers, asymptomatic carriers, and patients. Thus, appropriate infection control measures will be necessary when caring for patients with dysphagia. As oral care and swallowing therapy have been explained in a separate section, this section will mention the handling of meal support and suctioning. It is important that appropriate preventive measures be taken while providing nursing care depending on the local infection situation and the patient's infection status. The proper PPE for each procedure should be determined based on regional classification, presence of SARS-CoV-2 infection, and the existence of AGPs . If use of the appropriate PPE is not possible, the best alternative, in accordance with the circumstances of individual facilities (e.g., discontinuing care, changing the content of care, and shortening intervention time), should be considered.
## Selection of dietary methods and meal support during the covid-19 outbreak
To make diet and nutritional selections for patients with suspected dysphagia, it is necessary to consider the risk of aspiration, regardless of the presence of SARS-CoV-2 infection.
In particular, as patients with COVID-19 are prone to developing respiratory disorders, it is important to select meals considering a patient's swallowing ability and not to increase the risk of aspiration pneumonia. Patients requiring meal support should be attended to while using the appropriate PPE. Note that meal support to such patients can produce aerosols when the patient coughs or expectorates sputum accumulated in the pharynx. of 30 min depending on the patient's level of fatigue. 5 Explanation to patients: Considering the possibility of a patients being an asymptomatic carrier of SARS-CoV-2, all patients and their families should be advised of the necessity of observing the general requests to avoid close contact, narrow spaces, and crowded areas, as well as taking measures to control the spread of sputum droplets caused by coughing. If a patient who is positive or suspected for SARS-CoV-2 is anticipated to exhibit coughing or aspiration following taking food orally, such patients should be advised to take due care to prevent the exacerbation of pneumonia and spread of infection when they restart eating.
## Oral/tracheal suctioning
Suctioning must be considered as an AGP, although it conventionally requires protection only against droplet infection.
- During suctioning, anticipate splashes due to coughing and gag reflex and do not stand in front of the patient. - Outdoor-air ventilation (entrance door should be closed) is highly recommended in endemic or epidemic regions. - Do not look into the oral cavity or tracheostomy site carelessly. - Use a closed suction system while patients are supported by mechanical ventilation. - Regarding suctioning at tracheostomy sites, refer to the previous chapter "Tracheostomy care".
# Disclosure statement
There are no competing interests. All authors consent to the publication of the manuscript in ANL.
## Declaration of competing interest
None.
# Funding
This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
## Appendix: message from the president of ssdj
The New Coronavirus Infectious Diseases Control Committee of SSDJ issued an urgent alert "it is recommended to refrain from swallowing training and endoscopic swallowing function tests that involve contact with the "non-emergency" upper respiratory mucosa" on HP on April 2, 2020. On the premise of this alert, this position statement, which consists of all seven chapters, was released on April 21, starting with the introduction, terminology, and clinical swallowing assessment on April 14. While the swift action has received great praise from various sides, some medical institutions and even those of care facilities other than medical institutions have criticized it as unrealistic. In the background, there is a lack of medical resources, such as PPE and rubbing alcohol, but healthcare professionals must recognize that they may need to diverge from conventional protective measures. Moreover, management of dysphagia produces droplets and aerosols in many situations. We must recognize that procedures should always be performed using the same PPE and knowledge. These standards should apply not only for SARS-Cov-2, but other dysphagia cases suspected to be complicated because of infection from multidrug-resistant bacteria or unknown pathogens. Therefore, as a responsible medical association in this field, it is inevitable that our society repeatedly uses the terms for standard precautions and abbreviations of equipment, such as PPE and full PPE, which are globally used, in creating this statement. Although these terms may make it difficult to read this statement, please be sure to read the first section "Terminology used in this statement and basic concept of classification" before reading each medical treatment category because they have been briefly explained. This committee consists of medical doctors, dentists, speech therapists, and registered nurses who are experts in the medical treatment of dysphagia with a deep knowledge of infectious diseases and public health selected from the members of this society. Needless to say, this statement is not a standard manual for dysphagia management but a guide for all healthcare workers involved in treatment of dysphagia during the COVID-19 epidemic. We would appreciate it if you could operate it flexibly according to the supply of medical resources at each medical institution.
Toshiro Umezaki, MD, PhD. SSDJ President 2020-2021.
[fig] AFigure 1: sPPE (standard PPE) : PPE based on standard precautions "Surgical mask, gloves" ( Fig. 1 A) B) E-PPE (Eye-PPE) : PPE in which eye protection (E) is added to sPPE Surgical mask, gloves, face shield, or goggles" ( Fig. 1 B) C) EB-PPE (Eye/Body-PPE) : PPE in which eye protection (E) and body protection (B) are added to sPPE Surgical mask, gloves, face shield or goggles, gown, or apron" (clean exposed skin of the upper extremities after using the apron) ( Fig. 1 C) D) Full-PPE : Preventive measure against aerosol infections "N95 mask, cap, double gloves, face shield ± goggles, impermeable long-sleeved gown" ( Fig. 1 D) (A) sPPE (standard PPE): PPE based on standard precautions. "Surgical masks, gloves" (B) E-PPE (Eye-PPE): PPE in which eye protection (E) is added to sPPE. "Surgical mask, gloves, face shields, or goggles" (C) EB-PPE (Eye/Body-PPE): PPE in which eye protection (E) and body protection (B) are added to sPPE. "Surgical masks, gloves, face shields or goggles, and gown or apron" (clean exposed skin of the upper extremities after using the apron). (D) full-PPE: Preventive measures against aerosol infections. [/fig]
[table] Table 3: Recommended management of swallowing therapy. PPE: personal protective equipment, sPPE: standard PPE, E-PPE: Eye-PPE, EB-PPE: Eye/Body-PPE, AGP: aerosol generating procedure. [/table]
[table] Table 4: Recommended management of oral care. All regions Non-epidemic regions Endemic regions Epidemic regions Non-epidemic regions Endemic regions Epidemic regions PPE: personal protective equipment, E-PPE: Eye-PPE, EB-PPE: Eye/Body-PPE. [/table]
[table] Table 5: Recommended management of surgeries for patients with swallowing disorders. [/table]
[table] 1 Environment: Avoid taking meals in groups as much as possible regardless of infection status. If difficult, take measures, such as spacing patients (spatial separation), staggering meal time (temporal separation), and avoiding face-to-face contact. When providing meal support to unidentified people in epidemic or endemic regions, windows should be opened, and the space should be sufficiently ventilated.2 Assistance: Minimize droplets and aerosols originating from patients. Discuss the proper way of taking food (posture, food texture, and swallowing technique) with doctors, speech therapists, or certified swallowing nurses. Provide assistance while avoiding moving in front of the patient; minimize conversation during meals. Pay particular attention to patients at high risk of aspiration in endemic/epidemic regions. 3 Dietary selection: Cases with pneumonia unrelated to COVID-19 in endemic/epidemic regions must be differentiated from cases of SARS-CoV-2 infection; however, these cases could be forced to be dealt with in a similar manner as cases derived from SARS-CoV-2 infection. From the viewpoints of maintaining health system ca-pacity, preventing the spread of nosocomial infections, and avoiding pneumonia in patients themselves, patients with dysphagia require careful diet selection compared to normal circumstances. 4 Time: Meal times should be kept to within a maximum [/table]
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Clinical practice guidelines standardisation of immunosuppressive and anti-infective drug regimens in UK paediatric renal transplantation: the harmonisation programme
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Clinical practice guidelines standardisation of immunosuppressive and anti-infective drug regimens in UK paediatric renal transplantation: the harmonisation programme
# Introduction
This guideline makes recommendations for immunosuppressive and anti-infective prescribing and monitoring in children and young people (CYP) receiving routine, kidney-only transplants.
Current variation in practice of immunosuppressive and anti-infective prescribing in CYP undergoing kidney transplantation impairs assessment of outcomes post transplant and may disadvantage some CYP. Different regimens employed in the UK currently include 'steroid maintenance' therapy comprising prednisolone, azathioprine and tacrolimus (PAT); steroid maintenance (PAT) with IL-2 receptor antagonist induction with basiliximab (PAT-B); early steroid withdrawal regimens comprising IL-2 receptor antagonist induction, tacrolimus, mycophenolate mofetil (MMF), and short course of prednisolone (the 'TWIST' regimen) and variations of these according to levels of immunological risk, primary disease or co-morbidities (obesity / diabetes / bone disease).
Early steroid withdrawal has been reported to significantly improve growth at 6 months post transplant, with associated improvements in lipid and glucose metabolism. NICE Technology appraisal (TA482, October 2017) recommends that CYP undergoing a first kidney transplant receive IL-2 receptor antagonist, tacrolimus (Adoport®/Modi-graf®) and MMF (mycophenolate mofetil) as routine therapy. No recommendations were made for prednisolone or azathioprine, however, some CYP have more adverse events with MMF compared with azathioprine (particularly gastro-intestinal symptoms and bone marrow suppression). Furthermore, there are reports of increased rates of acute rejection in early steroid withdrawal regimens . For these reasons, ISD regimens containing prednisolone or azathioprine continue to be widely used in the UK. In order to improve quality of care and reduce variation in practice, the British Association for Paediatric Nephrology (BAPN), in collaboration with key partners, proposes to undertake a project to develop best practice guidance in the area.
Summary of recommendations for immunosuppressive (ISD) and anti-infective drug prescribing and monitoring in children and young people receiving routine, initial therapy for kidney-only transplantation. We recommend that parents, carers and, where appropriate, the young person should be offered information on steroid maintenance and early steroid withdrawal ISD regimens by health professionals with specialist knowledge in this area. (1D) 2. We recommend that a choice of early steroid withdrawal (short course prednisolone-MMFtacrolimus-basiliximab, 'TWIST') or steroid maintenance (prednisolone-azathioprine-tacrolimus-basiliximab, 'PAT-B') ISD regimen should be made jointly by health professionals and parents or carers and, wherever possible, the young person. (1D) 3. We recommend that, for the early steroid withdrawal regimen, the TWIST (short course prednisolone-MMF-tacrolimus-basiliximab) published schedule should be followed per below: (1D)
Basiliximab should be administered 2 h before transplant surgery (d0) and after 4 days (d4) at the following weight-banded doses: Tacrolimus should be prescribed (initial dosing) at 0.15 mg/kg twice daily with a maximum initial dose of 5 mg twice daily.
Mycophenolate mofetil (MMF) should be prescribed as 600 mg / m 2 (maximum 1 g) twice daily on days 0-14, then 300 mg / m 2 twice daily from day 15 onwards.
4. We recommend that, for the PAT-B (prednisoloneazathioprine-tacrolimus-basiliximab) regimen:
Basiliximab should be administered 2 h before transplant surgery (d0) and after 4 days (d4) at the following weight-banded doses: Azathioprine should be prescribed at 2 mg/kg daily from day 0 (day of transplant) onwards.
Tacrolimus should be prescribed (initial dosing) at 0.15 mg/kg twice daily with a maximum initial dose of 5 mg twice daily.
## 5.
We recommend that, for children and young people receiving either PAT-B or TWIST regimens, Methylprednisolone 600 mg/m 2 (maximum dose 500 mg) should be given at induction or reperfusion on the day of transplant (day 0) (1D). 6. We recommend that, for children and young people receiving either PAT-B or TWIST regimens, tacrolimus should be commenced on the day of transplant (day 0) for living and deceased donor transplants (1D). 7. We recommend that, for children and young people receiving either PAT-B or TWIST regimens, Target ranges for tacrolimus 12 h trough levels should be: Summary of research recommendations for immunosuppressive and anti-infective drug prescribing and monitoring in children and young people receiving routine, initial therapy for kidney-only transplantation. In children and young people receiving initial therapy for routine, kidney only transplantation, is early steroid withdrawal associated with improved outcomes compared with steroid maintenance therapy?
Rationale for clinical practice recommendations for immunosuppressive and anti-infective drug prescribing and monitoring in children and young people receiving routine, initial therapy for kidney-only transplantation. We recommend that parents, carers and, where appropriate, the young person should be offered information on steroid maintenance and early steroid withdrawal ISD regimens by health professionals with specialist knowledge in this area. (1D)
## Audit measure
Proportion of parents or carers of CYP undergoing renal transplantation offered information on steroid maintenance and early steroid withdrawal ISD regimens by health professionals with specialist knowledge in this area.
## Rationale
No relevant studies were identified for this review question, however, NICE guidance on patient experience in adult NHS services recommends that patients should be provided with information, and the support they need to promote their active participation in care and selfmanagement. This should include information about relevant treatment options and services that they are entitled to, even if these are not provided locally. There was 91% agreement with this recommendation in the Delphi consensus process (consensus reached).
## 2.
We recommend that a choice of early steroid withdrawal (short course prednisolone-MMFtacrolimus-basiliximab, 'TWIST') or steroid maintenance (prednisolone-azathioprine-tacrolimus-basiliximab, 'PAT-B')) ISD regimen should be made jointly by health professionals and parents or carers and, wherever possible, the young person. (1D)
## Rationale
No relevant studies were identified for this review question, however, as discussed above, NICE guidance on patient experience in adult NHS services recommends that patients should be provided with information, and the support they need to promote their active participation in care and self-management. This should include information about relevant treatment options and services that they are entitled to, even if these are not provided locally. There was 81% agreement with this recommendation in the Delphi consensus process (consensus reached), however, both Health professionals and lay representatives expressed concern that the issue of ISD regimens is so complex that it is the responsibility of health care professionals to a make clear recommendation with regard to the preferred regimen in each particular case, as the need for one or other regimens will vary in different clinical situations.
3. We recommend that, prescribing for the early steroid withdrawal regimen, should be based on the TWIST (short course prednisolone-MMFtacrolimus-basiliximab) published schedule per below: (1D)
Basiliximab should be administered 2 h before transplant surgery (d0) and after 4 days (d4) at the following weight-banded doses: Tacrolimus should be prescribed (initial dosing) at 0.15 mg/kg twice daily with a maximum initial dose of 5 mg twice daily.
Mycophenolate mofetil (MMF) should be prescribed as 600 mg / m2 (maximum 1 g) twice daily on days 0-14, then 300 mg / m2 twice daily from day 15 onwards.
## Audit measure
Proportion of CYP prescribed an early steroid withdrawal regimen post renal transplant, receiving medications per the TWIST (short course prednisolone-MMF-tacrolimus-basiliximab) published schedule as detailed above.
## Rationale
There was 83% agreement with this recommendation in the Delphi consensus process (consensus reached).
Early steroid withdrawal is reported to be associated with better growth and a reduced incidence of new onset diabetes post transplant in CYP undergoing renal transplantation. NICE Technology appraisal (TA482, October 2017) recommends that CYP undergoing a first renal transplant receive IL-2 receptor antagonist, tacrolimus (Adoport®/Modigraf®) and MMF (mycophenolate mofetil) as routine therapy. The NICE guidance does not, however, specify dosing of medication and members of the guideline committee were in agreement that prednisolone prescribing should be standardised per the published protocol in the TWIST study, whilst tacrolimus prescribing should be in line with recommendations in the British National Formulary for Children (BNFC). Due to concerns about higher concentrations of tacrolimus in adolescents, the committee agreed to propose an upper dose limit of 5 mg at initiation, as is undertaken in some adult units, with subsequent dosing being directed by tacrolimus monitoring.
## We recommend that, for the pat-b (prednisolone-azathioprine-tacrolimus-basiliximab) regimen: (1d)
Basiliximab should be administered 2 h before transplant surgery (d0) and after 4 days (d4) at the following weight-banded doses: Azathioprine should be prescribed at 2 mg/kg daily from day 0 (day of transplant) onwards. Tacrolimus should be prescribed (initial dosing) at 0.15 mg/kg twice daily with a maximum initial dose of 5 mg twice daily.
## Audit measure
Proportion of CYP prescribed a steroid maintenance regimen post renal transplant, receiving medications per the PAT-B (prednisolone-azathioprine-tacrolimus-basiliximab) regimen published schedule as detailed above.
## Rationale
There was 77% agreement with this recommendation in the Delphi consensus process (consensus reached).
NICE Technology appraisal (TA482, October 2017) recommends that CYP undergoing a first renal transplant receive IL-2 receptor antagonist, tacrolimus (Adoport®/Modigraf®) and MMF (mycophenolate mofetil) as routine therapy. No recommendations were made for prednisolone or azathioprine, however, some CYP have more adverse events with MMF compared with azathioprine, particularly gastro-intestinal symptoms and bone marrow suppression. Furthermore, recent studies have reported an increased incidence of acute rejection in adults and children receiving steroid avoidance and withdrawal drug regimens after kidney transplantation. Authors of a systematic review in 2016 concluded that long-term consequences of steroid avoidance and withdrawal remain unclear because prospective long-term studies have not been conducted . For these reasons, committee members agreed that a steroid maintenance regimen should continue to be offered as one of 2 ISD regimens as initial therapy to CYP undergoing routine, kidney-only transplants.
The committee identified marked variability in prednisolone prescribing in CYP receiving 'steroid maintenance' therapy in the UK and some variability in prescribing IL-2 receptor antagonist induction between UK centres when reviewing centre protocols. In order to reduce variations in practice, the committee agreed to propose standardisation of prednisolone dosing and the use of IL-2 receptor antagonist induction for all CYP undergoing routine, kidney-only transplants. The committee agreed that the addition of IL-2 receptor antagonist induction may allow a reduction in initial steroid dosing and proposed the steroid reduction schedule described above. The committee also agreed that tacrolimus prescribing should be in line with recommendations in the British National Formulary for Children (BNFC). Due to concerns about higher concentrations of tacrolimus in adolescents, the committee agreed to propose an upper dose limit of 5 mg at initiation, as is undertaken in some adult units, with subsequent dosing being directed by tacrolimus monitoring.
## 5.
We recommend that, for children and young people receiving either PAT-B or TWIST regimens, Methylprednisolone 600 mg/m 2 (maximum dose 500 mg) should be given at induction or reperfusion on the day of transplant (day 0) (1D)
## Audit measure
Proportion of CYP receiving either PAT-B or TWIST regimens receiving Methylprednisolone 600 mg/m 2 (maximum dose 500 mg) at induction or reperfusion on the day of transplant.
## Rationale
No relevant studies assessing precise dosing for Methylprednisolone in CYP undergoing routine kidneyonly transplantation were identified for this review question. There was 78% agreement with this recommendation (statement) by the Delphi panelists in the 2nd round (consensus reached). Some panelists rejected the statement in the 1st round due to a concern about the timing of administration, with some clinicians preferring to administer the methyl-prednisolone at reperfusion rather than induction. The committee agreed to include 'at induction or reperfusion' in the recommendation. It was noted in both rounds of the Delphi consensus process that a number of panelists had raised concerns that the recommended upper dose of 500 mg may be too low, whilst one panelist expressed concerns about Methylprednisolone being used at all in the absence of evidence, and in the face of improvements of techniques to assess histocompatibility and improvements in immunosuppression. The committee agreed that it was reasonable to make this recommendation, retaining the recommended upper dose on the basis of the overall support received.
6. We recommend that, for children and young people receiving either PAT-B or TWIST regimens, tacrolimus should be commenced on the day of transplant (day 0) for living and deceased donor (DD) transplants (1D)
## Audit measure
Proportion of CYP receiving either PAT-B or TWIST regimens, commencing tacrolimus on the day of transplant (day 0; living and deceased donor transplants).
## Rationale
No relevant studies were identified for this review question. There was 85% agreement with this recommendation in the Delphi consensus process (consensus reached). The committee noted the existing variation in practice across the UK, with some centres commencing tacrolimus up to 48 h prior to living donor transplant. In the absence of evidence of improved outcomes in CYP receiving tacrolimus prior to the day of transplant, the committee agreed to recommend that time of commencement of tacrolimus for CYP receiving living donor transplants should be the same as that for CYP receiving deceased donor (DD) transplants.
## 7.
We recommend that, for children and young people receiving either PAT-B or TWIST regimens, Target ranges for tacrolimus 12 h trough levels should be: (1D)
8-12 ng/ml for months 1 and 2 post transplant. 5-8 ng/ml for months 3 to 12 post transplant. Beyond the first year, tacrolimus levels may be individualized.
## Audit measure
Proportion of CYP receiving either PAT-B or TWIST regimens maintaining tacrolimus 12 h trough levels as detailed above.
## Rationale
No relevant studies were identified for this review question. There was 83% agreement with this recommendation in the Delphi consensus process.
The committee identified variability in tacrolimus target levels in CYP undergoing renal transplantation in the UK. In order to reduce variation in practice, the committee agreed to propose standardisation of tacrolimus target levels for CYP undergoing routine, kidney-only transplants. The committee agreed that the addition of IL-2 receptor antagonist induction may allow a reduction in tacrolimus target levels, noting that tacrolimus toxicity may be more problematic than acute rejection. The committee also agreed that there will need to be flexibility to alter thresholds before 12 months in those patients showing evidence of tacrolimus toxicity.
## Rationale
No relevant studies were identified for this review question. There was 86% agreement with this recommendation in the Delphi consensus process (consensus reached), however, some panelists expressed concern about the proposed duration of 6 months, due to the potential for side effects including bone marrow suppression and nephrotoxicity. The committee agreed that dose adjustment or cessation due to tolerability would be at clinicians' discretion.
## Rationale
Valganciclovir has been widely used for cytomegalovirus (CMV) prophylaxis in solid-organ transplant recipients. Limited evidence suggests that 6 months of prophylaxis may be associated with a lower rate of late-onset disease than 3 month regimens in CYP receiving valganciclovir, however, the committee agreed to propose a recommendation for 'at least 3 months' of valganciclovir due to concerns about its significant side effect profile (infection, diarrhoea, leukopenia, neutropenia).
There was 93% agreement with this recommendation in the Delphi consensus process (consensus reached). (Continued)
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Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society
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Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society
DE Moulin, A Boulanger, Aj Clark, et al. Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society. Pain Res Manag 2014;19(6):328-335.BACKgROuND: Neuropathic pain (NeP), redefined as pain caused by a lesion or a disease of the somatosensory system, is a disabling condition that affects approximately two million Canadians. OBjECTIVE: To review the randomized controlled trials (RCTs) and systematic reviews related to the pharmacological management of NeP to develop a revised evidence-based consensus statement on its management. METHODS: RCTs, systematic reviews and existing guidelines on the pharmacological management of NeP were evaluated at a consensus meeting in May 2012 and updated until September 2013. Medications were recommended in the consensus statement if their analgesic efficacy was supported by at least one methodologically sound RCT (class I or class II) showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment were based on the degree of evidence of analgesic efficacy, safety and ease of use. RESulTS: Analgesic agents recommended for first-line treatments are gabapentinoids (gabapentin and pregabalin), tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors. Tramadol and controlledrelease opioid analgesics are recommended as second-line treatments for moderate to severe pain. Cannabinoids are now recommended as third-line treatments. Recommended fourth-line treatments include methadone, anticonvulsants with lesser evidence of efficacy (eg, lamotrigine, lacosamide), tapentadol and botulinum toxin. There is support for some analgesic combinations in selected NeP conditions. CONCluSIONS: These guidelines provide an updated, stepwise approach to the pharmacological management of NeP. Treatment should be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Additional studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes and treatment of pediatric, geriatric and central NeP.
N europathic pain (NeP) has been redefined as pain caused by a lesion or a disease of the somatosensory system, and may be generated by either the peripheral or central nervous system, or both [bib_ref] Neuropathic pain: Redefinition and a grading system for clinical and research purposes, Treede [/bib_ref]. Pain may be a manifestation of nerve injury, but there are few predictors to indicate which patients will develop this complication. For example, 50% of diabetic patients develop neuropathy during the course of their illness, but only approximately 15% report actual dysesthesias or pain [bib_ref] Chronic painful peripheral neuropathy in an urban community: A controlled comparison of..., Daousi [/bib_ref]. Similarly, breast surgery with transection of the intercostal brachial nerve results in NeP in up to 50% of patients [bib_ref] Neuropathic pain following breast cancer surgery: Proposed classification and research update, Jung [/bib_ref]. Previous prevalence estimates indicated that 2% to 3% of the population in the developed world experience NeP [bib_ref] Neuropathic pain: A practical guide for the clinician, Gilron [/bib_ref]. However, newer studies using population-based questionnaires estimate a higher rate of 4% to 8% [bib_ref] The epidemiology of chronic pain of predominantly neuropathic origin. Results from a..., Torrance [/bib_ref] , which suggest that approximately two million Canadians experience this disabling condition. Even more striking is that the prevalence of NeP is likely to increase for a number of reasons. The population is aging, and a pandemic of obesity is occurring in the developed world. These factors are largely responsible for increasing rates of postherpetic neuralgia and painful diabetic neuropathy [bib_ref] An observational descriptive study of the epidemiology and treatment of neuropathic pain..., Hall [/bib_ref]. In addition, survival rates are increasing among cancer patients, and many of the medical and surgical interventions used in the treatment of cancer (including chemotherapy) can cause NeP [bib_ref] Burden of chemotherapy-induced neuropathy -a cross-sectional study, Kautio [/bib_ref]. la prise en charge pharmacologique de la douleur neuropathique chronique : une déclaration de consensus révisée de la Société canadienne de la douleur HISTORIQuE : La douleur neuropathique (DNe), redéfinie comme une douleur causée par une lésion ou une maladie du système somatosensoriel, est un trouble invalidant dont sont affligés environ deux millions de Canadiens. OBjECTIF : Examiner les essais aléatoires et contrôlés (EAC) et les analyses systématiques liées à la prise en charge pharmacologique de la DNe pour préparer une déclaration de consensus révisée, fondée sur des faits probants, à l'égard de sa prise en charge. MÉTHODOlOgIE : Les EAC, les analyses systématiques et les lignes directrices sur la prise en charge pharmacologique de la DNe ont été évaluées lors d'une réunion de consensus en mai 2012, puis mises à jour en septembre 2013. Les médicaments étaient recommandés dans le document de consensus si leur efficacité analgésique était soutenue par au moins une EAC solide sur le plan méthodologique (classe I ou II), qui démontrait des avantages marqués par rapport à un placebo ou à un autre groupe témoin pertinent. Les recommandations thérapeutiques reposaient sur la qualité des preuves d'efficacité analgésique, d'innocuité et de facilité d'utilisation. RÉSulTATS : Les analgésiques recommandés pour le traitement de première intention sont les gabapentinoïdes (gabapentine et prégabaline), les antidépresseurs tricycliques et les inhibiteurs spécifiques du recaptage de la sérotonine et de la noradrénaline. Le tramadol et les opioïdes à libération contrôlée sont recommandés en deuxième intention pour la douleur modérée à grave. Les cannabinoïdes sont désormais recommandés en troisième intention, tandis que la méthadone, les anticonvulsivants dont l'efficacité est moins attestée (p. ex., lamotrigine, lacosamide), le tapentadol et la toxine botulique sont recommandés en quatrième intention. Certaines polythérapies analgésiques sont acceptées pour traiter des troubles de DNe particuliers. CONCluSIONS : Ces lignes directrices fournissent une démarche mise à jour et graduelle pour la prise en charge pharmacologique de la DNe. Le traitement devrait être personnalisé en fonction de chaque patient, compte tenu de l'efficacité, du profil d'effets secondaires et de l'accessibilité du médicament, y compris son coût. D'autres études s'imposent pour faire des comparaisons directes entre analgésiques et examiner des combinaisons d'analgésiques, les résultats à long terme et le traitement de la DNe en pédiatrie, de la DNe en gériatrie et de la DNe centrale.
# Methods
In 2007, the Canadian Pain Society (CPS) produced the first guidelines on pharmacological management of NeP tailored to the clinical practices of Canadian health professionals including analgesic agents specifically available in Canada [bib_ref] Pharmacological management of chronic neuropathic pain -Consensus statement and guidelines from the..., Moulin [/bib_ref]. A consensus meeting was held in Whistler, British Columbia under the direction of the Neuropathic Pain Special Interest Group of the CPS in May 2012 to update these guidelines, given the plethora of systematic reviews and meta-analyses published since 2007 (Appendix A). There is also recent evidence from community-based studies that management of NeP, including postherpetic neuralgia, is not consistent with evidence-based recommendations [bib_ref] Is treatment of postherpetic neuralgia in the community consistent with evidence-based recommendations?, Dworkin [/bib_ref]. Funding for this consensus meeting was provided by the Neuropathic Pain Special Interest Group of the CPS. This involved a multidisciplinary group of individuals with research and clinical expertise relevant to the pathophysiology and management of NeP. This group met to review the randomized controlled trials (RCTs) and systematic reviews related to the pharmacological management of NeP to develop a revised evidence-based consensus statement on the management of NeP [bib_ref] When should clinical guidelines be updated?, Shekelle [/bib_ref]. Subsequent literature was reviewed by the group until September 2013.
Systematic searches on Medline and Cochrane databases were conducted to identify recent systematic reviews, meta-analyses and treatment recommendations, guidelines and/or consensus statements published since the first 2007 CPS consensus statement. Other selected publications and references were also considered. Medications could be recommended in the consensus statement if their analgesic efficacy was supported by at least one methodologically sound RCT (class I or class II) showing significant benefit relative to placebo or another relevant control group. Trials were excluded if they represented uncontrolled studies, had sample sizes of <10 patients or studied cancer NeP except for well-defined postsurgical pain syndromes (eg, postmastectomy pain syndrome) and chemotherapy-induced NeP. Trials were also excluded if they studied trigeminal or glossopharyngeal neuralgia because these conditions have their own specific medical and surgical treatments [bib_ref] Medical management of trigeminal neuropathic pains, Zakrzewska [/bib_ref]. The initial draft of the present manuscript was prepared by the first author and subsequent revisions were based on feedback from the other authors until consensus was achieved.
The current guidelines are based on quality of evidence of analgesic efficacy, side-effect profiles and ease of use. Medications were considered to be first line if there was high-quality evidence of efficacy (at least one class I study or two consistent class II studies -level of recommendation grade B or better) (15); positive results in at least two NeP models [bib_ref] Considerations for extrapolating evidence of acute and chronic pain analgesic efficacy, Dworkin [/bib_ref] ; and if they were considered to be straightforward and of sufficient tolerability to prescribe and monitor. Medications were considered to be second or third line if there was high-quality evidence of efficacy, but the medication required more specialized follow-up and monitoring. Fourth-line treatments had at least one positive RCT, but require further study. A limitation of this algorithmic classification is that grading of tolerability and ease of use was based solely on consensus opinion of the authors.
Target users for these guidelines are physicians, nurse practitioners and other allied health care individuals involved in the management of NeP. These guidelines have been endorsed by the Canadian Pain Coalition, an advocacy group for patients living with chronic pain. The published guidelines will be disseminated through various websites, including the CPS website, and reprints will be made available to undergraduate and postgraduate trainees, and practicing health care workers attending continuing medical education events. They will be updated periodically by the Neuropathic Pain Special Interest Group of the CPS.
## Clinical characteristics and differential diagnoses of nep
The clinical features of NeP can be divided into spontaneous pain and stimulus-evoked pain. Spontaneous pain is commonly described as burning or intense tightness with superimposed shooting or lancinating pain. Stimulus-evoked pain includes allodynia, defined as painful sensations in response to a normally nonpainful stimulus, and hyperalgesia, defined as increased pain sensitivity in response to a normally painful stimulus. Superimposed autonomic features, such as alterations in temperature, colour and sweating as well as the development of trophic changes, suggest a diagnosis of reflex sympathetic dystrophy or complex regional pain syndrome [bib_ref] Diagnostic criteria: The statistical derivation of the four criterion factors, Harden [/bib_ref].
The differential diagnosis of NeP is extensive and includes central and peripheral causes. Examples of central NeP include poststroke pain ('thalamic pain syndrome'), pain related to multiple sclerosis and pain due to spinal cord injury. Common causes of peripheral NeP include painful diabetic neuropathy, postherpetic neuralgia and surgically induced NeP, following thoracotomy, amputation, breast surgery and back surgery sometimes associated with nerve root fibrosis.
The diagnosis of NeP is based primarily on the patient's history and physical examination. Postherpetic neuralgia and painful diabetic neuropathy are typically easy to diagnose when there is a history of shingles and diabetes mellitus, respectively. However, pain radiating into an extremity can be either referred myofascial pain or NeP, and these can be much more challenging to diagnose. Simple questionnaires based on sensory descriptors and sensory examination have been developed to differentiate between somatic pain and NeP. Instruments such as the Douleur Neuropathique 4 and the Leeds Assessment of Neuropathic Symptoms and Signs have been shown to be valid and reliable discriminators of NeP [bib_ref] Comparison of pain syndromes associated with nervous or somatic lesions and development..., Bouhassira [/bib_ref] [bib_ref] The S-LANSS score for identifying pain of predominantly neuropathic origin: Validation for..., Bennett [/bib_ref]. In addition, the presence of true weakness (sometimes difficult to differentiate from pain-related or antalgic weakness), reduced or absent reflexes, allodynia and hyperalgesia all favour a diagnosis of NeP. Electromyography and nerve conduction studies are sometimes useful to provide more objective evidence of nerve injury, although electromyography study results are often normal in small-fibre neuropathies. Guidelines are available to determine the diagnostic certainty of NeP (possible, probable or definite) based on history, sensory signs, neurophysiological testing and neuroimaging (1).
## General considerations
Because NeP can be severe and unrelenting, it is important to recognize and treat comorbidities such as anxiety and depression. It is also important to recognize secondary treatment goals such as improving sleep, ability to function and overall quality of life. However, treatment goals must be realistic. Caregivers should validate the patient's pain to gain their trust and should set realistic treatment goals. This is typically straightforward from the caregiver's point of view because most NeP states are based on well-defined injuries to the nervous system. The primary goal in most cases is to make the pain 'bearable' or 'tolerable' -not to eliminate the pain. Such goal setting can make a considerable difference in patient satisfaction when pharmacological treatments are instituted.
Due to the lack of head-to-head trials to guide treatment choices, one approach to estimate the relative efficacy of analgesic agents in RCTs is to use the number needed to treat (NNT) -the number of patients that need to be treated with a certain drug to provide one additional patient with at least 50% pain relief relative to the comparator group. The NNT is used to estimate treatment efficacy, recognizing that there are limitations to this methodology including variability in RCTs (eg, crossover versus parallel design) and the shortterm nature of most RCTs. Another approach to estimate efficacy is to determine the effect size -defined as the mean difference between active agent and placebo divided by the SD. The effect size can be classified as small (<0.5), medium (0.5 to <0.8) or large (≥0.8).
Appendix A summarizes the results of a systematic search of systematic reviews, meta-analyses and treatment recommendations, guidelines and/or consensus statements published since the first 2007 CPS consensus statement. These results were reviewed and approved by two coauthors (DEM and IG) and provide the basis for the consensus statement presented here.
## First-line analgesics
Two classes of medications are recommended for first-line treatment in the management of NeP -anticonvulsants and certain antidepressants.
## Anticonvulsants
The gabapentinoids, gabapentin and pregabalin, bind to presynaptic voltage-gated calcium channels in the dorsal horn, reducing the release of excitatory neurotransmitters such as glutamate and substance P [bib_ref] The biology and pharmacology of calcium channel alpha2-delta proteins, Taylor [/bib_ref]. These agents have been studied in large clinical trials, although mainly in the management of painful diabetic neuropathy and postherpetic neuralgia. Gabapentin has shown efficacy in three trials involving painful diabetic neuropathy and two trials involving postherpetic neuralgia [bib_ref] EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision, Attal [/bib_ref] ; however, four RCTs involving gabapentin have been negative, including a trial of gabapentin in chemotherapyinduced painful neuropathy [bib_ref] Gabapentin in traumatic nerve injury pain: A randomized, double-blind, placebo-controlled, crossover, multi-centre..., Gordh [/bib_ref] [bib_ref] Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: A phase..., Rao [/bib_ref] [bib_ref] Comparison of the effectiveness of amitriptryline and gabapentin on chronic neuropathic pain..., Rintala [/bib_ref] [bib_ref] Efficacy of gabapentin in treating chronic phantom limb and residual limb pain, Smith [/bib_ref]. The combined NNTs for gabapentin in the management of painful polyneuropathy and postherpetic neuralgia were 6.4 and 4.3, respectively [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref].
Pregabalin is an analogue of gabapentin, with the same mechanism of action, but it manifests linear pharmacokinetics and has higher affinity for the presynaptic calcium channel. Four studies have shown that pregabalin provides significant pain relief and improved quality of life in painful diabetic neuropathy [bib_ref] Evidence-based guideline: Treatment of painful diabetic neuropathy, Bril [/bib_ref] and an additional four trials have shown efficacy in postherpetic neuralgia [bib_ref] EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision, Attal [/bib_ref]. The combined NNTs for pregabalin in the management of painful diabetic neuropathy and postherpetic neuralgia were 4.5 and 4.2, respectively [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref]. Pregabalin has also been studied in chronic central NeP following spinal cord injury, with evidence of significant pain relief [bib_ref] Pregabalin in central neuropathic pain associated with spinal cord injury: A placebocontrolled..., Siddall [/bib_ref] [bib_ref] Pregabalin in patients with central neuropathic pain: A randomized, double-blind, placebo-controlled trial..., Vranken [/bib_ref]. However, a study investigating pregabalin in the treatment of NeP associated with chronic lumbosacral radiculopathy was negative (31), as was a recent trial involving refractory painful diabetic neuropathy [bib_ref] Pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy: A randomized..., Philip [/bib_ref]. A study investigating the safety and efficacy of pregabalin in patients with central poststroke pain showed no significant improvement in the primary end point of pain intensity; however, there were some improvements in secondary end points including sleep and anxiety [bib_ref] Safety and efficacy of pregabalin in patients with central post-stroke pain, Kim [/bib_ref].
Carbamazepine remains the drug of first choice for tic douloureux (idiopathic trigeminal neuralgia), but otherwise is not recommended for the management of NeP [bib_ref] Medical management of trigeminal neuropathic pains, Zakrzewska [/bib_ref]. Anecdotally, it may also be useful in the management of glossopharyngeal neuralgia [bib_ref] Medical management of trigeminal neuropathic pains, Zakrzewska [/bib_ref].
## Antidepressant agents
The tricyclic antidepressants (TCAs) have been shown to provide significant pain relief in various NeP conditions in many clinical trials, although the sample sizes have tended to be relatively small and most of these trials have used a crossover design [bib_ref] Algorithm for neuropathic pain treatment: An evidence-based proposal, Finnerup [/bib_ref]. The combined NNTs for TCAs in the management of painful diabetic neuropathy and postherpetic neuralgia were 2.1 and 2.8, respectively [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref].
The serotonin noradrenaline reuptake inhibitors (SNRIs), duloxetine and venlafaxine, have mainly been studied in painful diabetic neuropathy. Duloxetine has demonstrated significant pain relief relative to placebo in three RCTs [bib_ref] Evidence-based guideline: Treatment of painful diabetic neuropathy, Bril [/bib_ref] , with a combined NNT of 5.0 [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref]. A recent study investigating duloxetine in the management of chemotherapy-induced painful peripheral neuropathy showed a significant reduction in pain intensity relative to placebo, with a moderate effect size of 0.51 [bib_ref] Effect of duloxetine on pain, function and quality of life among patients..., Smith [/bib_ref]. However, duloxetine has also been studied in patients with central NeP due to spinal cord injury or stroke, and the results of this trial were negative [bib_ref] Duloxetine in patients with central neuropathic pain caused by spinal cord injury..., Vranken [/bib_ref].
Venlafaxine has shown efficacy in trials involving painful diabetic neuropathy [bib_ref] Venlafaxine extended release in the treatment of painful diabetic neuropathy: A double-blind,..., Rowbotham [/bib_ref] and mixed painful polyneuropathy [bib_ref] Venlafaxine versus imipramine in painful polyneuropathy: A randomized, controlled trial, Sindrup [/bib_ref] at doses of 150 mg to 225 mg daily. However, the latter trial, comparing venlafaxine with imipramine, showed a higher proportion of responders in the venlafaxine group. Another trial investigating venlafaxine plus gabapentin in the management of painful diabetic neuropathy showed significant pain relief relative to placebo plus gabapentin [bib_ref] Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy, Simpson [/bib_ref].
## Second-line analgesics
Two opioid-type medications are recommended for second-line treatment in the management of NeP.
## Tramadol
Tramadol is a weak opioid agonist and mimics some of the properties of the TCAs in that it inhibits reuptake of noradrenalin and serotonin [bib_ref] Tramadol -a new oral analgesic, Abramowicz [/bib_ref]. Tramadol has shown significant benefit in three RCTs investigating painful diabetic neuropathy and mixed NeP syndromes, and has an overall NNT of 4.9 [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref]. Tramadol leads to less constipation and nausea than other weak opioid analgesics, such as codeine (41), but is more expensive in Canada. Tramadol should be used with caution in conjunction with selective serotonin reuptake inhibitors (SSRIs) because of increased risk of confusion and serotonin syndrome, especially among elderly patients [bib_ref] Tramadol for neuropathic pain, Hollingshead [/bib_ref].
## Opioid analgesics
A recent meta-analysis of opioids for chronic noncancer pain included 16 randomized trials for chronic NeP [bib_ref] A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids..., Furlan [/bib_ref]. Most of these trials investigated painful diabetic neuropathy and postherpetic neuralgia; however, other trials focused on postamputation pain, sciatica and spinal cord injury pain. The authors found that opioids were more effective than placebo, with a moderate effect size (0.56) for pain. There was a small effect size (0.24) in favour of opioids for function in 13 of these RCTs. The combined NNT for opioids in the management of painful polyneuropathy and postherpetic neuralgia was 2.6 (27).
## Third-line analgesics
One class of medication is recommended for third-line treatment in the management of NeP -cannabinoids.
## Cannabinoids
The cannabinoids are analgesic agents with increasing evidence of efficacy in central NeP states, with a combined NNT of 3.4 [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref]. Dronabinol produced modest analgesia in a trial investigating central pain in multiple sclerosis [bib_ref] Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomized double-blind..., Svendsen [/bib_ref]. A 50/50 mixture of tetrahydrocannabinol and cannabidiol in the form of an oral mucosal spray provided significant benefit in another trial investigating central pain in multiple sclerosis [bib_ref] Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis, Rog [/bib_ref]. A recent systematic review of clinical trials investigating cannabinoids in chronic pain determined that, since 2006, there have been seven highquality (class I and II) studies investigating NeP, and all of these studies except one were positive [bib_ref] Cannabinoids for treatment of chronic non-cancer pain: A systematic review of randomized..., Lynch [/bib_ref]. Four of these studies involved smoked cannabis for the management of HIV neuropathy (two studies), posttraumatic or postsurgical NeP, and combined central and peripheral NeP states. Two trials involved the cannabinoid oral mucosal spray in the management of multiple peripheral NeP states with allodynia and painful diabetic neuropathy. The single negative trial compared the synthetic cannabinoid nabilone with dihydrocodeine in peripheral NeP conditions, and found that dihydrocodeine was superior to nabilone. A more recent trial found that nabilone was effective in relieving symptoms of painful diabetic neuropathy, and also improved disturbed sleep and overall quality of life using an enriched enrollment withdrawal design [bib_ref] An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of..., Toth [/bib_ref].
## Fourth-line analgesics
Several classes of medications can be considered to be fourth-line treatments for NeP -SSRIs, other anticonvulsants, methadone, topical lidocaine and miscellaneous agents.
## Ssris
SSRIs appear to have a weak analgesic effect in the management of NeP. Citalopram [bib_ref] The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy, Sindrup [/bib_ref] , paroxetine [bib_ref] The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of..., Sindrup [/bib_ref] and escitalopram [bib_ref] Escitalopram in painful polyneuropathy: A randomized, placebo-controlled, Otto [/bib_ref] have been found to be efficacious in the management of painful diabetic neuropathy and painful polyneuropathy independent of their antidepressant effects, but fluoxetine has not [bib_ref] Effects of desipramine, amitriptyline and fluoxetine on pain in diabetic neuropathy, Max [/bib_ref]. However, the combined NNT for all four studies was 6.8 [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref]. SSRIs used primarily for depression may inhibit the metabolism of TCAs and may increase the risk for serotonin syndrome [bib_ref] Selective serotonin reuptake inhibitors and CNS drug interactions. A critical review of..., Sproule [/bib_ref].
## Other anticonvulsants
Lamotrigine has been studied in a variety of peripheral and central NeP conditions, with variable results. Four studies investigating painful diabetic neuropathy, two studies investigating mixed NeP and single studies investigating chemotherapy-induced NeP and spinal cord injury pain were negative. Positive trials investigating HIV-related neuropathy, trigeminal neuralgia and central poststroke pain were reported; however, the sample sizes tended to be small, with significant dropout rates [bib_ref] Lamotrigine for acute and chronic pain, Wiffen [/bib_ref].
Lacosamide is an anticonvulsant agent with sodium channelblocking properties. Lacosamide has been studied in five RCTs investigating painful diabetic neuropathy. There was modest benefit in each trial, with an NNT in the range of 10 to 12. Lacosamide, therefore, has limited efficacy in the treatment of painful diabetic neuropathy [bib_ref] Lacosamide for neuropathic pain and fibromyalgia in adults, Hearn [/bib_ref].
Topiramate and valproic acid have produced mixed results in NeP trials [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref].
## Methadone
Methadone is a synthetic opioid analgesic that may be useful in the management of NeP related to its N-methyl-D-aspartate antagonist properties [bib_ref] The d-and l-isomers of methadone bind to the non-competitive site on the..., Gorman [/bib_ref]. Two small RCTs demonstrated benefit from methadone in chronic NeP [bib_ref] Low dose methadone has an analgesic effect in neuropathic pain: A double-blind..., Morley [/bib_ref] [bib_ref] Methadone in the treatment of neuropathic pain, Gagnon [/bib_ref] and survey data suggested efficacy in mixed NeP conditions [bib_ref] Methadone in the management of intractable neuropathic noncancer pain, Moulin [/bib_ref]. Methadone has excellent oral bioavailability and a duration of action of at least 8 h with repetitive dosing. It has an elimination half-life of 24 h to 36 h, which requires close observation during the titration phase. There are no high-quality RCTs to support the use of methadone in the management of NeP, although guidelines for the use of methadone in the management of chronic pain are available [bib_ref] A review of the use of methadone for the treatment of chronic..., Lynch [/bib_ref]. An RCT comparing methadone with other oral opioids is urgently needed.
## Topical lidocaine
Topical lidocaine, as a sodium channel blocker, may be useful in the management of NeP. Systemic side effects are extremely rare as a result of negligible blood levels [bib_ref] Pharmacokinetics and tolerability of lidocaine patch 5% with extended dosing, Gammaaitoni [/bib_ref]. Topical lidocaine is most practical for patients with localized peripheral NeP, such as postherpetic neuralgia, and remains a second-line agent for this condition based on three positive RCTs investigating lidocaine patch 5% in the management of postherpetic neuralgia [bib_ref] The evidence for pharmacological treatment of neuropathy pain, Finnerup [/bib_ref]. However, recent trials of lidocaine cream or patch 5% failed to provide benefit in patients with postsurgical peripheral nerve injury [bib_ref] Use of a lidocaine patch in the management of postsurgical neuropathic pain..., Cheville [/bib_ref] or in mixed NeP [bib_ref] Topical amitriptyline versus lidocaine in the treatment of neuropathic pain, Ho [/bib_ref]. Therefore, there are conflicting results among placebo-controlled trials investigating topical lidocaine for NeP.
## Miscellaneous agents
Tapentadol is a novel analgesic that has recently become available in Canada. It is pharmacologically similar to tramadol in that it has a dual mechanism of action, but has higher affinity for the mu opioid receptor and has only noradrenergic activity as a monoamine reuptake inhibitor. Tapentadol is approximately one-fifth as potent as oxycodone and has shown efficacy in the management of painful diabetic neuropathy, with greater tolerability [bib_ref] Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral..., Schwartz [/bib_ref].
Topical capsaicin may have utility in the management of localized NeP such as postherpetic neuralgia. Following application to the skin, capsaicin initially causes enhanced sensitivity of nociceptors, followed by persistent desensitization after repeated application of low-concentration (<1%) capsaicin or a single application of highconcentration (8%) capsaicin. Several older studies involving small sample sizes indicate that low-concentration capsaicin provides minimal benefit relative to placebo creams [bib_ref] Topical capsaicin (low concentration) for chronic neuropathic pain in adults, Derry [/bib_ref]. On the other hand, high-concentration capsaicin has recently been studied in four trials investigating postherpetic neuralgia and two trials investigating painful HIV neuropathy using 0.04% topical capsaicin as the control to maintain blinding. All of these studies showed significant benefit relative to the control for up to 12 weeks after a single application. The NNT for the postherpetic neuralgia studies was in the range of eight to 10 and, for the HIV-neuropathy studies, was approximately 6.2 [bib_ref] Topical capsaicin (high concentration) for chronic neuropathic pain in adults, Derry [/bib_ref]. High-concentration capsaicin requires preapplication of local anesthetic because of the intense burning sensation it produces. This agent is quite expensive and only available in Canada through compassionate release from Health Canada.
Botulinum toxin has been studied in two RCTs involving NeP. Both studies were positive, with significant reduction in pain intensity for 12 to 14 weeks, but these studies were likely underpowered due to small sample sizes. A crossover trial involving patients with painful diabetic neuropathy included only 18 patients (66) and a parallel design trial involving patients with focal painful neuropathies included only 29 patients [bib_ref] Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain, Ranoux [/bib_ref]. Evidence for the role of botulinum toxin in the management of NeP, therefore, remains preliminary.
## Combination pharmacotherapy
Combining ≥2 analgesic agents in the management of NeP is an attractive option because combination pharmacotherapy may improve analgesic efficacy and has the potential to reduce the overall side effect profile if synergistic effects allow for dose reductions of combined drugs [bib_ref] Combination pharmacotherapy for management of chronic pain: From bench to bedside, Gilron [/bib_ref]. A recent Cochrane review of combination pharmacotherapy for the treatment of NeP in adults identified 21 eligible studies [bib_ref] Combination pharmacotherapy for the treatment of neuropathic pain in adults, Chaparro [/bib_ref]. The majority of these studies evaluated the combination of an opioid with gabapentin, pregabalin or a TCA, the combination of gabapentin and nortriptyline, and various topical medications. Meta-analysis was possible for only one combination -gabapentin plus opioid versus gabapentin alone. The meta-analysis demonstrated modest superiority of gabapentin plus opioid versus gabapentin alone, although the combination produced significantly more dropouts due to accentuated side effects related to combination treatments. A recent RCT comparing a combination of standard doses of duloxetine (60 mg daily) and pregabalin (300 mg daily) with high-dose monotherapy (duloxetine 120mg daily or pregabalin 600 mg daily) found no significant difference in 24 h average pain, although side effects were comparable [bib_ref] Duloxetine and pregabalin: High-dose monotherapy or their combination? The "COMBO-DN study" -a..., Tesfaye [/bib_ref]. Available studies do not support a recommendation of any one specific drug combination for NeP, although these studies do provide a rationale for combination pharmacotherapy.
## Stepwise pharmacological
MANAgEMENT OF NeP [fig_ref] Figure 1: Algorithm for the pharmacological management of neuropathic pain [/fig_ref] provides an updated algorithm for the pharmacological management of NeP, and [fig_ref] TAbLE 1: Dosing regimens for selected agents for neuropathic pain [/fig_ref] provides dosing guidelines for selected agents. Nonpharmacological interventions, including physiotherapy, exercise programs and psychological treatment modalities, are essential to enhance outcome. Relative to the previous guidelines for management of NeP published in 2007 (9), duloxetine has been upgraded from a second-line to a first-line agent based on recent evidence of efficacy in the management of chemotherapy-induced painful neuropathy [bib_ref] Effect of duloxetine on pain, function and quality of life among patients..., Smith [/bib_ref] in addition to previously established efficacy in painful diabetic neuropathy.
TCAs, gabapentinoids and SNRIs are, therefore, now all considered to be first-line agents in the management of chronic NeP. TCAs have the advantage of low cost and once-daily dosing, but can produce drowsiness and significant anticholinergic side effects, including dry mouth, constipation and urinary retention, and are, thus, poorly tolerated in the elderly. Secondary amine TCAs (nortriptyline and desipramine) are better tolerated than tertiary amine TCAs (amitriptyline and imipramine) with comparable analgesic efficacy [bib_ref] A systematic review of antidepressants in neuropathic pain, Mcquay [/bib_ref]. Cardiac toxicity is also a risk factor with TCAs, which are relatively contraindicated in patients with a history of arrhythmia [bib_ref] Treatment of neuropathic pain: An overview of recent guidelines, O'connor [/bib_ref].
Gabapentin and pregabalin appear to be similar in their mechanisms of action and side-effect profiles, and allow for more rapid titration than antidepressant agents. Pregabalin carries the advantage of twice-daily dosing and linear pharmacokinetics relative to gabapentin. Gabapentinoids in general have few drug interactions, but are dependent on renal excretion and, therefore, require dosage reductions in patients with renal insufficiency [bib_ref] Treatment of neuropathic pain: An overview of recent guidelines, O'connor [/bib_ref].
If a TCA fails or is contraindicated, the use of a gabapentinoid or an SNRI, such as duloxetine, should be considered. If one of the latter agents provides only partial pain relief, it is reasonable to add the other agent because there is evidence that combination pharmacotherapy can be helpful [bib_ref] Combination pharmacotherapy for management of chronic pain: From bench to bedside, Gilron [/bib_ref].
When first-line medications fail or provide inadequate pain relief, tramadol or a conventional opioid analgesic may be useful as a secondline treatment. It is also reasonable to consider a short-acting opioid, such as codeine or oxycodone (sometimes combined with acetaminophen), for breakthrough pain during titration of a first-line agent if needed for severe pain. Controlled-release opioid analgesics are considered to be second-line agents in the management of NeP because of their extensive side-effect profile and the risk of opioid misuse, abuse and addiction leading to cautionary prescribing and monitoring. A recent meta-analysis of 62 RCTs found that the most common adverse effects associated with opioids were nausea (28%), constipation (25%), drowsiness (24%), dizziness (18%) and vomiting (15%) [bib_ref] A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids..., Furlan [/bib_ref]. Although tolerance may occur to several of these side effects, there is very little tolerance to constipation and almost all patients placed on a controlledrelease opioid analgesic require a bowel regimen with continued monitoring of bowel function. Potential long-term complications of opioid analgesia include opioid-induced hyperalgesia [bib_ref] Opioid-induced abnormal pain sensitivity: Implications in clinical opioid therapy, Mao [/bib_ref] and opioid-induced endocrinopathy [bib_ref] Hypogonadism in men consuming sustained-action oral opioids, Daniell [/bib_ref] [bib_ref] Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant..., Daniell [/bib_ref]. Endocrine effects manifest as hypogonadism and increased risk for osteopenia. Monitoring for risk for opioid addiction is also challenging. A review suggested that aberrant drug-related behaviours and illicit drug use occurred in 10% to 15% of patients receiving chronic opioid therapy [bib_ref] What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic..., Fishbain [/bib_ref]. Canadian guidelines for the safe and effective use of opioids for chronic noncancer pain, including monitoring for addiction, are strongly recommended. The cannabinoids have now advanced to third-line agents in the management of chronic NeP based on increasing evidence of efficacy in multiple pain models including HIV neuropathy, post-traumatic and postsurgical NeP, painful diabetic neuropathy and spinal cord injury pain [bib_ref] Cannabinoids for treatment of chronic non-cancer pain: A systematic review of randomized..., Lynch [/bib_ref] [bib_ref] An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of..., Toth [/bib_ref]. However, the cannabinoids also require close monitoring, are contraindicated in patients with a history of psychosis and most of these agents, including the oral mucosal spray, are expensive.
Fourth-line agents in the management of NeP include methadone, tapentadol and anticonvulsants, with lesser evidence of efficacy such as lacosamide, lamotrigine and topiramate. Topical lidocaine has been relegated to fourth-line status because of conflicting evidence of efficacy except in the management of postherpetic neuralgia, for which it remains a second-line option.
It is more challenging to provide a stepwise systematic approach to the management of central NeP because of the relative paucity of highquality studies and conflicting evidence of efficacy. For instance, lamotrigine was found to be useful in the management of central poststroke pain, but not for spinal cord injury pain [bib_ref] Lamotrigine for acute and chronic pain, Wiffen [/bib_ref]. Similarly, pregabalin has been found to be efficacious in the management of spinal cord injury pain [bib_ref] Pregabalin in central neuropathic pain associated with spinal cord injury: A placebocontrolled..., Siddall [/bib_ref] [bib_ref] Pregabalin in patients with central neuropathic pain: A randomized, double-blind, placebo-controlled trial..., Vranken [/bib_ref] , but not in central poststroke pain [bib_ref] Safety and efficacy of pregabalin in patients with central post-stroke pain, Kim [/bib_ref]. However, it is reasonable to consider the gabapentinoids and cannabinoids as first-line agents for the management of spinal cord injury pain [bib_ref] A systematic review of pharmacologic treatments of pain after spinal cord injury, Teasell [/bib_ref] , and TCAs (79) and lamotrigine [bib_ref] Lamotrigine for acute and chronic pain, Wiffen [/bib_ref] in the management of central poststroke pain.
## Invasive techniques in the management of nep
Although interventional techniques for NeP management are beyond the scope of the present consensus statement, they are usually considered when standard pharmacological treatments fail and psychological screening shows emotional stability. Intravenous lidocaine infusions are generally safe, but evidence of efficacy is limited to one to two weeks postinfusion [bib_ref] Systemic administration of local anesthetics to relieve neuropathic pain: A systematic review..., Tremont-Lukats [/bib_ref]. Two recent comprehensive reviews of interventional management of NeP concluded that weak recommendations could be made for epidural steroid injections for radiculopathy, and spinal cord stimulation for failed back surgery syndrome and complex regional pain syndrome type 1 [bib_ref] Evidence-based guideline for neuropathic pain interventional treatments: Spinal cord stimulation, intravenous infusions,..., Mailis [/bib_ref] [bib_ref] Interventional management of neuropathic pain: NeuPSIG recommendations, Dworkin [/bib_ref].
## Summary
The present updated consensus statement provides a stepwise pharmacological approach to the management of NeP. Gabapentinoids, TCAs and SNRIs represent first-line treatments for NeP either individually or in combination. When these agents fail, conventional opioid analgesics and tramadol provide important avenues of treatment, bearing in mind their associated risks and adverse effect profiles. Cannabinoids are now considered to be third-line agents based on recent evidence of efficacy, but also require judicious prescribing practices. Novel treatment approaches are required to improve our management of NeP and further studies are necessary to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes and treatments of pediatric, geriatric and central NeP. APPENDIx A: SYSTEMATIC lITERATuRE SEARCH RESulTS Results from Medline and Cochrane databases for pharmacological management of neuropathic pain using TITLE terms 'systematic reviews', 'meta-analyses' and 'guideline OR statement OR recommendation OR consensus' (English language literature since 2007) were tabulated. Articles related to nonpharmacological interventions, cancer pain due to tumour infiltration of nerve, and prevention and epidemiology of neuropathic pain were excluded. A total of 87 systematic reviews and meta-analyses, and 21 consensus statements/guidelines were reviewed. A full list of the included references is available from the authors on request.
## Acknowledgements
[fig] Figure 1: Algorithm for the pharmacological management of neuropathic pain. *Topical lidocaine (second line for postherpetic neuralgia), methadone, lamotrigine, lacosamide, tapentadol, botulinum toxin; + Limited randomized controlled trial evidence to support add-on combination therapy. TCA Tricyclic antidepressants; SNRI Serotonin noradrenaline reuptake inhibitors [/fig]
[table] TAbLE 1: Dosing regimens for selected agents for neuropathic pain [/table]
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https://downloads.hindawi.com/journals/prm/2014/754693.pdf
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Neuropathic pain is defined as a lesion or disease of the somatosensory system, and may involve the central or peripheral nervous systems. Treatment of neuropathic pain is a challenge for clinicians involved in affected patients' care. In 2007, the first guidelines for the treatment of neuropathic pain in the Canadian context were produced by the Canadian Pain Society. This update to these guidelines incorporates new evidence published since the first guidelines were released.
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Sarcopenia: European consensus on definition and diagnosis
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Sarcopenia: European consensus on definition and diagnosis
The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics-European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document. The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity? For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as 'presarcopenia', 'sarcopenia' and 'severe sarcopenia'. EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research. Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.
## Sarcopenia as a geriatric syndrome
A grave change associated with human ageing is progressive decline in skeletal muscle mass, a downward spiral that may lead to decreased strength and functionality. In 1989, Irwin Rosenberg proposed the term 'sarcopenia' (Greek 'sarx' or flesh + 'penia' or loss) to describe this age-related decrease of muscle mass [bib_ref] Summary comments: epidemiological and methodological problems in determining nutritional status of older..., Rosenberg [/bib_ref] [bib_ref] Sarcopenia: origins and clinical relevance, Rosenberg [/bib_ref]. Sarcopenia has since been defined as the loss of skeletal muscle mass and strength that occurs with advancing age. However, a widely accepted definition of sarcopenia suitable for use in research and clinical practice is still lacking.
Geriatric syndromes are common, complex and costly states of impaired health in older individuals. Geriatric syndromes result from incompletely understood interactions of disease and age on multiple systems, producing a constellation of signs and symptoms. Delirium, falls and incontinence are examples of geriatric syndromes [bib_ref] Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept, Inouye [/bib_ref]. We suggest it may be likewise helpful to recognise sarcopenia as a geriatric syndrome because this view promotes its identification and treatment even when the exact causes remain unknown [bib_ref] Geriatric syndromes: medical misnomer or progress in geriatrics?, Rikkert [/bib_ref] [bib_ref] Understanding sarcopenia as a geriatric syndrome, Landi [/bib_ref].
What is the evidence that age-related sarcopenia fits the current definition of a geriatric syndrome? Sarcopenia is prevalent in older populations [bib_ref] Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older..., Iannuzzi-Sucich [/bib_ref] [bib_ref] Prevalence of sarcopenia estimated using a bioelectrical impedance analysis prediction equation in..., Chien [/bib_ref]. Sarcopenia has multiple contributing factors-the ageing process over the life course, early life developmental influences, less-than-optimal diet, bed rest or sedentary lifestyle, chronic diseases and certain drug treatments [bib_ref] Role of dietary protein in the sarcopenia of aging, Paddon-Jones [/bib_ref] [bib_ref] The developmental origins of sarcopenia, Sayer [/bib_ref] [bib_ref] Aging and sarcopenia, Thompson [/bib_ref]. Sarcopenia represents an impaired state of health with a high personal toll-mobility disorders, increased risk of falls and fractures, impaired ability to perform activities of daily living, disabilities, loss of independence and increased risk of death [bib_ref] Frailty in older men: prevalence, progression, and relationship with mortality, Cawthon [/bib_ref] [bib_ref] Age-associated changes in skeletal muscles and their effect on mobility: an operational..., Laurentani [/bib_ref] [bib_ref] Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives, Rolland [/bib_ref] [bib_ref] Aging, disability and frailty, Topinkova [/bib_ref] [bib_ref] Resistance training improves metabolic economy during functional tasks in older adults, Hartman [/bib_ref].
## European working group on sarcopenia in older people
# Rationale and methods
While age-related sarcopenia is common and has huge personal and financial costs, sarcopenia still has no broadly accepted clinical definition, consensus diagnostic criteria, International Classification of Diseases 9th Revision (ICD-9) codes or treatment guidelines. To address these shortfalls, the European Union Geriatric Medicine Society (EUGMS) decided in 2009 to create a Sarcopenia Working Group that would develop operational definitions and diagnostic criteria for sarcopenia to be used in clinical practice as well as in research studies. Other European scientific organisations (the European Society of Clinical Nutrition and Metabolism , the International Academy of Nutrition and Aging and the International Association of Gerontology and Geriatrics-European Region [IAGG-ER]) were invited to join this group, accepted the request and nominated representatives who became members of the Sarcopenia Working Group.
The European Working Group on Sarcopenia in Older People (EWGSOP, the Sarcopenia Working Group) first met in January 2009, followed by two additional meetings during the year and by extensive email contacts. Literature reviews and discussions were guided by the following questions:
- What is sarcopenia?
- What parameters define sarcopenia?
- What variables will measure them, and what measurement tools and cut-off points will be used? - How does sarcopenia relate to other diseases/conditions?
The document developed by the Sarcopenia Working Group was circulated to the Boards of the four participant organisations (EUGMS, ESPEN, IAGG-ER, IANA) for input, and then revised in accord with review comments, and sent back to the organisations for final endorsement.
What is sarcopenia?
## Working definition
Sarcopenia is a syndrome characterised by progressive and generalised loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death [bib_ref] Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging..., Delmonico [/bib_ref] [bib_ref] The loss of skeletal muscle strength, mass, and quality in older adults:..., Goodpaster [/bib_ref]. The EWGSOP recommends using the presence of both low muscle mass and low muscle function (strength or performance) for the diagnosis of sarcopenia. Thus, diagnosis requires documentation of criterion 1 plus documentation of either criterion 2 or criterion 3 [fig_ref] Table 1: Criteria for the diagnosis of sarcopenia Diagnosis is based on documentation of... [/fig_ref].
The rationale for use of two criteria is: muscle strength does not depend solely on muscle mass, and the relationship between strength and mass is not linear [bib_ref] The loss of skeletal muscle strength, mass, and quality in older adults:..., Goodpaster [/bib_ref] [bib_ref] Skeletal muscle cutpoints associated with elevated physical disability risk in older men..., Janssen [/bib_ref]. Thus, defining sarcopenia only in terms of muscle mass is too narrow and may be of limited clinical value. Some have argued that the term dynapenia is better suited to describe age-associated loss of muscle strength and function. However, sarcopenia is already a widely recognised term, so replacing it might lead to further confusion.
## Mechanisms of sarcopenia
There are several mechanisms that may be involved in the onset and progression of sarcopenia [fig_ref] Figure 1: Mechanisms of sarcopenia [/fig_ref]. These mechanisms involve, among others, protein synthesis, proteolysis, neuromuscular integrity and muscle fat content. In an individual with sarcopenia, several mechanisms may be involved, and relative contributions may vary over time. Recognising these mechanisms and their underlying causes is expected to facilitate design of intervention trials that target one or more underlying mechanisms. [fig_ref] Table 2: Sarcopenia categories by cause [/fig_ref]. In many older people, the aetiology of sarcopenia is multi-factorial so that it may not be possible to characterise each individual as having a primary or secondary condition. This situation is consistent with recognising sarcopenia as a multi-faceted geriatric syndrome. Sarcopenia staging, which reflects the severity of the condition, is a concept that can help guide clinical management of the condition. EWGSOP suggests a conceptual staging as 'presarcopenia', 'sarcopenia' and 'severe sarcopenia' [fig_ref] Table 3: EWGSOP conceptual stages of sarcopenia [/fig_ref]. The 'presarcopenia' stage is characterised by low muscle mass without impact on muscle strength or physical performance. This stage can only be identified by techniques that measure muscle mass accurately and in reference to standard populations. The 'sarcopenia' stage is characterised by low muscle mass, plus low muscle strength or low physical performance. 'Severe sarcopenia' is the stage identified when all three criteria of the definition are met (low muscle mass, low muscle strength and low physical performance). Recognising stages of sarcopenia may help in selecting treatments and setting appropriate recovery goals. Staging may also support design of research studies that focus on a particular stage or on stage changes over time.
## Sarcopenia and other syndromes
Sarcopenia is featured in other syndromes associated with prominent muscle wasting. The main reason to differentiate between them is to encourage research into age-related me-chanisms of sarcopenia and to guide targeted and appropriate therapy for each.
## Cachexia
'Cachexia' (Greek 'cac' or bad + 'hexis' or condition) is widely recognised in older adults as severe wasting accompanying disease states such as cancer, congestive cardiomyopathy and end-stage renal disease [bib_ref] Loss of skeletal muscle mass in aging: examining the relationship of starvation,..., Thomas [/bib_ref]. Cachexia has recently been defined as a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass [bib_ref] Cachexia: a new definition, Evans [/bib_ref]. Cachexia is frequently associated with inflammation, insulin resistance, anorexia and increased breakdown of muscle proteins [bib_ref] Cachexia and aging: an update based on the Fourth International Cachexia Meeting, Morley [/bib_ref] [bib_ref] Inflammatory burden and amino acid metabolism in cancer cachexia, Durham [/bib_ref]. Thus, most cachectic individuals are also sarcopenic, but most sarcopenic individuals are not considered cachectic. Sarcopenia is one of the elements of the proposed definition for cachexia [bib_ref] Cachexia: a new definition, Evans [/bib_ref]. Very recently, a consensus paper expanding this definition of cachexia and identifying relevant issues on how to differentiate cachexia and sarcopenia was published by ESPEN, one of the EWGSOP-endorsing societies [bib_ref] Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special..., Muscaritoli [/bib_ref].
## Frailty
Frailty is a geriatric syndrome resulting from age-related cumulative declines across multiple physiologic systems, with impaired homeostatic reserve and a reduced capacity of the organism to withstand stress, thus increasing vulnerability to adverse health outcomes including falls, hospitalisation, institutionalisation and mortality [bib_ref] Sarcopenia and frailty: a clinician's controversial point of view, Bauer [/bib_ref] [bib_ref] Frailty in older adults: evidence for a phenotype, Fried [/bib_ref]. Associated with advanced organ failure (heart, lung, liver, kidney, brain), inflammatory disease, malignancy or endocrine disease Nutrition-related sarcopenia Results from inadequate dietary intake of energy and/or protein, as with malabsorption, gastrointestinal disorders or use of medications that cause anorexia
[formula] Presarcopenia ↓ Sarcopenia ↓ ↓ Or ↓ Severe sarcopenia ↓ ↓ ↓ A.J. Cruz-Jentoft et al. [/formula]
physical aspects; three or more of the following characteristics support a frailty diagnosis-unintended weight loss, exhaustion, weakness, slow gait speed and low physical activity [bib_ref] Frailty in older adults: evidence for a phenotype, Fried [/bib_ref]. Frailty and sarcopenia overlap; most frail older people exhibit sarcopenia, and some older people with sarcopenia are also frail. The general concept of frailty, however, goes beyond physical factors to encompass psychological and social dimensions as well, including cognitive status, social support and other environmental factors [bib_ref] Sarcopenia and frailty: a clinician's controversial point of view, Bauer [/bib_ref].
## Sarcopenic obesity
In conditions such as malignancy, rheumatoid arthritis and ageing, lean body mass is lost while fat mass may be preserved or even increased [bib_ref] Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours..., Prado [/bib_ref]. This state is called sarcopenic obesity, and thus the relationship between age-related reduction of muscle mass and strength is often independent of body mass. It had long been thought that age-related loss of weight, along with loss of muscle mass, was largely responsible for muscle weakness in older people [bib_ref] Sarcopenic obesity: definition, cause and consequences, Stenholm [/bib_ref]. However, it is now clear that changes in muscle composition are also important, e.g. 'marbling', or fat infiltration into muscle, lowers muscle quality and work performance [bib_ref] Leg muscle mass and composition in relation to lower extremity perform-Definition and..., Visser [/bib_ref]. While weight changes vary widely between individuals, certain patterns of age-related change in body composition have been observed. In ageing men, the percentage of fat mass increases initially, then levels off or decreases. Such change has been attributed to an accelerated decrease in lean mass, along with an initial increase and a later decrease in fat mass [bib_ref] Effects of birth cohort and age on body composition in a sample..., Ding [/bib_ref]. Women show a generally similar pattern [bib_ref] Effects of birth cohort and age on body composition in a sample..., Ding [/bib_ref]. Intramuscular and visceral fat increase with ageing while subcutaneous fat declines [bib_ref] The loss of skeletal muscle strength, mass, and quality in older adults:..., Goodpaster [/bib_ref] [bib_ref] Anthropometric assessment of 10-y changes in body composition in the elderly, Hughes [/bib_ref] [bib_ref] Sarcopenia and increased adipose tissue infiltration of muscle in elderly African American..., Song [/bib_ref].
## Identifying sarcopenia in research and practice
The parameters of sarcopenia are the amount of muscle and its function. The measurable variables are mass, strength and physical performance. The challenge is to determine how best to measure them accurately. It is also important to recognise change by repeating the same measures over time in the same individuals. The following sections briefly review measurement techniques that can be used and discuss their suitability for research and clinical practice settings.
## Assessment techniques
## Muscle mass
A wide range of techniques can be used to assess muscle mass. Cost, availability and ease of use can determine whether the techniques are better suited to clinical practice or are more useful for research. [fig_ref] Table 4: Measurements of muscle mass, strength, and function in research and practice a [/fig_ref] lists the suggestions of EWGSOP for use of these techniques in research and in routine clinical practice.
Body imaging techniques. Three imaging techniques have been used for estimating muscle mass or lean body mass-computed tomography (CT scan), magnetic resonance imaging (MRI) and dual energy X-ray absorptiometry (DXA). CT and MRI are considered to be very precise imaging systems that can separate fat from other soft tissues of the body, making these methods gold standards for estimating muscle mass in research. High cost, limited access to equipment at some sites and concerns about radiation exposure limit the use of these whole-body imaging methods for routine clinical practice [bib_ref] Prevalence of sarcopenia estimated using a bioelectrical impedance analysis prediction equation in..., Chien [/bib_ref]. DXA is an attractive alternative method both for research and for clinical use to distinguish fat, bone mineral and lean tissues. This whole-body scan exposes the patient to minimal radiation. The main drawback is that the equipment is not portable, which may preclude its use in largescale epidemiological studies [bib_ref] Prevalence of sarcopenia estimated using a bioelectrical impedance analysis prediction equation in..., Chien [/bib_ref].
> CT and MRI are gold standards for estimating muscle mass in research. DXA is the preferred alternative method for research and clinical use.
Bioimpedance analysis. Bioimpedance analysis (BIA) estimates the volume of fat and lean body mass. The test itself is inexpensive, easy to use, readily reproducible and appropriate for both ambulatory and bedridden patients. BIA measurement techniques, used under standard conditions, have been studied for >10 years, and BIA results under standard conditions have been found to correlate well with MRI predictions [bib_ref] Estimation of skeletal muscle mass by bioelectrical impedance analysis, Janssen [/bib_ref]. Prediction equations have been validated for multiethnic adults [bib_ref] Estimation of skeletal muscle mass by bioelectrical impedance analysis, Janssen [/bib_ref] and reference values established for adult white men and women, including older subjects [bib_ref] Fat-free and fat mass percentiles in 5225 healthy subjects aged 15 to..., Kyle [/bib_ref] [bib_ref] Application of bioelectrical impedance analysis to elderly populations, Roubenoff [/bib_ref] [bib_ref] Single prediction equation for bioelectrical impedance analysis in adults aged 20-94 years, Kyle [/bib_ref]. Thus, BIA might be a good portable alternative to DXA.
> BIA may be considered as a portable alternative to DXA.
## Definition and diagnosis of sarcopenia
Total or partial body potassium per fat-free soft tissue. As skeletal muscle contains >50% of the total body potassium (TBK) pool, TBK is the classic method for estimation of skeletal muscle. More recently, partial body potassium (PBK) of the arm has been proposed as a simpler alternative [bib_ref] Measuring partial body potassium in the arm versus total body potassium, Wielopolski [/bib_ref]. PBK of the arm is safe and inexpensive.
> TBK is the classic method for the estimation of skeletal muscle, but this method is not used routinely.
Anthropometric measures. Calculations based on mid-upper arm circumference and skin fold thickness have been used to estimate muscle mass in ambulatory settings. Calf circumference correlates positively with muscle mass; calf circumference <31 cm has been associated with disability [bib_ref] calf circumference, and physical function of elderly women: a cross-sectional study, Rolland [/bib_ref]. However, age-related changes in fat deposits and loss of skin elasticity contribute to errors of estimation in older people. There are relatively few studies validating anthropometric measures in older and obese people; these and other confounders make anthropometric measures vulnerable to error and questionable for individual use [bib_ref] Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives, Rolland [/bib_ref].
> Anthropometric measures are vulnerable to error and not recommended for routine use in the diagnosis of sarcopenia.
# Muscle strength
There are fewer well-validated techniques to measure muscle strength. Although lower limbs are more relevant than upper limbs for gait and physical function, handgrip strength has been widely used and is well correlated with most relevant outcomes. Again, cost, availability and ease of use can determine whether the techniques are better suited to clinical practice or are useful for research [fig_ref] Table 4: Measurements of muscle mass, strength, and function in research and practice a [/fig_ref]. It must be remembered that factors unrelated to muscle, e.g. motivation or cognition, may hamper the correct assessment of muscle strength.
Handgrip strength. Isometric hand grip strength is strongly related with lower extremity muscle power, knee extension torque and calf cross-sectional muscle area [bib_ref] Age-associated changes in skeletal muscles and their effect on mobility: an operational..., Laurentani [/bib_ref]. Low handgrip strength is a clinical marker of poor mobility and a better predictor of clinical outcomes than low muscle mass [bib_ref] Age-associated changes in skeletal muscles and their effect on mobility: an operational..., Laurentani [/bib_ref]. In practice, there is also a linear relationship between baseline handgrip strength and incident disability for activities of daily living (ADL) [bib_ref] Hand grip strength and incident ADL disability in elderly Mexican Americans over..., Snih [/bib_ref]. Muscle strength measures of different body compartments are correlated, so when feasible, grip strength measured in standard conditions with a well-studied model of a handheld dynamometer with reference populations can be a reliable surrogate for more complicated measures of muscle strength in the lower arms or legs.
> Grip strength is a good simple measure of muscle strength, and it correlates with leg strength.
Knee flexion/extension. Strength is about the magnitude of force generation, whereas power is about work rate (work done per unit time). In healthy older people, power is lost faster than strength. Both are important, but power is a better predictor of certain functional activities [bib_ref] The relationship between leg power and physical performance in mobility-limited older people, Bean [/bib_ref] [bib_ref] Muscle power of the ankle flexors predicts functional performance in community-dwelling older..., Suzuki [/bib_ref] [bib_ref] Association of muscle power with functional status in community-dwelling elderly women, Foldvari [/bib_ref].
The ability of the muscle to generate force can be measured in several ways. Leg extensor power can be measured with a commercially available power rig [bib_ref] A new method for measuring power output in a single leg extension:..., Bassey [/bib_ref]. Strength can be measured isometrically or isokinetically, the latter being a closer reflection of muscle function in everyday activity. Isometric strength testing of maximal voluntary contractions can be measured with relatively simple custom-made equipment. It is usually measured as the force applied to the ankle, with the subject seated in an adjustable straight-back chair, the lower leg unsupported and the knee flexed to 90° [bib_ref] Human skeletal muscle function: description of tests and normal values, Edwards [/bib_ref]. Modern, commercial isokinetic dynamometers allow both isometric and isokinetic measurements of strength as concentric torque at various angular velocities [bib_ref] Test-retest reliability of the biodex isokinetic dynamometer, Feiring [/bib_ref] [bib_ref] Reproducibility of an isokinetic strength-testing protocol of the knee and ankle in..., Hartmann [/bib_ref]. Measurement is feasible in frail older people [bib_ref] Physical and performance measures for the identification of mild to moderate frailty, Brown [/bib_ref] [bib_ref] Assessment of lower extremity muscle power in functionally-limited elders, Callahan [/bib_ref]. Some data are available for older populations [bib_ref] Reference values for concentric knee isokinetic strength and power in nonathletic men..., Neder [/bib_ref] [bib_ref] Attenuation of skeletal muscle and strength in the elderly: The Health ABC..., Goodpaster [/bib_ref] [bib_ref] Strength and muscle quality in a well-functioning cohort of older adults: The..., Newman [/bib_ref] , but more are needed from a wider range of ages and ethnicities. These techniques are suitable for research studies, but their use in clinical practice is limited by the need for special equipment and training.
> Knee flexion techniques are suitable for research studies, but their use in clinical practice is limited by the need for special equipment and training.
Peak expiratory flow. In people without lung disorders, peak expiratory flow (PEF) is determined by the strength of respiratory muscles. PEF is a cheap, simple and widely accessible technique that has prognostic value [bib_ref] Relationship between respiratory muscle function and age, sex, and other factors, Chen [/bib_ref] [bib_ref] Effect of expiratory muscle strength training on elderly cough function, Kim [/bib_ref]. However, research on the use of PEF as a measure of sarcopenia is limited, so PEF cannot be recommended as an isolated measure of muscle strength at this time.
> PEF measures the strength of respiratory muscles, but it cannot be recommended as an isolated measure.
## Physical performance
A wide range of tests of physical performance are available, including the Short Physical Performance Battery (SPPB), usual gait speed, 6-min walk test and the stair climb power test [fig_ref] Table 4: Measurements of muscle mass, strength, and function in research and practice a [/fig_ref].
Short Physical Performance Battery. The SPPB evaluates balance, gait, strength and endurance by examining an individual's ability to stand with the feet together in side-by-side, semi-tandem and tandem positions, time to walk 8 ft and time to rise from a chair and return to the seated position five times [bib_ref] A short physical performance battery assessing lower extremity function: association with self-reported..., Guralnik [/bib_ref]. It is a composite of some separate tests that have also been used individually in sarcopenia research. It has been recently recommended by an international working group for use as a functional outcome measure in clinical trials in frail older persons. Meaningful changes in the SPPB have been defined [bib_ref] Meaningful change and responsiveness in common physical performance measures in older adults, Perera [/bib_ref] [bib_ref] What is a meaningful change in physical performance? Findings from a clinical..., Kwon [/bib_ref]. Thus, the SPPB can be used as a standard measure of physical performance both for research and in clinical practice.
> The SPPB, a composite measure of physical performance, is a standard measure both for research and clinical practice. relationship explained how small changes in physiological capacity may have substantial effects on performance in frail adults, while large changes in capacity have little or no effect in healthy adults [bib_ref] Evidence for a non-linear relationship between leg strength and gait speed, Buchner [/bib_ref]. Since then, a study by suggested that timed usual gait provides a predictive value for the onset of disability [bib_ref] Lower extremity function and subsequent disability: consistency across studies, predictive models, and..., Guralnik [/bib_ref]. Most recently, Cesari et al. confirmed the importance of gait speed (over a 6-m course) as a predictor of adverse health events (severe mobility limitation, mortality) but showed that poor performance on other tests of lower extremity function (standing balance and time to rise from a chair five times) had comparable prognostic value [bib_ref] Added value of physical performance measures in predicting adverse health-related events: results..., Cesari [/bib_ref]. Usual gait speed can be used in clinical and research settings.
> Gait speed is part of the SPPB, but it can also be used as a single parameter for clinical practice and research.
Timed get-up-and-go test. The timed get-up-and-go (TGUG) test measures the time needed to complete a series of functionally important tasks. TGUG requires the subject to stand up from a chair, walk a short distance, turn around, return and sit down again. It thus serves as an assessment of dynamic balance. Balance function is observed and scored on a five-point scale [bib_ref] Balance in elderly patients: the "get-up and go" test, Mathias [/bib_ref].
> The TGUG, used in geriatric assessment, can serve as a performance measurement.
Stair climb power test. The stair climb power test (SCPT) has been proposed as a clinically relevant measure of leg power impairment [bib_ref] Is stair climb power a clinically relevant measure of leg power impairments..., Bean [/bib_ref]. SCPT results are consistent with more complex techniques for measuring leg power (double leg press at 40 and 70% of the one-repetition maximum; DLP40, DLP70) and performance (SPPB with components of gait speed chair stand time and standing balance). The SCPT has been suggested for research settings [bib_ref] Is stair climb power a clinically relevant measure of leg power impairments..., Bean [/bib_ref].
> The SCPT may be useful in some research settings.
## Defining cut-off points
Cut-off points depend upon the measurement technique chosen and on the availability of reference studies. EWG-SOP recommends use of normative (healthy young adult) rather than other predictive reference populations, with cut-off points at two standard deviations below the mean reference value. More research is urgently needed in order to obtain good reference values for populations around the world. Various options to define sub-normal values for sarcopenia designation have been suggested. The following section provides some examples of how cut-off points have been derived and validated by correlation with other relevant clinical features.
Baumgartner et al. summed the muscle mass of the four limbs from a DXA scan as appendicular skeletal muscle mass (ASM) and defined a skeletal muscle mass index (SMI) as ASM/height 2 (kg/m 2 ) [bib_ref] Epidemiology of sarcopenia among the elderly in New Mexico, Baumgartner [/bib_ref]. A SMI two standard deviations below the mean SMI of young male and female reference groups was defined as the gender-specific cut point for sarcopenia. Defined in this way, sarcopenia was significantly associated with physical disability and was inde-pendent of ethnicity, age, comorbidity, health behaviours and fat mass [bib_ref] Epidemiology of sarcopenia among the elderly in New Mexico, Baumgartner [/bib_ref]. This method depends upon a measurement of appendicular skeletal muscle mass by DXA or estimation by BIA [bib_ref] Skeletal muscle cutpoints associated with elevated physical disability risk in older men..., Janssen [/bib_ref] [bib_ref] Epidemiology of sarcopenia among the elderly in New Mexico, Baumgartner [/bib_ref].
In a cross-sectional survey of people aged ≥18 years in the USA (n = 14,818 adults >18 years, including n = 4,504 adults >60 years), Janssen et al. [bib_ref] Low relative skeletal muscle mass (sarcopenia) in older persons is associated with..., Janssen [/bib_ref] also used standard deviations to define sarcopenia, measured in terms of skeletal muscle index (SMI), where SMI = (skeletal muscle mass/ body mass) × 100. Subjects were considered to have a normal SMI if their SMI was higher than one standard deviation below the gender-specific mean for young adults (aged 18-39 years). Class I sarcopenia was considered present in subjects whose SMI was within one to two standard deviations below mean values for young adults, and Class II sarcopenia was present in subjects whose SMI was below two standard deviations of young adult values. With these definitions, sarcopenia was found to be a relatively common occurrence in American men and women >60 years; the likelihood of functional impairment and disability was two times greater in older men and three times greater in older women with Class II sarcopenia compared to older people who had a normal SMI.
Newman et al. [bib_ref] Sarcopenia: alternative definitions and association with lower extremity function, Newman [/bib_ref] performed an observational cohort study of older people living in the USA (ages 70-79 years, n = 2,984, 52% women, 41% black). Participants were assessed using DXA and were classified as sarcopenic using two different approaches to adjust lean mass to body size: appendicular lean mass divided by height squared (aLM/ht 2 ) and appendicular lean mass adjusted for height and body fat mass (residuals). Because population norms for young adult blacks and whites are not currently available, the genderspecific 20th percentile was arbitrarily chosen as the cutoff point for each method. In men, both classifications of sarcopenia were associated with smoking, poorer health, lower activity and impaired lower extremity function. In women, the classification based on both height and fat mass was more strongly associated with impaired lower extremity function, while other associations were fewer. As a result of these findings, the authors suggested that fat mass should be considered in estimating prevalence of sarcopenia in women and in overweight or obese individuals [bib_ref] Sarcopenia: alternative definitions and association with lower extremity function, Newman [/bib_ref].
Norman et al. conducted a study that investigated the association between BIA and muscle function [bib_ref] Bioimpedance vector analysis as a measure of muscle function, Norman [/bib_ref]. The study investigated the association between resistance and reactance normalised for height (R/H and Xc/H) and hand grip strength, an assessment of muscle function. The study included 363 men and women with a mean age of 63.1 years. Patients were grouped in quintiles by hand grip strength. Results showed that BIA resistance and reactance normalised for height were both associated with hand grip strength independent of other predictors of hand grip strength, such as age and gender. Xc/H was positively correlated with increases in hand grip strength, while R/H was negatively correlated with strength; significant differences in hand grip strength by quintile were associated with vector migration in the RXc graph. The re-Definition and diagnosis of sarcopenia searchers concluded that BIA was a clinically relevant measure muscle function, which would be particularly useful for patients unable or unwilling to perform grip strength tests. [fig_ref] Table 5: Diagnosis of sarcopenia [/fig_ref] shows some cut-off points available from the sarcopenia literature, based on normative populations when available or on predictive populations when normative population data were unavailable.
## Sarcopenia screening and assessment
Identifying subjects with sarcopenia, both for clinical practice and for selection of individuals for clinical trials, seems to be an important task. The EWGSOP has developed a suggested algorithm based on gait speed measurement as the easiest and most reliable way to begin sarcopenia case finding or screening in practice [fig_ref] Figure 2: EWGSOP-suggested algorithm for sarcopenia case finding in older individuals [/fig_ref]. A cut-off point of >0.8 m/s identifies risk for sarcopenia [bib_ref] Gait speed as a marker of adverse outcomes, Abellan Van Kan [/bib_ref].
## Treatment outcomes for research
While reduced mobility and functionality are increasingly prevalent in older people, only a handful of clinical trials are under way to test potential sarcopenia treatments. The absence of standardised primary outcomes is a major challenge for the design of such studies. For intervention trials, EWGSOP presently recommends three primary outcome variables-muscle mass, muscle strength and physical per- formance [fig_ref] Table 6: Suggested primary and secondary outcome domains for intervention trials in sarcopenia Primary... [/fig_ref]. Other outcomes can be considered secondary and of particular interest in specific research areas and intervention trials. For each of these outcomes, one or more variables can be measured. Selection of measurement tools for research studies will depend on availability, access to data for relevant reference populations (considering age, gender and ethnicity), type of study (longitudinal vs cross-sectional), aim of the study and cost.
## Challenges of managing sarcopenia
Depending on the literature definition used for sarcopenia, the prevalence in 60-70-year-olds is reported as 5-13%, while the prevalence ranges from 11 to 50% in people >80 years [bib_ref] Sarcopenia: diagnosis and treatment, Morley [/bib_ref]. The number of people around the world aged ≥60 years was estimated at 600 million in the year 2000, a figure that is expected to rise to 1.2 billion by 2025 and 2 billion by 2050. Even with a conservative estimate of prevalence, sarcopenia affects >50 million people today and will affect >200 million in the next 40 years.
The impact of sarcopenia on older people is far reaching; its substantial tolls are measured in terms of morbidity [bib_ref] Type 2 diabetes, muscle strength, and impaired physical function: the tip of..., Sayer [/bib_ref] , disability [bib_ref] Low relative skeletal muscle mass (sarcopenia) in older persons is associated with..., Janssen [/bib_ref] , high costs of health care [bib_ref] The healthcare costs of sarcopenia in the United States, Janssen [/bib_ref] and mortality [bib_ref] Grip strength, body composition, and mortality, Gale [/bib_ref]. Because the consequences of sarcopenia in older people are serious and life-changing, health care professionals everywhere are challenged to work together to turn our growing body of knowledge into actions that will improve the health and wellbeing of millions of older people around the world.
Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment. To this end, the ESWGOP committee members and their allied organisations encourage health care professionals to seek answers to the following questions:
- What is the role of nutrition in prevention and treatment of age-related sarcopenia? What amounts of macronutrients are needed for older people with or at risk for sarcopenia, especially protein and specific amino acids? What micronutrients, e.g. vitamin D, play important roles in protecting and building lean body mass? And does the timing for intake of meals and/or dietary supplements make a difference? - What is the role of physical activity in prevention and treatment of sarcopenia in older people? What exercises
# Summary and conclusions
Several European organisations working in nutrition and geriatric medicine created a joint European Working Group on Sarcopenia in Older People (EWGSOP). This final EWGSOP paper offers a working definition of sarcopenia, summarises what is currently known about underlying mechanisms and reviews techniques for measuring variables of sarcopenia. This paper also offers guidelines for use of these tools as a way to identify sarcopenia and evaluate treatment effectiveness, and offers advice about which tools are best suited for clinical practice and for research studies. Further, examples of currently used cut-off points for the diagnosis of sarcopenia are offered. Based on increased awareness of sarcopenia in older people and widespread use of tools for screening and assessment, the ultimate goal is to identify dietary strategies, lifestyle changes and treatments that can prevent or delay the onset of sarcopenia.
## Key points
- Age-related sarcopenia is common and has huge personal and financial costs. - This paper presents a clinical definition and consensus diagnostic criteria for sarcopenia, as developed by the European Working Group on Sarcopenia in Older People (EWGSOP) and endorsed by four participating professional medical societies. A.J. Cruz-Jentoft et al.
- The overall goal was to compile a set of tools that would promote recognition and treatment of age-related sarcopenia in practice and also encourage conduct of well-designed research studies of its causes and consequences.
[fig] Figure 1: Mechanisms of sarcopenia. [/fig]
[fig] Figure 2: EWGSOP-suggested algorithm for sarcopenia case finding in older individuals. [/fig]
[table] Table 1: Criteria for the diagnosis of sarcopenia Diagnosis is based on documentation of criterion 1 plus (criterion 2 or criterion 3) ............................................................ no evident cause can be isolated. Thus, the categories of primary sarcopenia and secondary sarcopenia may be useful in clinical practice. Sarcopenia can be considered 'primary' (or age-related) when no other cause is evident but ageing itself, while sarcopenia can be considered 'secondary' when one or more other causes are evident [/table]
[table] Table 2: Sarcopenia categories by cause [/table]
[table] Table 3: EWGSOP conceptual stages of sarcopenia ............................................................ [/table]
[table] Table 4: Measurements of muscle mass, strength, and function in research and practice a ............................................................ Timed get-up-and-go test Stair climb power test a Please refer to the text for a description and references on these measurement techniques. [/table]
[table] Table 5: Diagnosis of sarcopenia: measurable variables and cut-off points ............................................................................................................................. [/table]
[table] Table 6: Suggested primary and secondary outcome domains for intervention trials in sarcopenia Primary outcome domains • Physical performance • Muscle strength • Muscle mass Secondary outcome domains • Activities of daily living (ADL; basic, instrumental) • Quality of life (QOL) • Metabolic and biochemical markers • Markers of inflammation • Global impression of change by subject or physician • Falls • Admission to nursing home or hospital • Social support • Mortality * Comorbidity and individual circumstances that may explain each finding must be considered + This algorithm can also be applied to younger individuals at risk [/table]
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https://academic.oup.com/ageing/article-pdf/39/4/412/49273228/ageing_39_4_412.pdf
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The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics—European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document. The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity? For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as ‘presarcopenia’, ‘sarcopenia’ and ‘severe sarcopenia’. EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research. Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.
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2015 Guidelines for Osteoporosis in Saudi Arabia: Recommendations from the Saudi Osteoporosis Society
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2015 Guidelines for Osteoporosis in Saudi Arabia: Recommendations from the Saudi Osteoporosis Society
# Background and objectives:
To provide guidelines for medical professionals in Saudi Arabia regarding osteoporosis. design and settings: A panel of 14 local experts in osteoporosis assembled to provide consensus based on the strength of evidence and expert opinions on osteoporosis treatment. Patients and Methods: The Saudi Osteoporosis Society (SOS) formed a panel of experts who performed an extensive published studies search to formulate recommendations regarding prevention, diagnosis, and treatment of osteoporosis in Saudi Arabia. Both local and international published studies were utilized whenever available. results: Dual x-ray absorptiometry (DXA) scanning is still the golden standard for assessing bone mineral density (BMD). In the absence of local, country-specific fracture risk assessment tool (FRAX), the SOS recommends using the USA (White) version of the FRAX tool. All women above 60 years of age should be evaluated for BMD. This is because the panel recognized that osteoporosis and osteoporotic fractures occur at a younger age in Saudi Arabia. Hormone replacement therapy (HRT) is not recommended for treating postmenopausal women with osteoporosis. BMD evaluation should be performed 1-2 years after initiating intervention, and the assessment of bone turnover biomarkers should be performed whenever available to determine the efficacy of intervention. conclusion: All Saudi women above the age of 60 years must undergo a BMD assessment using DXA. Therapy decisions should be formulated with the use of the USA (White) version of the FRAX tool.
T he National Institute of Health in the United States Consensus Development Conference has redefined osteoporosis as a skeletal disorder characterized by compromised bone strength that increases the risk of fracture.Bone strength primarily reflects the integration of bone density and bone quality. An osteoporotic fracture occurs when a traumatic force is applied on an osteoporotic bone. Thus, osteoporosis is a significant risk factor for fractures. Osteoporosis, once thought to be a natural part of aging among women, is no longer considered age or gender dependent. It is largely preventable due to the remarkable progress in the scientific understanding of its causes, diagnosis, and treatment. [bib_ref] Ho pr, o'Malley Cd. declining rates of osteoporosis management following fragility fractures..., Balasubramanian [/bib_ref] Optimization of bone health is a process that must be met regardless of age and gender. Factors that influence positive bone health are essential to prevent osteoporosis and its devastating complications. Osteoporosis is widely recognized as a major public health concern. Because individual clinicians cannot systemically collect all the evidence bearing on osteoporosis, they require summaries of the current international guidelines as recommended by the International Osteoporosis Foundation (IOF). Nation-specific guidelines are requested to take into consideration the specificities of each and every health care environment. These guidelines are unfortunately unavailable in Saudi Arabia where genetic background, customs, diet, and geographical location have been identified as predisposing factors for osteoporosis not found in other ethnic groups. [bib_ref] Fuleihan gel-H. geographic and ethnic disparities in osteoporotic fractures, Cauley [/bib_ref] To fill this gap, the current document was provided to help guide physicians on the proper approach to patients with osteoporosis.
# Patients and methods
The development of the present recommendations was done following Best Practice Guidelines by an expert panel consisting of members from the Saudi Osteoporosis Society (SOS). Panel members included various medical disciplines such as, endocrinology, rheumatology, gynecology, orthopedic surgery, family implications Osteoporosis is a major threat to human health. Among the industrialized nations in North America, Europe, Japan, and Australia, osteoporosis at the hip/spine affects 49 million adults ranging from 9%-38% in women and 1%-8% in men. [bib_ref] estimating prevalence of osteoporosis: examples from industrialized countries, Wade [/bib_ref] Fortunately, though mortality is highest during the year of fracture, the rates of incident osteoporotic fractures appear to be stabilizing globally. [bib_ref] Fracture mortality: associations with epidemiology and osteoporosis treatment, Se [/bib_ref] Estimated direct costs for the treatment of osteoporotic fractures in the US amount to $17 billion in 2005 and is expected to increase by as much as 50% in 2025. [bib_ref] King A, tosteson A. incidence and economic burden of osteoporosis-related fractures in..., Burge R, Dawson-Hughes B [/bib_ref] In Europe, the economic burden of incident and prior fragility fractures was €37 billion in 2010. [bib_ref] osteoporosis in the european union: a compendium of country-specific reports, Svedboum [/bib_ref] The only study that estimated the cost of hip fracture in Saudi Arabia was published in 2007 from the eastern province. [bib_ref] Khan bA. bone mineral density of spine and femur in healthy Saudi..., Bubshait D [/bib_ref] iii At least one well-designed, non-experimental descriptive study (e.g., comparative studies, correlation studies, case studies) b iV expert committee reports, opinions, and/or experience of respected authorities C common in the country than its Western counterparts. 11-14 Worthy to note is that vitamin D deficiency is extremely common among Saudis overall, more in females as well as in children and adolescents. [bib_ref] increased vitamin d supplementation recommended during summer season in the gulf region:..., Al-Daghri Nm [/bib_ref] [bib_ref] Vitamin d deficiency and calcium intake in reference to increased body mass..., Al-Musharaf [/bib_ref] [bib_ref] 25-Hydroxyvitamin d levels among healthy Saudi Arabian Women, Ha [/bib_ref] This was attributed to the dressing customs and avoidance of sun exposure. This fact might have confounded studies on osteoporosis in Saudi Arabia. The largest osteoporosis-related local study was performed in Jeddah in the western part of Saudi Arabia where the reference values of BMD were determined in 1980 randomly selected healthy Saudis of both sexes and compared with US/Northern European and other reference data. [bib_ref] Al-raddadi rM. bone mineral density of the spine and femur in healthy..., Ardawi [/bib_ref] Age-related changes in BMD were similar to those described in US/Northern European and Lebanese reference data. Based on the BMD of total femur, the overall prevalence of osteoporosis using the manufacturer' s versus Saudi reference data was 6.3%-7.8% versus 1.2%-4.7% (P<.001), respectively. Saudis (≥50 years) in the lowest quartile of body weight exhibited the higher prevalence of osteoporosis (25.6% in females and 15.5% in males) as compared to that of the highest quartiles (0.0% in females and 0.8% in males). The manufacturer' s reference data overestimated the prevalence of osteoporosis among Saudi females and underestimated the prevalence in Saudi males. Consequently, at a national level, 3 separate studies from different regions were done to determine the prevalence of male osteoporosis and osteopenia (either spine or femur) and revealed a prevalence of 37.8% and 54.1%, respectively, in Jeddah; [bib_ref] Al-raddadi rM. bone mineral density of the spine and femur in healthy..., Ardawi [/bib_ref] [bib_ref] prevention of bone loss with alendronate in postmenopausal women under 60 years..., Hosking D [/bib_ref].4% and 33.9%, respectively, in Al Khobar, 19 and 21.4% and 35.7%, respectively, in Riyadh. [bib_ref] Al elq A. osteoporosis among male Saudi Arabs: a pilot study, Sadat-Ali [/bib_ref] The studies highlighted the importance of using population-specific reference values for BMD measurements to avoid overdiagnosis and/or underdiagnosis of osteoporosis. 18
## Steroid-induced osteoporosis
Steroids adversely affect bones at multiple levels. [bib_ref] the role of dietary protein and vitamin d in maintaining musculoskeletal health..., Seibel [/bib_ref] These drugs directly suppress the function of osteoblasts. Prolonged steroid therapy leads to increased unfilled resorption cavities, reduced osteoid, thinned trabeculae, and decreased production of new bone during each remodeling cycle. They also prevent calcium absorption from the gut and increase urinary calcium excretion resulting in negative calcium balance. All patients planned for prolonged steroid use should be fully evaluated for the risk of osteoporosis and should receive calcium and vitamin D supplements. These agents have been recommended for better musculoskeletal health and may reduce the risk of fractures in patients using long-term steroids. 22,23 Studies using the bisphosphonates have clearly shown the great efficacy of these agents in reducing the risk of steroid-induced osteoporosis and fractures. [bib_ref] teriparatide or alendronate in glucocorticoid-induced osteoporosis. new engl, Saag [/bib_ref] diagnosis and approach to patients The World Health Organization (WHO) operationally defines osteoporosis as bone density 2.5 standard deviations (SD) below the mean for young white adult women. This diagnostic criterion, however, does not apply to premenopausal women and children. The follow-up BMD should not be done before (on average) 1-and-a-half to 2 years after starting any intervention and whenever there is a need for follow-up. [bib_ref] Fuerst t, He YQ, tsuda-Futami e, et al. Comparison of six calcaneal..., Ito [/bib_ref] Newer measures of bone strength, such as ultrasound, have been introduced. Recent prospective studies using quantitative ultrasound (QUS) scanners perform nearly as well as DXA for assessing bone health. 26 These techniques, however, cannot be used for diagnosing or following up patients with osteoporosis. Information regarding the efficacy in young premenopausal or early menopausal women is lacking. Clinical trials of pharmacologic therapies have utilized DXA, rather than QUS, for entry criterion in studies, and there is uncertainty whether the results of these trials can be generalized to patients identified by QUS to have a high risk of fracture. Accordingly, DXA scanning is still the gold standard for assessing risk. Results from the various ultrasound devices (at least 6 commercial devices) are available and are not interchangeable. The launch of WHO technical report: Assessment of osteoporosis at the primary health care level and the related FRAX tool has been a major milestone toward helping health professionals worldwide to improve the identification of patients at high risk of fracture for treatment. 28-32 However, the FRAX assessment does not tell one absolutely whom to treat, which remains a matter of clinical judgment. In many countries, guidelines are provided that are based on the expert opinion and/or on health economic grounds. In the absence of the lo-cal data, the committee suggests continuing to use the index on a trial basis using the reliable data from the USA (White) version of the FRAX tool in the index until the local data becomes available. The FRAX tool can be reached through the web page: http://www.shef. ac.uk/FRAX
## Recommendations:
In the absence of a local, country-specific FRAX tool for Saudi Arabia, the committee recommends using the USA (White) version of the FRAX tool . This is because the National Health and Nutrition Examination Survey (NAHNES) III data are very accurate and reliable, and studies have shown the USA (White) bone mineral content to be close to the Saudi figures. The committee recognizes that hip fractures data are different between the 2 populations, and these are the basis for establishing FRAX data for any country and not the bone mineral content. Yet, this approach seems to be the best option until local figures are available.
## Who should be evaluated?
Until good evidence becomes available to support the cost-effectiveness of routine screening, or the efficacy of early initiation of preventive drugs, an individualized approach is recommended. A bone density measurement should be considered based on certain criteria (see below). The FRAX tool mentioned above uses a combination of risk factor evaluation and bone density measurement to predict the fracture risk and help with treatment decisions. Until assessment by randomized clinical trials is conducted, individual decisions regarding screening could be informed by the preliminary evidence that the risk for fracture increases with age, and with an increased number of additional risk factors.
The guidelines committee endorses the American Association of Clinical Endocrinologist 33 recommendations that state BMD should be measured in the following settings:
· All women ≥40 years who have sustained lowtrauma fragility fracture · All women >60 years of age in Saudi Arabia (expert opinion). This is because the panel recognizes that osteoporosis and osteoporotic fractures occur at a younger age in Saudi Arabia; hence, early diagnosis is important · Previous fragility fracture or maternal history of hip fracture · Premature menopause (age <45) · Prolonged secondary amenorrhea (>1 year) · For risk assessment in peri-menopausal and/or postmenopausal women who have risk factors for fractures and are willing to consider available interventions · Patients who had x-ray findings suggestive of osteoporosis such as fragility fracture, loss of height, or thoracic kyphosis · Patients who are beginning to receive a long-term glucocorticoid therapy or other drugs associated with bone loss · Adults with primary hyperparathyroidism or other diseases or nutritional conditions associated with bone loss in whom the evidence of bone loss would result in adjustment of management · For establishing skeletal stability and monitoring therapeutic response in patients receiving treatment of osteoporosis (baseline testing should be made before intervention)
What are the available effective medical treatments?
In the past 30 years, major strides have been made in the treatment of osteoporosis. Evidence-based reports systematically reviewing the data from randomized clinical trials, including meta-analyses for each of the major treatments, are available and permit conclusions regarding the role of each modality of osteoporosis therapy. [fig_ref] Table 2: pharmacological aspects of various agents for osteoporosis [/fig_ref] shows the different pharmacologic agents (and their characters) for osteoporosis available in Saudi Arabia.
## The bisphosphonates
The potent bisphosphonates alendronate and risedronate are one of the first-line agents to treat postmenopausal osteoporosis. Randomized placebo-controlled trials (RCTs) of alendronate and risedronate analyzed by a systematic review and meta-analysis have revealed that all of these bisphosphonates increase BMD at the spine and hip in early as well as in late postmenopausal women in a dose-dependent manner. 34-36 Alendronate and risedronate reduce the risk of subsequent non-vertebral fractures in women with osteoporosis and adults with glucocorticoid-induced osteoporosis. The data with alendronate in particular is overwhelming. [bib_ref] prevention of bone loss with alendronate in postmenopausal women under 60 years..., Hosking D [/bib_ref] [bib_ref] Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double blind,..., Mr [/bib_ref] [bib_ref] effect of alendronate on risk of fracture in women with low bone..., Sr [/bib_ref] [bib_ref] Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density..., Pols [/bib_ref] In Saudi Arabia, the 70 mg formulation of alendronate is available. It has been found to have the same degree of improvement in BMD, and the suppression of markers of bone turnover in the urine as the 10 mg daily dose, with much less side effects on the gastrointestinal tract. 41,42 As expected, compliance and patients' preference are much more with the 70 mg once-a-week dose. [bib_ref] Verbruggen n. patients with osteoporosis prefer once weekly to once daily dosing..., Kendler D [/bib_ref] intravenous Bisphosphonates Intravenous (IV) bisphosphonates may play a major role in treating osteoporosis in the future. Uncontrolled studies have reported that on average, spine BMD increased by 9% and femoral neck increased by 3% over a year with pamidronate at a dose of 30 mg every 3 months. [bib_ref] treatment of osteoporosis with intravenous pamidronate: a retrospective analysis, Calderari [/bib_ref] When given in a dose of 90 mg every 6 months, IV pamidronate increased spine and femoral neck BMD by 14% and 10%, respectively, over a 4-year period, and these changes were greater than occurred with once daily oral alendronate. [bib_ref] intravenous pamidronate therapy: highly effective treatment for postmenopausal osteoporosis, Wimalawansa [/bib_ref] IV zoledronate increased BMD in women with postmenopausal osteoporosis. After 1 year of treatment in a variety of regimens (0.25 mg q3 months, 0.5 mg q3 months, 1 mg q3 months, 2 g q 6 months, or 5 mg once yearly), spine and femoral neck BMDs were 5% and 3% higher, respectively, in women who received zoledronate compared to placebo. The HORIZON study (a landmark study) showed that infusing zoledronic acid at a dose of 5 mg once yearly during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. However, this drug was associated with a slightly significant risk of serious atrial fibrillation and renal impairment in atrisk patients than placebo. 47
## Some important adverse effects of antiresorptives
In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving anti-resorptives including bisphosphonates and denosumab (see below) were published. These cases occurred in patients with cancer receiving high-dose IV bisphosphonate. [bib_ref] Melakopoulos i, bozas g, et al. osteonecrosis of the jaw in cancer..., Bamias [/bib_ref] Subtrochanteric and diaphyseal femur fractures have also been associated with long-term bisphosphonate use and could be a consequence of excessive suppression of bone turnover or subsequent use of steroids or proton pump inhibitors with bisphosphonates. [bib_ref] 50. gedmintas l, Solomon dH, Kim SC. bisphosphonates and risk of subtrochanteric,..., Abrahamsen B, Eiken P [/bib_ref] Despite the accumulating evidence of risk, data gathered both from the European Society on Economic and Clinical Aspects of Osteoporosis and Osteoarthritis and the IOF 2012 statement indicated that bisphosphonates have established fracture efficacy up to 3 years, and alendronate and risedronate up to 4-5 years. [bib_ref] Knickerbocker rK, nickelsen t, genant HK, et al. reduction of vertebral fracture..., Cooper [/bib_ref] Therapy should be withheld after maximum of 5 years except in very high-risk patients. BMD should be repeated 1-and-a-half to 2 years after withdrawal. Therapy with another agent should be instituted if there is significant deterioration or in case an osteoporotic fracture occurred at any time.
## Recommendations:
(Please refer to for Guideline Strength).
In postmenopausal women with osteoporosis:
a. Alendronate, residronate, and zoledronate are ef-
## Selective estrogen receptor modulators
Selective estrogen receptor modulators (SERMs) are non-hormonal agents that bind to estrogen receptors with an affinity equivalent to that of estradiol, but they have estrogen agonist effects in some tissues and antagonist effects in others. The structure of any ligand is an important factor in determining the conformational changes that occur in the estrogen receptor when the ligand binds to it. Each ligand seems to produce a different final shape in the estrogen receptor, and this shape determines interactions with protein cofactors and DNA response elements that ultimately translate into tissue-specific estrogen agonist or antagonist effects. Raloxifene is the only SERM that is available in Saudi Arabia and has been approved for the treatment of osteoporosis. [bib_ref] pd, ensrud K. the effects of raloxifene on incident vertebral fractures in..., Khan [/bib_ref] It is taken as a single tablet (60 mg/d) without regard to meals, calcium, and vitamin D supplements or time of the day. It has no estrogen-agonistic effects in the breast and uterus. RCTs on the effects of raloxifene have shown increases in bone density, but less than those reported with bisphosphonates or estrogen.
Skeletal effects: Data from the Multiple Outcomes of Raloxifene Evaluation (MORE) suggest a sustained vertebral anti-fracture efficacy. The drug is also associated with a 60%-70% reduction in the risk of breast cancer especially those with positive estrogen receptors. [bib_ref] raloxifene and Cardivascular events in osteoporotic postmenopausal women: four years results from..., Cauley [/bib_ref] It also decreases low-density lipoprotein cholesterol and total cholesterol; high-density lipoprotein cholesterol decreases and triglycerides increases. The post hoc analysis of secondary endpoints from MORE found no overall change in cardiovascular or cerebrovascular risk but a potential benefit in women at an increased baseline cardiovascular risk. These risks were not primary outcomes and, therefore, the results were looked at in other trials wherein the researchers found that among 10 101 postmenopausal women who were followed for median of 5.6 years, raloxifene reduced the risk of invasive breast cancer and clinical vertebral fracture but increased the risk of fatal stroke and venous thromboembolism. There was no alteration in risk for coronary events. 59
## Recommendations:
a. Raloxifene increases BMD at the spine and hip; however, it is efficacious in preventing only vertebral fractures in postmenopausal women with osteoporosis. [Evidence Ia] b. In postmenopausal women with osteoporosis, raloxifene decreases the incidence of estrogenreceptor-positive invasive breast cancer; however, it is not recommended for preventing or treating breast cancer. [Evidence Ib] c. Raloxifene has no beneficial effect on vasomotor symptoms and may increase their incidence.
[Evidence Ib] d. In the majority of patients with osteoporosis, raloxifene should be used as a second-line therapy, especially, in younger patients who are not at high risk for hip fractures.
[formula] [Evidence Ib] calcitonin [/formula]
Calcitonin is a naturally occurring peptide hormone. Only 1 study-Prevent Recurrence of Osteoporotic Fractures study-had a sample size that was enough to detect significance and was designed to detect a change in fracture rates. [bib_ref] Christiansen C. effect of salcatonin given intranasally on bone mass and fracture..., Overgaard [/bib_ref] In this investigation, a daily dose of 200 IU of nasal salmon calcitonin significantly reduced vertebral fractures by 33%-36%. Although this study was a prospective RCT, its results were classified as Level 2 evidence because of concerns about the absence of a dose response (no significant fracture reduction with the daily dose of 400 IU) and a high drop-out rate. Note: As of March 5, 2013, the US Food and Drug Administration (FDA) panel has ordered to STOP marketing Salmon Calcitonin after the evidence of increased malignancy among patients treated for osteoporosis (http://www.medscape.com/viewarticle/780323). 61
## Recommendations:
Nasal and subcutaneous calcitonin should not be used to treat osteoporosis.
## Recombinant human parathyroid hormone (hpth)
Although continuous exposure to parathyroid hormone (PTH) decreases bone mass, its intermittent administration leads to the opposite effect and improves bone density through increasing bone formation. Thus, it is the only bone-forming agent that is approved for the treatment of osteoporosis. Recombinant human parathyroid hormone (hPTH) or teriparatide (trade name: Forteo) was reported as a clinical treatment for osteoporosis in 1980; however, animal studies were conducted back in early 1930s. The use of large amounts of this agent for prolonged duration was found to result in osteosarcoma in rat studies. The synthetic N-terminal fragment (1-34) has been used almost exclusively in clinical trials. It also showed efficacy in the treatment of steroid-induced osteoporosis and osteoporosis in men. 62,63 The pivotal randomized controlled trial of teriparatide evaluated its efficacy in reducing vertebral and non-vertebral fractures in 1637 postmenopausal women with at least 1 vertebral fracture at enrolment. Compared with placebo treatment, teriparatide resulted in dose-dependent increases in BMD at both the lumbar spine (10%-14%) and total hip (3%-4%) after a median of 21 months. This has been confirmed in other smaller studies. [bib_ref] A randomized controlled trial to compare the efficacy of cyclical parathyroid hormone..., Ab [/bib_ref] strontium ranelate This is a divalent cation that can substitute for calcium in hydroxyapatite crystals of bone. It has a particular profile characterized by an inhibition of bone resorption and stimulation of formation. In a randomized controlled trial, SOTI (Spinal Osteoporosis Therapeutic Intervention) (N=1649, mean age 69 years) reported after 3 years that strontium ranelate at 2 g/d increases BMD and reduces the vertebral fracture risk in postmenopausal osteoporotic women. [bib_ref] the effects of strontium ranelate on the risk of vertebral fracture in..., Meunier Pj [/bib_ref] The other landmark study for this agent, the TROPOS (Treatment of Peripheral Osteoporosis), included 5091 postmenopausal women with osteoporosis. [bib_ref] Strontium ranelate: an anti-osteoporotic treatment demonstrated vertebral and non-vertebral anti-fracture efficacy over..., Reginster [/bib_ref] It showed that the drug reduced (in the entire sample) the relative risk for all non-vertebral fractures by 16% (P=.04) and by 19% for major fragility fractures at these sites (P-.031). Only in a certain subgroup of the study population did the drug remarkably reduce the risk for hip fractures. These were women at very high risk for hip fractures (age ≥74 years and femoral neck BMD T score ≤ -3 corresponding to -2.4 according to NHANES reference) (n=1977). Strontium has recently received European approval for the treatment of osteoporosis in men at an increased risk of fracture (previously approved only for postmenopausal women). The decision was based on a recent RCT conducted among 243 male patients followed up for 2 years, which showed improved bone density compared to the placebo group. [bib_ref] efficacy and safety of strontium ranelate in the treatment of osteoporosis in..., Kaufman [/bib_ref] [bib_ref] efficacy and safety of strontium ranelate in the treatment of osteoporosis in..., Kaufman [/bib_ref] Note: In June 2014, the SFDA decided to stop the registration of strontium ranelate in Saudi Arabia based on its high cardiovascular risks. This decision came after a subcommittee in the European Medication Agency concluded increased cardiovascular risks with the use of Strontium for Osteoporosis. The drug is still available in the European Union.
The European Medicines Agency (EMA) restricted the use of strontium to patients who cannot be treated with other medicines approved for osteoporosis.72 (http://www.ema.europa.eu/ema/index.jsp?curl=pages/ medicines/human/referrals/Protelos_and_Osseor/hu-man_referral_prac).
## Recommendations:
Strontium ranelate should no longer be used to treat osteoporosis in Saudi Arabia.
anti-cytokines: the rank-rankl system The receptor activator on nuclear factor kB ligand (RANKL) has been identified as an essential cytokine for forming and activating osteoblasts. [bib_ref] osteoprotegerin (opg) ligand is a cytokine that regulates osteoclast differentiation and activation, Lacey [/bib_ref] RANK, a member of the tumor necrosis factor super family, is expressed by osteoblasts with their immature precursors necessary and sufficient for osteoclastogenesis. RANKL activates its receptor, RANK, which is expressed on osteoclasts and their precursors, promoting osteoclast formation and activation, and prolonging osteoclast survival by suppressing apoptosis. [bib_ref] tumour necrosis factor receptor family member rAnK mediates osteoclast differentiation and activation..., Hsu [/bib_ref] RANKL is expressed on bone-forming osteoblasts, which indicates that bone resorption and bone formations are coupled through RANKL. In vitro and in vivo studies suggest that RANKL expression can be blocked by synthetic osteoprotegerin fusion proteins, soluble RANK fusion protein, or RANKL antibodies. [bib_ref] osteoprotegerin blocks bone cancer induced skeletal destruction, skeletal pain and pain-related neurochemical..., Honore P [/bib_ref] [bib_ref] osteopprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevenst vascular calcification by..., Min [/bib_ref] denosumab This is a fully human monoclonal antibody against the RANK ligand and inhibits osteoclast-mediated bone resorption in the way mentioned above. It is an extremely potent anti-resorptive drug. The landmark study for denosumab is the FREEDOM trial (Fracture Reduction Evaluation of Denosumab) in osteoporosis every 6 months. [bib_ref] Kendler dl, et al. A randomized, placebo-controlled study of the effects of..., Simonet [/bib_ref] The study included 7868 women who received subcutaneous denosumab every 6 months and demonstrated reduction in the risk of vertebral, non-vertebral, and hip fractures versus placebo. As of September 2012, denosumab (Prolia) distributed by AMGEN has been approved by US FDA as a treatment for bone loss in men with osteoporosis at high risk for fracture, secondary to the findings of Orwoll and colleagues that 1-year denosumab therapy among men was well tolerated and resulted in a reduction in bone resorption with subsequent increase in BMD in all assessed skeletal sites. 78 summary statements (see also
## Selection of therapy
The selection of any of these agents used for osteo-porosis should be individualized based on the patient characteristics, efficacy, and health economics. There is no agent that is suitable for all patients, and clinical judgment should always be exercised. Referral for expert opinion is warranted in difficult or complicated patients, patients who continue to fracture despite being on therapy, patients who develop an adverse effect to a certain medication and in any time at the physician discretion.
## Fall prevention and hip protectors
Non-pharmacologic interventions directed at preventing falls and reducing their effect on fractures have been promising. These include studies to improve strength and balance in the elderly, as well as using hip protectors to absorb or deflect the impact of a fall. Deprez et al emphasized the importance of falls as a risk factor for non-vertebral and mainly hip fractures. The study concludes that falls occur at least once a year in 30% of individuals older than 65 years and in 50% of those older than 80 years of age with a 5%-6% fracture incidence. They considered environmental risk factors (inappropriate clothing, obstacles at home, slippery shower, the use of psychotropic agents with long halflife, etc.) or patient-related factors (lower limb weakness, neurological disturbances, etc.) and reviewed many clinical tools that could be used to evaluate the risk of falls.
A recent RCT involving 1801 frail, elderly adults demonstrated that an anatomically designed external hip protector reduces the risk of hip fracture by 60% relative hazard of 0.4 (95% CI 0.2-0.8). [bib_ref] prevention of hip fracture in elderly people with use of a hip..., Kannus P, Parkkari [/bib_ref] The main interventions likely to be beneficial are muscle strengthening and balance retraining. One study has shown that the benefits from 2 years of back exercise course continued even 8 years after cessation. [bib_ref] Stronger back muscles reduce the incidence of vertebral fractures: a prospective 10..., Sinaki [/bib_ref] Home hazards assessment by occupational therapist (removing any obstacles that may result in falls) and withdrawal of psychotropic medications are very important interventions. [bib_ref] Home visit by occupational therapist for assessment and modification of environmental hazards:..., Cumming R, Thomas [/bib_ref] [bib_ref] psychotropic medication withdrawal and a home based exercise program to prevent falls:..., Campbell [/bib_ref] Smoking cessation should be considered, although the effect on long-term outcomes has not been rigorously studied.
How should the response to treatment be monitored?
Several approaches have been introduced for the monitoring of patients receiving therapies for osteoporosis. The goals of monitoring are to increase compliance to treatment regimens and determine treatment responses. Many patients do not continue prescribed therapy or do not adhere to a treatment protocol, even when enrolled in formal clinical trials. The best tests for monitoring treatment response would reflect the largest changes with the least error, and these assessment tools are not readily available. The Fracture Intervention Trial (FIT) reveals an additional problem with monitoring. In this study, the larger the bone loss in the first year, the greater the gain the next year, for both the placebo and active treatment groups. Thus in most instances, repeating bone mass measurement at an interval shorter than 2 years after initiating therapy may not be helpful for physicians' decision-making about treatment efficacy. Although this holds true, many experts in the field prefer to repeat DEXA after 1 year of starting therapy.
## Universal recommendations
There are several interventions recommended for the general population, which includes vitamin D and calcium correction for maintaining muscle and bone strength, diet, and exercise. Calcium is the single most important nutrient for attaining peak bone mass and for preventing and treating osteoporosis. Factors contributing to low calcium intakes are restriction of dairy products, low level of fruit and vegetable consumption, and a high intake of low-calcium beverages such as sodas. For the general population, the recommended dietary allowance for calcium among older adults (>50 years) is 1200 mg/d and 600 IU/d of vitamin D. [bib_ref] the Malaysian clinical guidance on the management of postmenopausal osteoporosis, 2012: a..., Yeap [/bib_ref] In addition, there is strong evidence that physical activity early in life contributes to a higher peak bone mass. [bib_ref] Kohl HW 3rd. bone mineral density across a range of physical activity..., Whitfield Gp [/bib_ref] [bib_ref] Chrousos gp. effect of physical activity and sun exposure on vitamin d..., Al-Othman [/bib_ref] [bib_ref] physical activity-associated bone loading during adolescence and young adulthood is positively associated..., Strope [/bib_ref] It has been the observations of many experts in the field in Saudi Arabia that the fracture rate among elderly Saudi females especially that of the hip joint is much less than what is observed in Western countries. This observation can partially be explained by the lower exercise and motility rate of our elderly females compared to their Western counterparts.
In conclusion, the present recommendations of the SOS has focused on the evaluation and treatment of osteoporosis for Saudi adults. Separate recommendations for vitamin D and calcium as well as osteoporosis for children and adolescents are warranted.
## Conflicts of interest
None.
[table] Table 2: pharmacological aspects of various agents for osteoporosis. ficacious in preventing vertebral fractures and non-vertebral fractures in postmenopausal women with osteoporosis. Oral aendronate or residronate are the first-line agents to treat established osteoporosis especially when the` hip is affected. In Men with Osteoporosis: a. Alendronate and zoledronate are efficacious in preventing vertebral fractures and increases BMD at the spine and femoral neck [Evidence Ia] b. Hip fracture data are lacking for both. [/table]
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BACKGROUND AND OBJECTIVES To provide guidelines for medical professionals in Saudi Arabia regarding osteoporosis. DESIGN AND SETTINGS A panel of 14 local experts in osteoporosis assembled to provide consensus based on the strength of evidence and expert opinions on osteoporosis treatment. PATIENTS AND METHODS The Saudi Osteoporosis Society (SOS) formed a panel of experts who performed an extensive published studies search to formulate recommendations regarding prevention, diagnosis, and treatment of osteoporosis in Saudi Arabia. Both local and international published studies were utilized whenever available. RESULTS Dual x-ray absorptiometry (DXA) scanning is still the golden standard for assessing bone mineral density (BMD). In the absence of local, country-specific fracture risk assessment tool (FRAX), the SOS recommends using the USA (White) version of the FRAX tool. All women above 60 years of age should be evaluated for BMD. This is because the panel recognized that osteoporosis and osteoporotic fractures occur at a younger age in Saudi Arabia. Hormone replacement therapy (HRT) is not recommended for treating postmenopausal women with osteoporosis. BMD evaluation should be performed 1–2 years after initiating intervention, and the assessment of bone turnover biomarkers should be performed whenever available to determine the efficacy of intervention. CONCLUSION All Saudi women above the age of 60 years must undergo a BMD assessment using DXA. Therapy decisions should be formulated with the use of the USA (White) version of the FRAX tool.
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Clinical practice guideline monitoring children and young people with, or at risk of developing autosomal dominant polycystic kidney disease (ADPKD)
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Clinical practice guideline monitoring children and young people with, or at risk of developing autosomal dominant polycystic kidney disease (ADPKD)
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is thought to affect about 1 in 1000 people in the UK. ADPKD causes a progressive decline in kidney function, with kidney failure tending to occur in middle age. Children and young people with ADPKD may not have any symptoms. However they may have high blood pressure, which may accelerate progression to later stages of chronic kidney disease. There is uncertainty and variation in how health professionals manage children and young people with confirmed or a family history of ADPKD, because of a lack of evidence. For example, health professionals may be unsure about when to test children's blood pressure and how often to monitor it in the hospital clinic or at the GP. They may have different approaches in recommending scanning or genetic testing for ADPKD in childhood, with some recommending waiting until the young person is mature enough to make this decision his or herself. This guideline is intended to help families affected by ADPKD by making sure that:health professionals with specialist knowledge in ADPKD offer you information on inheritance and potential benefits and harms of testing for ADPKD. the decision to test and the method of testing for ADPKD in children and young people is shared between you or your family and the health professionals blood pressure assessment is undertaken regularly in children and young people at risk of developing ADPKDMethod used to arrive at a recommendationEvidence reviews were undertaken that focused on literature in relation to children and young people (CYP) with, or are at risk of developing Autosomal Dominant Polycystic Kidney Disease (ADPKD). Medline (1980( -December 2017, EMBASE (1980 -December 2017 and PsychInfo databases were searched as well as websites of national associations in this field. A search strategy was developed by the guideline committee to ensure that all papers addressing the questions were identified using search terms based on PICO methodology(Table 1). The clinical leads also hand searched reference lists of reviews and included papers.Abstracts were screened for relevance by a clinical lead and 1 other member of the guideline committee according to pre-defined inclusion and exclusion criteria as detailed in the scope. Abstracts identified for review by the two reviewers were compared and any disputed abstracts were resolved by the guideline committee. The full papers were then reassessed by the clinical lead to further exclude any study that does not meet the following predefined criteria: Randomised controlled trials (RCT), non-randomised
studies if adjusted for key confounders (age, health at baseline, co-morbidities).
Clinicians on the guideline committee critically appraised any eligible papers using critical appraisal skills programme tools. Where evidence was lacking, formal Delphi consensus methodology was employed. A Delphi panel was constituted, comprising representation from each specialist area covered by the guideline: Nephrology services (3 adult and 3 paediatric nephrologists), clinical genetics (3 representatives), paediatrics with an interest in nephrology (3 representatives), lay members [bib_ref] Demographics and outcomes study in patients with autosomal dominant polycystic kidney disease..., Shaw [/bib_ref] and general practitioners (3 invited, 2 responded). A Likert scale was used for panellists to provide their responses to statements. Consensus agreement and disagreement was defined as 80% of panellists selecting 'agree' or 'disagree' respectively. Individual responses were anonymised to panellists and the working group, with the exception of the chair. No literature was sent to participants to avoid risk of bias. The process was iterative (participants able to change their views in subsequent rounds). Three rounds were undertaken.
# Background
This guideline makes recommendations for monitoring children and young people (CYP) up to 18 years of age with, or at risk of developing Autosomal Dominant Polycystic Kidney Disease (ADPKD).
ADPKD is the commonest inherited renal disease with an incidence of around 1 in 1000 and accounts for 5-7% of adults commencing renal replacement therapy [bib_ref] Genetics and pathogenesis of polycystic kidney disease, Igarashi [/bib_ref] [bib_ref] Demographics and outcomes study in patients with autosomal dominant polycystic kidney disease..., Shaw [/bib_ref]. Whilst ADPKD has traditionally been thought of as an adult disease, with established renal failure tending to occur in or after the 6th decade, there is clear evidence of earlier manifestation in children and young people (CYP), in whom hypertension and proteinuria may accelerate progression to later stages of chronic kidney disease. There is wide variation in clinical practice facing CYP with confirmed or a family history of ADPKD, with regard to a) assessment of blood pressure and urine testing for the presence of proteinuria b) ultrasound testing to evaluate presence of cysts and c) genetic counselling and testing. In order to improve quality of care and reduce variation in practice, the British Association for Paediatric Nephrology (BAPN) and the UK Renal Association (RA) in collaboration with key partners, has undertaken this work to develop best practice guidance in the area.
## Summary of clinical practice guidelines
## Guideline 1
We recommend that parents or carers of children at risk of developing ADPKD should be offered information on ADPKD inheritance and potential benefits and harms of testing for ADPKD, by health professionals with specialist knowledge in this area. (1D).
## Guideline 2
We recommend that children and young people aged 5 years and above with, or at risk of developing ADPKD, should have an assessment of blood pressure (BP) at least once every 2 years. (1B).
## Guideline 3
We recommend that the decision to test for ADPKD in asymptomatic children and young people (CYP) at risk of developing ADPKD, should be undertaken jointly between health professionals and parents or carers and, wherever possible, the young person. (1D).
## Guideline 4
If testing is decided on, we suggest that either kidney ultrasound or genetic testing may be offered to asymptomatic children and young people at risk of ADPKD, where testing has been agreed by parents or carers (and, wherever possible, the young person) and health professionals (2D).
## Guideline 5
We suggest that, if asymptomatic children at risk of ADPKD do not have cysts on ultrasound, further ultrasound testing should be deferred until adolescence , or later if preferred by the young person (2D).
## Guideline 6
We recommend that if genetic testing is planned in children and young people at risk of ADPKD, identification of the mutation in the affected adult family member (if not already known) should be undertaken prior to testing the child or young person. (1D).
## Summary of audit measures
Audit Measure 1: Proportion of parents or carers of children at risk of developing ADPKD offered information on ADPKD inheritance and potential benefits and harms of testing for ADPKD Audit Measure 2: Proportion of children and young people aged 5 years and above with, or at risk of developing ADPKD, having an assessment of blood pressure (BP) at least once every 2 years Audit Measure 3: Proportion of asymptomatic children and young people at risk of developing ADPKD offered testing for ADPKD Audit Measure 4: a. Proportion of asymptomatic children and young people at risk of developing ADPKD offered genetic testing for ADPKD b. Proportion of asymptomatic children and young people at risk of developing ADPKD offered ultrasound testing for ADPKD Audit Measure 5: Proportion of asymptomatic children at risk of ADPKD who do not have cysts on ultrasound, having repeated ultrasound testing prior to adolescence (15-18 years) Audit Measure 6: Proportion of asymptomatic children at risk of ADPKD whose parents have been tested for a genetic mutation prior to the child being tested
## Summary of research recommendations
Research recommendation 1: In children and young people with ADPKD, does regular (e.g. yearly or every 2 years) urine albumin: creatinine monitoring and treatment reduce disease progression?
Research recommendation 2: In children and young people with ADPKD what is a) the incidence of sub-arachnoid haemorrhage and b) the prevalence of intracranial aneurysm?
Research recommendation 3: In adults, children and young people with ADPKD with a family history of intracranial aneurysm or sub-arachnoid haemorrhage does Intracranial Magnetic Resonance (MR) imaging reduce the risk of intracranial events?
## Rationale for clinical practice guidelines
## Guideline 1
We recommend that parents or carers of children and young people at risk of developing ADPKD should be offered information on ADPKD inheritance and potential benefits and harms of testing for ADPKD, by health professionals with specialist knowledge in this area. (1D) Audit Measure 1: Proportion of parents or carers of children at risk of developing ADPKD offered information on ADPKD inheritance and potential benefits and harms of testing for ADPKD
## Rationale
No relevant studies were identified for this review question; however, NICE guidance on patient experience in adult NHS services recommends that patients should be provided with information, and the support they need to promote their active participation in care and self-management. This should include information about relevant treatment options and services that they are entitled to, even if these are not provided locally. There was 100% agreement with this recommendation in the Delphi consensus process. Health professionals should be aware of the anxiety suffered by families relating to uncertainty of diagnosis as well as at times of testing for ADPKD.
Health professionals should discuss the limitations of testing modalities for ADPKD. Renal ultrasound cannot effectively exclude ADPKD in children [bib_ref] Utility of ultrasonography in the diagnosis of autosomal dominant polycystic kidney disease..., Gabow [/bib_ref]. In a retrospective cohort study of ultrasound assessment in children and young people under the age of 15 at risk of ADPKD, 193/ 420 CYP were diagnosed with cysts at baseline visit (mean age 8.6 +/− 4.2 years) with 227 having no cysts (8.0 ± 4.1 years). In follow up to age fifteen, 18/77 (23%) of the latter group who underwent repeat ultrasound developed cysts. In other words, 23% of CYP with no cysts visible on initial renal ultrasound who received a further ultrasound, were diagnosed with ADPKD [bib_ref] Renal ultrasonographic evaluation in children at risk of autosomal dominant polycystic kidney..., Reed [/bib_ref]. No standardised criteria for renal ultrasound diagnosis of ADPKD exist for children under the age of 15 years, and even below the age of 30, there is a significant false negative rate. This is particularly so in families carrying a PKD2 mutation, which is typically associated with milder disease. In these families, 16.5% of patients between the ages of 15-29, with no cysts on initial ultrasound scan, go on to a diagnosis of ADPKD later in life [bib_ref] Unified criteria for ultrasonographic diagnosis of ADPKD, Pei [/bib_ref]. While genetic testing is more definitive, it is most likely to be informative in families of known genotype, as around 10% of families phenotypically affected by ADPKD do not carry a pathogenic mutation of PKD1 or PKD2 that is detected by current technologies [bib_ref] Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2..., Audrézet [/bib_ref]. Health professionals (generally nephrologists, geneticists or paediatricians with interest in nephrology) providing information on testing should have a good understanding of these issues.
## Guideline 2
We recommend that children and young people aged 5 years and above with, or at risk of developing ADPKD, should have an assessment of blood pressure (BP) at least once every 2 years. (1B).
Audit Measure 2: Proportion of children and young people aged 5 years and above with, or at risk of developing ADPKD, having an assessment of blood pressure (BP) at least once every 2 years.
## Rationale
Low quality evidence identified for this review question was deemed by the committee to be sufficient to make a recommendation without the need for formal consensus. A recent systematic review of 928 children with ADPKD across 14 studies estimated the prevalence of hypertension to be 20% (95% CI 15-27%) [bib_ref] Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis, Marlais [/bib_ref]. There is also evidence to suggest that children with ADPKD whose BP is high or borderline high have an increased left ventricular mass index on echocardiography, a marker of cardiac target organ damage [bib_ref] Increased left ventricular mass in children with autosomal polycystic kidney disease and..., Cadnapaphornchai [/bib_ref]. Studies have also shown that children with ADPKD who are hypertensive show an increased total kidney volume, compared to those that are normotensive [bib_ref] Progression of autosomal-dominant polycystic kidney disease in children, Fick-Brosnahan [/bib_ref] [bib_ref] Ambulatory blood pressure correlates with renal volume and number of renal cysts..., Seeman [/bib_ref] [bib_ref] Magnetic resonance imaging of kidney and cyst volume in children with ADPKD, Cadnapaphornchai [/bib_ref]. There are, as yet, no studies assessing long term outcomes for the treatment of hypertension in children with ADPKD. However, there is clear evidence of benefit of treating hypertension in children generally and especially in those with chronic kidney disease [bib_ref] Strict blood-pressure control and progression of renal failure in children, The [/bib_ref].
We recommend that both children with a confirmed diagnosis of ADPKD and those at risk of ADPKD through family history should have BP monitored, since some families may choose not to undertake testing for ADPKD in childhood. The risk of developing hypertension in children with ADPKD rises with age [bib_ref] Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis, Marlais [/bib_ref]. Hypertension under the age of 5 years is uncommon in ADPKD [bib_ref] Prognosis of autosomal dominant polycystic kidney disease diagnosed in utero or at..., Boyer [/bib_ref] and should prompt a search for an alternative diagnosis. In the absence of any other disease process BP rises slowly in children with ADPKD, therefore monitoring BP every 2 years should be sufficient to detect a rise in BP requiring treatment during childhood.
## Guideline 3
We recommend that the decision to test for ADPKD in asymptomatic children and young people (CYP) at risk of developing ADPKD, should be undertaken jointly between health professionals and parents or carers and, wherever possible, the young person. (1D).
Audit Measure 3: Proportion of asymptomatic children and young people at risk of developing ADPKD offered testing for ADPKD.
## Rationale
No relevant studies were identified for this review question. There was 88% agreement with this recommendation in the Delphi consensus process.
Inheriting and passing on a genetic disease may have significant psychological impact, ranging from frank depression through anxiety, guilt, anger, uncertainty and sadness [bib_ref] The emotional effects of genetic diseases: implications for clinical genetics, Mcallister [/bib_ref]. This genetic anxiety or 'guilt' may increase with uncertainty over disease variability and where there is a perceived lack of diagnosis or effective therapy. These are common issues in CYP with ADPKD, which may be further compounded by mixed messages from the medical community, with conflicting opinions as to the clinical significance of ADPKD in childhood. Genetic Counselling and testing for a condition in at risk individuals has been reported to ameliorate the psychological burden for some families and children [bib_ref] Parents' and children's communication about genetic risk: a qualitative study, learning from..., Metcalfe [/bib_ref] [bib_ref] Communicating inherited genetic risk between parent and child: a meta-thematic synthesis, Rowland [/bib_ref] [bib_ref] Genetic counselling in the era of genomic medicine, Patch [/bib_ref] , however, wherever possible, the child or young person should be involved in this decision. Article 12 of the United Nations Convention on the Rights of the Child (1989) states that we must assure 'the child who is capable of forming his or her own views has the right to express those views freely' and that 'the views are given due weight in accordance with the age and maturity of the child'.
Important issues to be discussed in counselling before deciding to test for ADPKD include:
Age and 'Gillick' competence of the CYP and consideration of whether to wait until they can make a fully-informed decision. Risk of false negative results for ultrasound and genetic tests as described on page 9 Implications for ongoing management. Blood pressure monitoring is likely to be as important as making the diagnosis in preventing long term complications, but this should be balanced against the psychological benefits of confirming / refuting (noting risk of false negative results) ADPKD. The discussion is likely to change when new treatments become available for children and young people with ADPKD.
A recent European ADPKD Forum multidisciplinary position statement states that 'Individuals with ADPKD should have access to lifelong, multidisciplinary, specialist and patient-centred care, with information and support to help patients and their families act as fully informed and active partners in care.
## Guideline 4
If testing is decided on, we suggest that either kidney ultrasound or genetic testing may be offered to asymptomatic children and young people at risk of ADPKD, where testing has been agreed by parents or carers (and, wherever possible, the young person) and health professionals (2D).
Audit Measure 4:
a. Proportion of asymptomatic children and young people at risk of developing ADPKD offered genetic testing for ADPKD b. Proportion of asymptomatic children and young people at risk of developing ADPKD offered ultrasound testing for ADPKD
## Rationale
No relevant studies comparing outcomes in CYP at risk of ADPKD undergoing genetic versus ultrasound testing for ADPKD were identified for this review question. There was 70% agreement with this recommendation (statement) by the Delphi panellists, i.e. consensus not reached. Areas for disagreement largely related to concerns about the utility of ultrasound, particularly in younger children with no standardised criteria for renal ultrasound diagnosis of ADPKD under the age of 15 years and significant false negative rates [bib_ref] Renal Ultrasonographic evaluation in children at risk of autosomal dominant polycystic kidney..., Reed [/bib_ref]. The importance of involving CYP in the decision making process was also noted in the Delphi responses. The committee believed that to offer genetic but not ultrasound testing to asymptomatic children and young people at risk of ADPKD could result in a significant change in practice in the absence of evidence and that the importance of individual choice between the two testing modalities should be emphasised given the lack of clear superiority of one over the other. The committee also noted that, although not reaching consensus, the majority (70%) of panellists supported offering a choice of kidney ultrasound or genetic testing to asymptomatic CYP at risk of ADPKD, where testing has been agreed by parents or carers and health professionals (and, wherever possible, the young person) and agreed to make a weaker 'we suggest' recommendation.
## Guideline 5
We suggest that, if asymptomatic children at risk of ADPKD do not have cysts on ultrasound, further ultrasound testing should be deferred until adolescence , or later if preferred by the young person (2D). Audit Measure 5: Proportion of asymptomatic children at risk of ADPKD who do not have cysts on ultrasound, having repeated ultrasound testing prior to adolescence .
## Rationale
No relevant studies assessing outcomes in asymptomatic children at risk of ADPKD undergoing repeated ultrasound testing for ADPKD, compared with those not undergoing repeated ultrasound testing, were identified for this review question. There was 70% agreement with this recommendation (statement) by the Delphi panellists, i.e. consensus not reached. Areas for disagreement largely related to the age of the child at the time of the first negative ultrasound scan and a preference to perform more regular ultrasound scans if requested by parents. There may also be concern by health professionals about the risk of missing very early onset ADPKD, however, these children comprise less than 1% of cases and are likely to be genetically distinct from typical ADPKD, perhaps with multiple compound mutations combining to generate such an aggressive phenotype [bib_ref] Mutations in multiple PKD genes may explain early and severe polycystic kidney..., Bergmann [/bib_ref] [bib_ref] Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst..., Rossetti [/bib_ref]. This recommendation does not apply to these children, who undergo diagnostic testing for symptomatic disease (e.g. severe renal enlargement, hypertension) and are found to have radiological abnormalities at presentation.
Repeated ultrasound testing is not routinely undertaken in adults with ADPKD where significant progression usually occurs over decades. In the absence of evidence of benefit of repeated ultrasound testing in asymptomatic CYP, together with its resource implications, and the importance of considering the wishes of the young person in the decision making process where possible, the committee was of the view that a recommendation for repeated ultrasound testing prior to adolescence could not be made. The committee considered whether repeated ultrasound testing might help to alleviate parental anxiety, but noted in their experience that repeated ultrasound testing may also add to the psychological burden for families.
The committee also noted that, although not reaching consensus, the majority (70%) of panellists supported deferring further ultrasound testing until adolescence (15-18 years, or later if preferred by the young person) in asymptomatic children at risk of ADPKD who do not have cysts on initial ultrasound. The committee therefore agreed to make a weaker 'we suggest' recommendation.
## Guideline 6
We recommend that if genetic testing is planned in children and young people at risk of ADPKD, identification of the mutation in the affected adult family member (if not already known) should be undertaken prior to testing the child or young person. (1D).
Audit Measure 6: Proportion of asymptomatic children at risk of ADPKD whose parents have been tested for a genetic mutation prior to the child being tested.
## Rationale
No relevant studies were identified for this review question. There was 88% agreement with this recommendation in the Delphi consensus process. ADPKD is associated with a wide range of mutations in the genes PKD1 and PKD2, many of which occur only in one family. As a result, genetic testing of PKD1 and PKD2 can find sequence variations that have not been previously described, and it can be difficult to determine the pathogenicity of these changes. First identifying the mutation in the affected adult family member allows for the use of segregation analysis to help assign pathogenicity to any mutations identified in the child or young person. Furthermore, up to 10% of ADPKD is not associated with detectable mutations in PKD1 or PKD2 [bib_ref] Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2..., Audrézet [/bib_ref]. This means that failure to identify a PKD1 or PKD2 mutation in a predictive genetic test cannot reliably exclude ADPKD, unless the familial mutation is known be in those genes.
## Rationale for research recommendations
Research recommendation 1: In children and young people with ADPKD does regular (e.g. yearly or every 2 years) urine albumin: creatinine monitoring and treatment improve outcome?
## Rationale
The guideline committee was not able to make a recommendation on monitoring of urine albumin: creatinine in CYP with ADPKD or at risk of ADPKD. No relevant studies assessing outcomes in CYP with proteinuria were identified and no consensus was achieved in 2 rounds of the Delphi survey; only 41% of panellists agreed with the statement 'Urine protein estimation (best assessed at urine albumin:creatinine) should be offered at least every 2 years to children and young people with confirmed ADPKD commencing at 5 years of age'. The prevalence of proteinuria in CYP with ADPKD has been reported to be as high as 20% [bib_ref] Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis, Marlais [/bib_ref] , however, a number of studies have failed to show a relationship between hypertension and proteinuria in children with ADPKD [bib_ref] Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis, Marlais [/bib_ref] [bib_ref] Progression of autosomal-dominant polycystic kidney disease in children, Fick-Brosnahan [/bib_ref] [bib_ref] Early renal abnormalities in children with postnatally diagnosed autosomal dominant polycystic kidney..., Selistre [/bib_ref]. In adults with ADPKD, established proteinuria and microalbuminuria are reported to be associated with increased mean arterial pressure and more severe renal cystic involvement [bib_ref] Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): the consortium for..., Chapman [/bib_ref] [bib_ref] Overt proteinuria and microalbuminuria in autosomal dominant polycystic kidney disease, Chapman [/bib_ref].
Research recommendation 2: In children and young people with ADPKD what is a) the incidence of subarachnoid haemorrhage and b) the prevalence of intracranial aneurysm?
Research recommendation 3: In adults, children and young people with ADPKD with a family history of intracranial aneurysm or sub-arachnoid haemorrhage does Intracranial Magnetic Resonance (MR) imaging reduce the risk of intracranial events?
## Rationale
The guideline committee was not able to make a recommendation on MR imaging in CYP with ADPKD or at risk of ADPKD. No relevant studies examining whether neurological imaging in CYP with ADPKD and a family history of intracranial events is associated with reduced cardiovascular morbidity compared with those who do not have neurological imaging, were identified. Three individual case reports of people under 18 years with ADPKD with intracranial events were found but did not meet inclusion criteria.
No consensus was achieved in 2 rounds of the Delphi survey; 61% of panellists agreed with the statement 'Intracranial Magnetic Resonance (MR) imaging should be offered to CYP with ADPKD with a family history of intracranial aneurysm or sub-arachnoid haemorrhage' (round 1), whilst 41% agreed with the statement 'Intracranial Magnetic Resonance (MR) imaging should not routinely be offered to CYP with ADPKD even with a family history of intracranial aneurysm or sub-arachnoid haemorrhage' (round 2). The lack of published data around screening in CYP < 18y was acknowledged and concern was noted with regard to thresholds for neurosurgical intervention if intracranial aneurysms were identified in CYP as a result of such testing.
A systematic review by Vlak et al. [bib_ref] Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country,..., Vlak [/bib_ref] estimated an overall prevalence of unruptured intracranial aneurysms (ICA) of 3.2% in a population without comorbidity. They calculated a prevalence ratio (PR) of 6.9 (95%CI 3. [bib_ref] Utility of ultrasonography in the diagnosis of autosomal dominant polycystic kidney disease..., Gabow [/bib_ref] [bib_ref] Renal ultrasonographic evaluation in children at risk of autosomal dominant polycystic kidney..., Reed [/bib_ref] [bib_ref] Unified criteria for ultrasonographic diagnosis of ADPKD, Pei [/bib_ref] [bib_ref] Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2..., Audrézet [/bib_ref] [bib_ref] Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis, Marlais [/bib_ref] [bib_ref] Increased left ventricular mass in children with autosomal polycystic kidney disease and..., Cadnapaphornchai [/bib_ref] [bib_ref] Progression of autosomal-dominant polycystic kidney disease in children, Fick-Brosnahan [/bib_ref] [bib_ref] Ambulatory blood pressure correlates with renal volume and number of renal cysts..., Seeman [/bib_ref] [bib_ref] Magnetic resonance imaging of kidney and cyst volume in children with ADPKD, Cadnapaphornchai [/bib_ref] [bib_ref] Strict blood-pressure control and progression of renal failure in children, The [/bib_ref] in patients with ADPKD compared to the population without comorbidity. Further analysis showed that the PR for patients with ADPKD and a family history of SAH or UIA was 2.0 (95%CI 0.5-7.4) compared with patients with ADPKD but no family history of SAH or UIA. The committee agreed that studies assessing the prevalence of SAH and ICA in CYP < 18y with ADPKD should be undertaken prior to making recommendations in this area.
## Lay summary
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is thought to affect about 1 in 1000 people in the UK. ADPKD causes a progressive decline in kidney function, with kidney failure tending to occur in middle age. Children and young people with ADPKD may not have any symptoms. However they may have high blood pressure, which may accelerate progression to later stages of chronic kidney disease.
There is uncertainty and variation in how health professionals manage children and young people with confirmed or a family history of ADPKD, because of a lack of evidence. For example, health professionals may be unsure about when to test children's blood pressure and how often to monitor it in the hospital clinic or at the GP. They may have different approaches in recommending scanning or genetic testing for ADPKD in childhood, with some recommending waiting until the young person is mature enough to make this decision his or herself.
This guideline is intended to help families affected by ADPKD by making sure that:
health professionals with specialist knowledge in ADPKD offer you information on inheritance and potential benefits and harms of testing for ADPKD. the decision to test and the method of testing for ADPKD in children and young people is shared between you or your family and the health professionals blood pressure assessment is undertaken regularly in children and young people at risk of developing ADPKD
[table] Table 1: PICO characteristics [/table]
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7th Brazilian Guideline of Arterial Hypertension: Chapter 5 - Therapeutic Decision and Targets
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7th Brazilian Guideline of Arterial Hypertension: Chapter 5 - Therapeutic Decision and Targets
# Introduction
The therapeutic management of elevated BP includes nonpharmacological measures and the use of antihypertensive drugs to reduce BP, protect target organs and prevent CV and renal outcomes. [bib_ref] Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension:..., Mancia [/bib_ref] [bib_ref] evidence-based guideline for the management of high blood pressure in adults: report..., James [/bib_ref] Non-pharmacological measures have proven efficient to reduce BP, although limited by mediumand long-term lack of adherence to treatment. A systematic review [bib_ref] Behavioral counseling to promote a healthy lifestyle for cardiovascular disease prevention in..., Lin [/bib_ref] of studies with a minimum duration of 12-24 months, combining dietary interventions and moderate-to-highintensity physical activity in patients using or not medications, has revealed a reduction in SBP and DBP for < 12 months of -4.47 (-7.91 to -1.04) mm Hg and -1.10 (-2.39 to 0.19) mm Hg, respectively. For 12 to 24 months, the reductions were -2.29 (-3.81 to -0.76) mm Hg and -1.00 (-3.22 to 1.22) mm Hg in SBP and DBP, respectively. The direct impact of those measures on the risk of CV outcomes is uncertain, the studies are small and short, and the effects on other RF could contribute to CV protection.
On the other hand, results of randomized placebocontrolled clinical trials on the use of antihypertensive drugs for hypertensive individuals have clearly shown a significant reduction in CV mortality, stroke, MI and HF. It is worth noting that most of those studies have assessed individuals aged ≥ 55 years, at high CV risk and for a follow-up period of 3 to 6 years, hindering, thus, the extrapolation of those benefits for long-term treatment and patients with other characteristics.
The therapeutic decision should be based not only on BP levels, but consider the presence of RF, TOD and/or established CVD.
## Treatment decision making
## Approach to stages 2 and 3 and/or high-risk hypertensives
Individuals with BP ≥ 160/100 mm Hg and/or high CV risk, even if stage 1, should begin immediately drug treatment associated with non-pharmacological therapy. [bib_ref] Blood pressure, antihypertensive drug treatment and the risks of stroke and of..., Collins [/bib_ref] [bib_ref] Effects of blood pressure reduction in mild hypertension: a systematic review and..., Sundstrom [/bib_ref] [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects..., Thomopoulos [/bib_ref] [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects..., Thomopoulos [/bib_ref] [bib_ref] Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal, Zanchetti [/bib_ref] Studies on antihypertensive drugs, most of which performed with patients with that profile, have shown efficacy in BP reduction and CV protection. [bib_ref] Blood pressure, antihypertensive drug treatment and the risks of stroke and of..., Collins [/bib_ref] [bib_ref] Effects of blood pressure reduction in mild hypertension: a systematic review and..., Sundstrom [/bib_ref] [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects..., Thomopoulos [/bib_ref] [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects..., Thomopoulos [/bib_ref] Non-pharmacological therapy alone cannot reduce BP sufficiently to meet the recommended BP target, 4 despite being an effective adjuvant treatment to control BP and other CVRF often present. Although the absolute benefit of therapy is higher in stages 2 and 3, it also increases the residual risk because of the frequent presence and influence of other RF and already installed TOD, neutralizing part of that benefit. This reinforces the importance of approaching CV risk globally. [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects..., Thomopoulos [/bib_ref] [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects..., Thomopoulos [/bib_ref] [bib_ref] Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal, Zanchetti [/bib_ref] Approach to stage 1 hypertensives at low and intermediate risk
The last international guidelines 2,3 point to a gap in the evidence favoring the impact of antihypertensive therapy on the outcome reduction of stage 1 hypertensives at lowto-intermediate risk. A meta-analysis 10 of four randomized studies with a minimum duration of 1 year has included 8,912 individuals with SBP of 140-159 mm Hg and/or DBP of 90-99 mm Hg. As compared to placebo, the treatment for 5 years has not reduced total mortality, CAD, stroke or CV events, having even increased by five times the chance of adverse events. Another meta-analysis 6 by the Blood Pressure Lowering Treatment Trialists' Collaboration, selecting ten randomized studies on treatment vs placebo for stage 1 hypertensives, has shown a reduction in the risk for stroke, total mortality and CVD, but had included individuals on antihypertensive therapy and/or individuals with DM. When such patients were excluded, the results lost statistical power. Later, the analysis of six studies on stage 1 SAH, involving 16,036 individuals, excluding those with DM and those on baseline antihypertensive therapy, has shown significant reductions in the risk of stroke (36%), CAD (12%), CV death (22%) and total mortality (18%). An analysis restricted to stage 1 SAH and low to intermediate risk of events (up to 5% in 10 years) has shown a reduction in the risk of those same outcomes, apparently strengthening those findings. However, the absolute benefit increased as the global CV risk increased. [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 2. Effects..., Thomopoulos [/bib_ref] [bib_ref] Effects of blood pressure lowering on outcome incidence in hypertension: 3. Effects..., Thomopoulos [/bib_ref] [bib_ref] Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal, Zanchetti [/bib_ref] Recently, the HOPE-3 Study has contributed to that subject. [bib_ref] Bloodpressure lowering in intermediate-risk persons without cardiovascular disease, Lonn [/bib_ref] In a significant population sample of 12,705 individuals at intermediate CV risk (38% hypertensive), the treatment combining candesartan and hydrochlorothiazide (16 mg/day and 12.5 mg/day, respectively) has shown a 27%-reduction in the risk of composite primary outcome (mortality, stroke and non-fatal AMI) in patients with initial SBP > 143.5 mm Hg (upper tertile). Those with lower SBP, in the first and second tertiles, however, showed no reduction in CV outcomes, and, on the contrary, the risk for the study's primary outcome tended to increase, although not significantly, in individuals of the first tertile of SBP.
The result of the HOPE-3 Study supports a recent metaanalysis on hypotensive therapy stratified by CV risk, in which a BP reduction of 4.6/3 mm Hg from baseline systolic levels around 155 mm Hg has determined an 18% reduction in the risk of outcomes. [bib_ref] Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient..., Sundstrom [/bib_ref] Thus, for stage 1 hypertensives at intermediate or low CV risk, non-pharmacological therapy should be attempted [bib_ref] Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood..., Elmer [/bib_ref] [bib_ref] Beyond salt: lifestyle modifications and blood pressure, Frisoli [/bib_ref] for 3 and 6 months, respectively (GR: I; LE: B), after which, the lack of BP control determines the beginning of pharmacological therapy. It is mandatory, however, to follow those individuals up with periodical assessment of adherence to the non-pharmacological measures. Once the lack of adherence or worsening of BP levels is detected, pharmacological therapy should be started. It is worth noting that the intervention in stage 1 hypertensives at low risk can prevent progression of the CV risk. Currently, the wide availability of antihypertensive drugs favors a safe and welltolerated treatment.
## Approach to bp levels of 130-139/85-89 mm hg
Several meta-analyses with individuals with PH have shown a greater risk of progression to SAH and of CV events in that group after adjusting for other RF. [bib_ref] Prehypertension--prevalence, health risks, and management strategies, Egan [/bib_ref] [bib_ref] Prehypertension and incidence of cardiovascular disease: a meta-analysis, Huang [/bib_ref] [bib_ref] Association between pre-hypertension and cardiovascular outcomes: a systematic review and meta-analysis of..., Guo [/bib_ref] [bib_ref] Prehypertension is not associated with all-cause mortality: a systematic review and metaanalysis..., Guo [/bib_ref] [bib_ref] Association of all-cause and cardiovascular mortality with prehypertension: a meta-analysis, Huang [/bib_ref] [bib_ref] Prehypertension and the risk of stroke: a meta-analysis, Huang [/bib_ref] Interventions in individuals with those BP levels are justified by the finding that half of the burden attributed to BP occurs in those with SBP between 130 and 150 mm Hg.It is worth noting, in that BP range, the expressive number of individuals with CVD, kidney disease, DM, metabolic syndrome and multiple CVRF.Non-pharmacological measures are recommended for that BP range. Prospective, observational studies of lifestyle intervention have shown lower risk of developing AH in those adopting a healthy lifestyle. 13,22-24 (GR: I; LE: A).
Drug treatment can be considered for prehypertensive individuals with BP of 130-139/85-89 mm Hg and previous history of CVD [bib_ref] Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without..., Thompson [/bib_ref] (GR: IIb; LE: B) or individuals at high CV risk with no CVD 26 (GR: IIb, LE: B), but there is no evidence of benefit for those at intermediate risk. [bib_ref] Bloodpressure lowering in intermediate-risk persons without cardiovascular disease, Lonn [/bib_ref] Studies of renin-angiotensin-aldosterone system (RAAS) blockers for individuals with BP of 130-139/85-89 mm Hg at high CV risk have shown a reduction in the incidence of AH. [bib_ref] Trial of preventing hypertension: design and 2-year progress report, Julius [/bib_ref] [bib_ref] PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in..., Luders [/bib_ref] There is no consistent evidence of the benefit of antihypertensive therapy to CV outcomes in that group. Thus, the decision to institute pharmacological therapy should be customized.
## Approach to hypertensive elderly
The most common mechanism of AH in the elderly is wall stiffness of the large arteries, leading to a predominant increase in SBP, and maintenance or decrease in DBP. There is no study assessing the impact of antihypertensive therapy in this group with baseline SBP between 140 and 159 mm Hg. Because of the inclusion criteria of the major studies, the BP level at entrance in the study was ≥ 160 mm Hg, clearly showing the advantage of the intervention from that level onward. Lower thresholds have not been tested, leaving a gap of evidence. Presumably, the benefits demonstrated on TOD for the general population should not differ from those of the elderly population. Studies conducted with individuals aged ≥ 80 years have shown favorable results of the use of antihypertensive drugs for those with BP ≥ 160 mm Hg, especially to prevent stroke and HF. [bib_ref] Antihypertensive drugs in very old people: a subgroup metaanalysis of randomised controlled..., Gueyffier [/bib_ref] [bib_ref] Treatment of hypertension in patients 80 years of age or older, Beckett [/bib_ref] Thus, antihypertensive pharmacological therapy in the elderly should begin from SBP levels ≥ 140 mm Hg onward, as long as well tolerated and considering the individual's general conditions. 31 (GR: IIb; LE: B).
In very old individuals (aged ≥ 80 years), the threshold to begin pharmacological therapy increases to SBP ≥ 160 mm Hg. [bib_ref] Antihypertensive drugs in very old people: a subgroup metaanalysis of randomised controlled..., Gueyffier [/bib_ref] [bib_ref] Treatment of hypertension in patients 80 years of age or older, Beckett [/bib_ref] (GR: I; LE: A).
## Approach to youngsters with isolated systolic hypertension
The ISH is frequent among healthy male youngsters aged < 30 years and can be associated with normal central BP. In such cases, the treatment yields no significant benefits, [bib_ref] Guidelines on guidelines: focus on isolated systolic hypertension in youth, O'rourke [/bib_ref] and non-pharmacological measures should be adopted, with TOD monitoring. When managing ISH, pharmacological therapy should begin immediately if the CV risk is high. If DBP elevation occurs, the same criteria for the treatment of the general population should be adopted. [fig_ref] Table 1 -: Recommendations to begin antihypertensive therapy [/fig_ref] show the grades of recommendation and levels of evidence for beginning the treatment.
## Bp targets
Recent international guidelines 2,3 have recommended more conservative BP targets for the elderly and those at high CV risk, such as diabetic individuals, mainly because of the lack of evidence supporting recommendations for different types of patients. However, meta-analyses 7,9 and the SPRINT Study [bib_ref] A Randomized trial of intensive versus standard blood-pressure control, Wright [/bib_ref] have suggested reviewing those recommendations. A meta-analysis 7 of 32 controlled and randomized studies with 104,359 individuals with different initial BP levels (stages 1 to 3) has compared the impact of the BP levels obtained (SBP: < 150 mm Hg, < 140 mm Hg and < 130 mm Hg; and DBP: < 90 mm Hg and < 80 mm Hg) on total and CV mortality and CV outcomes (stroke, CAD and HF). The The randomized, controlled clinical trial SPRINT 31 has included 9,361 individuals > 50 years, with SBP of 130-180 mm Hg and high CV risk (risk ≥ 15% within 10 years by the Framingham score, CVD, kidney disease or ≥ 75 years), excluding those with DM, polycystic kidney disease or previous stroke. The study population was randomized for more intense (< 120 mm Hg) and less intense (< 140 mmHg) SBP reduction. The composite primary outcome was the occurrence of AMI or other acute coronary syndrome, stroke, HF and CV death. In the first year, the BP levels achieved were 121.4/68.7 mm Hg and 136.2/76.3 mm Hg, respectively. The early interruption of the study in 3.26 years was due to the benefit demonstrated in the more intense SBP treatment arm, with a 25% reduction in the risk of the study's primary outcome as compared to that of the less intense SBP treatment arm (1.65%/year vs 2.19%/year, HR = 0.75; 95% confidence interval: 0.64-0.89; p < 0.001). In addition, the more intense treatment group had a 27% reduction (HR = 0.73; 95% confidence interval: 0.60-0.90; p = 0.003) in the risk of total mortality. The benefit was demonstrated in prespecified subgroups. The incidence of adverse events, mainly hypotension, syncope, electrolyte disorders and acute kidney injury, was higher in the group with more intense BP reduction. In individuals ≥ 75 years, the occurrence of adverse events was similar to that in the entire population studied. Despite the greater rate of severe adverse events, the CV benefits and the benefits on mortality overlapped the risks of adverse events.
There is a major controversy regarding diabetic patients. The ACCORD study, 33 including 4,733 diabetic patients, also randomized for SBP reduction < 120 mm Hg and < 140 mm Hg, could not reduce significantly the risk of the study's primary outcome (HR = 0.88; 95% confidence interval: 0.73-1.06; p = 0.20), and, thus, does not support the recommendations for stricter BP targets in that group of patients. In the ACCORD study, [bib_ref] Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes:..., Margolis [/bib_ref] the SBP means achieved in the first year of treatment were 119.3 mm Hg and 133.5 mm Hg for the arms of greater and smaller SBP reductions, respectively. In addition, it is worth noting that, even with a small number of events, the more intense treatment arm reduced the risk of stroke by 41% (HR = 0.59; 95% confidence interval: 0.39-0.89; p = 0.01) and had a low incidence of adverse events.
Several differences in the conception of the SPRINT [bib_ref] A Randomized trial of intensive versus standard blood-pressure control, Wright [/bib_ref] and ACCORD 33 studies indicate the need for caution when interpreting their apparently different conclusions: the number of patients recruited in the ACCORD study was almost half that of the SPRINT study and with a lower mean age. The SPRINT study included older individuals (28% ≥ 75 years) and with CKD. The 2X2 factorial design of the ACCORD study, simultaneously assessing the effect of glycemic control, might have contributed to reduce the statistical power of the population sample, because, in later analyses, the sample restriction to individuals with strict BP control regardless of their serum glucose levels has revealed a 26% risk reduction, in accordance with the SPRINT data. [bib_ref] A Randomized trial of intensive versus standard blood-pressure control, Wright [/bib_ref] Therefore, the findings suggest that the divergence in the results of the two studies could have been due to differences in study design, interactions between treatments, or to chance. However, specific changes in arteriolar function and blood flow in DM could have influenced the difference between the results of the two studies. Regarding DBP, the HOT study 34 has shown, in diabetic patients, a 51% reduction in the risk of major CV outcomes in the treatment arm aimed at reaching DBP < 80 mm Hg (actual mean achieved: 81 mm Hg) as compared to the treatment arm aimed at reaching DBP < 90 mm Hg.
Based on the results of clinical trials and systematic reviews cited, this guideline chose to recommend a BP target lower than 130/80 mm Hg for patients at high CV risk. Exceptions apply to two situations: 1) for diabetic patients -so far considered as at high risk -that PB target was not supported by the results of the ACCORD study, therefore, the recommendation was defined as GR: IIb; LE: B; 2) for patients with CAD, recent records and cohort studies have shown an increase in fatal and non-fatal CV events, 35 in addition to an increase in troponin 36 when BP levels were < 120/70 mm Hg, especially DBP < 60 mm Hg. Thus, for those patients, BP target should be within a narrower safe range (< 130/80 mm Hg, but not < 120/70 mm Hg). For elderly hypertensives ≥ 80 years, there is no evidence of benefits deriving from BP levels < 140 mm Hg, in addition to the increased likelihood of adverse effects. The HYVET Study supports the recommendation of BP target < 150/90 mm Hg with a reduction in the risk for stroke and HF. [bib_ref] Treatment of hypertension in patients 80 years of age or older, Beckett [/bib_ref] The presence of ISH requires care regarding the excessive reduction in DBP, which should be maintained over 60 mm Hg or even over 65 mm Hg in the presence of CAD. 34 (GR: IIb; LE: B). In the SPRINT Study, the elderly aged ≥ 75 years allocated to the more intense BP treatment arm (mean SBP achieved, 123.4 mm Hg) as compared to the group of standard SBP reduction (mean BP achieved, 134.8 mm Hg) had a 24% reduction in the risk of the study's primary outcome, regardless of the degree of fragility, and no increase in the number of adverse events in relation to the rest of the study population. Thus, the BP targets for the elderly should be defined in the same way they are for other adults; however, BP reduction should be performed carefully and considering the presence of comorbidities and the use of multiple medications. [fig_ref] Table 1 -: Recommendations to begin antihypertensive therapy [/fig_ref] shows the major recommendations for BP targets.
Hypertensives without proper BP control should undergo monthly medical assessments, aimed at reaching the BP target recommended as soon as possible by using sequential therapeutic adjustments. Whenever possible, BP control should be confirmed with outside-the-office BP measurements, by use of either 24-hour ABPM or HBPM. In the elderly and those with significant BP elevations, BP levels should be reduced carefully and progressively, on a case-bycase basis, depending on the patient's general conditions, presence of comorbidities and of concomitant medication.
[table] Table 1 -: Recommendations to begin antihypertensive therapy: lifestyle interventions and pharmacological therapy mm Hg) as compared to > 80 mm Hg reduced the risk of only stroke. Thus, the BP target < 140/90 mm Hg has unequivocal benefits in reducing the risk of CV mortality and outcomes, and the BP target < 130/80 mm Hg is safe and provides more protection against stroke. [/table]
[table] Table 2 -: Blood pressure targets to be met according to individual characteristics CV: cardiovascular; AH: arterial hypertension. *For patients with CAD, BP should not be < 120/70 mm Hg, particularly those with DBP < 60 mm Hg, because of the risk of coronary hypoperfusion, myocardial damage and CV events. **For diabetic patients, the class of recommendation is IIb, level of evidence B. BP target of stage 3 hypertensive individuals, despite their high CV risk, should be < 140/90 mm Hg, 7 because there is no scientific evidence supporting greater BP reductions. (GR: I; LE: A). [/table]
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The therapeutic management of elevated BP includes nonpharmacological measures and the use of antihypertensive drugs to reduce BP, protect target organs and prevent CV and renal outcomes.1-3 Non-pharmacological measures have proven efficient to reduce BP, although limited by mediumand long-term lack of adherence to treatment. A systematic review4 of studies with a minimum duration of 12-24 months, combining dietary interventions and moderate-to-highintensity physical activity in patients using or not medications, has revealed a reduction in SBP and DBP for < 12 months of -4.47 (-7.91 to -1.04) mm Hg and -1.10 (-2.39 to 0.19) mm Hg, respectively. For 12 to 24 months, the reductions were -2.29 (-3.81 to -0.76) mm Hg and -1.00 (-3.22 to 1.22) mm Hg in SBP and DBP, respectively. The direct impact of those measures on the risk of CV outcomes is uncertain, the studies are small and short, and the effects on other RF could contribute to CV protection.
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a87158585b08ea4979e91de9a1d6b10b287ec3b7
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pubmed
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Good Practice Recommendations from the Brazilian Society of Nephrology to Dialysis Units Concerning the Pandemic of the New Coronavirus (Covid-19)
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Good Practice Recommendations from the Brazilian Society of Nephrology to Dialysis Units Concerning the Pandemic of the New Coronavirus (Covid-19)
## Resumo
# Abstract
Dialysis units are environments potentially prone to the spread of Covid-19. Patients cannot suspend treatment, and they often have comorbidities, which assigns them a higher risk and worse prognosis. The Brazilian Society of Nephrology prepared this document of good practices, whose technical recommendations deal with general measures that can be implemented to reduce the risk of transmission and prevent the spread of the disease in the unit.
## Keywords:
Covid In view of the epidemiological scenario and scientific advances, the SBN updated its recommendations, which are technical indications of good practices and must be adapted to the context and local reality, depending on adequate funding by public managers. The SBN has been striving in search of resources for renal replacement therapy in Brazil at this time of the pandemic.
There is still a scarcity of well-established data on the behavior of the virus and the natural history of the disease, 1 so any changes to this document may be necessary due to other scientific evidence that may appear. The proposed measures serve to inform and alert, preventing the spread of the virus and promoting preservation of care to the population with Chronic Kidney Disease undergoing dialysis treatment.
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https://www.scielo.br/j/jbn/a/vVKBMMY8FtvqfpXsfBzdTMq/?lang=en&format=pdf
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ABSTRACT Dialysis units are environments potentially prone to the spread of Covid-19. Patients cannot suspend treatment, and they often have comorbidities, which assigns them a higher risk and worse prognosis. The Brazilian Society of Nephrology prepared this document of good practices, whose technical recommendations deal with general measures that can be implemented to reduce the risk of transmission and prevent the spread of the disease in the unit.
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f65ab61e0dbb4b5db445f1d5565fdf0ec17e619a
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pubmed
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Criteria of the German Society of Cardiology for the establishment of chest pain units: update 2014
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Criteria of the German Society of Cardiology for the establishment of chest pain units: update 2014
Since 2008, the German Cardiac Society (DGK) has been establishing a network of certified chest pain units (CPUs). The goal of CPUs was and is to carry out differential diagnostics of acute or newly occurring chest pain of undetermined origin in a rapid and goal-oriented manner and to take immediate therapeutic measures. The basis for the previous certification process was criteria that have been established and published by the task force on CPUs. These criteria regulate the spatial and technical requirements and determine diagnostic and therapeutic strategies in patients with chest pain. Furthermore, the requirements for the organization of CPUs and the training requirements for the staff of a CPU are defined. The certification process is carried out by the DGK; currently, 225 CPUs are certified and 139 CPUs have been recertified after running for a period of 3 years. The certification criteria have now been revised and updated according to new guidelines.
# Introduction
In 2008, the German Society of Cardiology (Deutsche Gesellschaft für Kardiologie-Herz-und Kreislaufforschung, DGK) [bib_ref] Kriterien der Deutschen Gesellschaft für Kardiologie-Herz-und Kreislaufforschung für, Breuckmann [/bib_ref] defined the criteria for the establishment of chest pain units (CPUs). The scope of this manuscript was to define minimum criteria for a CPU that was to be valid nationwide. Institutions that already ran a CPU were also given the possibility, through a continuous evaluation and re-evaluation process, to take advantage of technical innovations. Accordingly, a certification program was initiated in 2008; to date, 200 CPUs have been certified based on the criteria of the DGK, and 134 of these have already renewed their certification [fig_ref] Figure 1: Certified CPUs, CPUs in certification process and potential CPU sites in [/fig_ref] [2]. Using the same criteria, CPUs were also certified in Zurich and Lucerne in Switzerland. Furthermore, a consensus paper of the DGK defining the criteria to expand this process to private clinics was published in 2010 [bib_ref] Konsensuspapier der Task Force, Perings [/bib_ref] ; a certification process has since been established for the private sector and 30 private institutions have been certified to date. CPUs have received attention in national and international guidelines [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] [bib_ref] European Resuscitation Council Guidelines for Resuscitation 2010 Section 5. Initial management of..., Arntz [/bib_ref].
The general goal of a CPU was and is to carry out in a rapid and goal-oriented manner differential diagnosis of acute or newly occurring chest pain of undetermined origin. Data from similar processes in the USA and UK [bib_ref] Improved outcome in acute coronary syndrome by establishing a chest pain unit, Keller [/bib_ref] [bib_ref] Does having a chest pain center impact the treatment and survival of..., Kugelmass [/bib_ref] [bib_ref] Aktueller Stellenwert einer Chest Pain Unit in Deutschland, Post [/bib_ref] [bib_ref] Versorgung des akuten Koronarsyndroms in einer Chest Pain Unit-Eine sinnvolle Neuerung in..., Post [/bib_ref] demonstrate the superiority of CPUs compared with standard emergency care units. These data also show that the establishment of CPUs leads to a reduction in hospitalization times and a reduction in costs [bib_ref] Suspected angina pectoris: a rapid-access chest pain clinic, Dougan [/bib_ref] [bib_ref] Is a chest pain observation unit likely to be cost effective at..., Goodacre [/bib_ref] [bib_ref] Randomised controlled trial and economic evaluation of a chest pain observation unit..., Goodacre [/bib_ref] due to the better utilization of diagnostic and therapeutic methods [bib_ref] Aktueller Stellenwert einer Chest Pain Unit in Deutschland, Post [/bib_ref] [bib_ref] Suspected angina pectoris: a rapid-access chest pain clinic, Dougan [/bib_ref] [bib_ref] Is a chest pain observation unit likely to be cost effective at..., Goodacre [/bib_ref] [bib_ref] Randomised controlled trial and economic evaluation of a chest pain observation unit..., Goodacre [/bib_ref]. Finally, the establishment of CPUs also improves patient satisfaction [bib_ref] Patient satisfaction in acute coronary syndrome. Improvement through the establishment of a..., Tzikas [/bib_ref].
Through their participation in a national registry , certified CPUs also participate in a network whose scope is to collect clinically and academically relevant data on the epidemiology, treatment, and outcome of patients with chest pain. The first data from this registry have already been published [bib_ref] Pre-and early inhospital procedures in patients with acute coronary syndromes: first results..., Post [/bib_ref] [bib_ref] The German CPU Registry: comparison of troponin positive to troponin negative patients, Maier [/bib_ref]. The criteria for the certification of CPUs have been revised by the DGK ''Chest Pain Unit Task Force'' to replace the original publication from 2008 [bib_ref] Kriterien der Deutschen Gesellschaft für Kardiologie-Herz-und Kreislaufforschung für, Breuckmann [/bib_ref]. In the current, revised version, changes in the diagnosis of acute chest pain during the past 2 years have served as a basis for subsequent new certifications as well as recertifications.
The basic requirements, such as the availability of a cardiac catheterization laboratory around the clock, remain basically the same as originally stipulated in 2008. The experiences collected in these 6 years, and during the recertification process, as well as recent scientific findings and new guidelines, however, require that this position paper be revised.
## Space requirements
In terms of infrastructure, a CPU must be allocated at least four beds, all equipped with heart rhythm and blood pressure monitoring capabilities. These beds have to be under the clinical and organizational management of a cardiologist. They can be located in a separate spatial unit or be integrated into a central internal medicine facility or emergency room; however, the area of the CPU must be precisely identified and designated. The capacity must be sufficient for monitoring multiple patients over a period of at least 6-8 h. The exact number of beds can vary based on the size of the expected patient volume, taking into account sufficient reserves for situations with high patient volumes. As a minimum standard, however, four beds are to be present to qualify a unit as a CPU. Since the experience of recent years shows that the patient load can be high, it seems reasonable to plan at least one additional bed per 50,000 inhabitants in the region being served. A system that guarantees that sufficient flexible reserves can be allocated to the CPU for emergency or overflow situations must also be in place. Additional rooms for patient consultations, diagnostic instrumentation, ambulant patients, and patients' relatives are desirable. The CPU must be integrated in the emergency system of the hospital (including in-house resuscitation and emergency teams) (see [fig_ref] Table 1: Spatial requirements for the establishment of a CPU [/fig_ref].
## Technical requirements
A CPU must meet the basic technological requirements for the diagnosis of acute or recent onset chest pain of unclear origin. It has to be allocated a 12-lead ECG [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] and systems for rhythm monitoring, non-invasive blood pressure measurement, and pulse oximetry at each bedside [bib_ref] Recurrent ischaemia during continuous multilead ST-segment monitoring identifies patients with acute coronary..., Akkerhuis [/bib_ref] [bib_ref] Relative contributions of a single-admission 12-lead electrocardiogram and early 24-hour continuous electrocardiographic..., Holmvang [/bib_ref].
Transthoracic echocardiography by a trained examiner must be available on site within 30 min, 24 h a day, 7 days a week (24/7), for the diagnosis of wall motion abnormalities, heart defects, right heart failure, and pericardial effusion. Transesophageal echocardiography should also be available on site [bib_ref] SVM guidelines for the diagnosis and management of patients with Thoracic Aortic..., Hiratzka [/bib_ref] [bib_ref] Diagnosis and management of aortic dissection, Erbel [/bib_ref].
Standard emergency care infrastructure must be available. This includes both a fully equipped emergency unit (with a defibrillator, airway intubation equipment, oxygen, and a suction device) as well as the capacity to transport unstable patients (including ECG monitor, infusion pump, transportable ventilator). The emergency equipment must be checked regularly and be in line with the current state of the art.
Twenty-four-hour access to emergency laboratory diagnostics is required. The time from blood collection to delivery of the results must not exceed 45-60 min; it should be checked regularly that this interval remains within these limits [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref]. If this is not the case, a Point-of-Care Test Unit (POCT) for the measurement of cardiac biomarkers should be available in the CPU [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref]. Results of ischemic markers must be quantitative (as compared with positive/negative). Blood gas analysis should be available within 15 min.
Availability of instruments and trained personnel for the analysis of internal cardioverter/defibrillators (ICD) and pacemakers should be guaranteed 24/7 with a response time of less than 6 h. Percutaneous pacemaker therapy should be available.
A multi-slice CT must be on hand for further investigation of relevant differential diagnoses after exclusion of acute coronary syndrome (pulmonary embolism, aortic dissection) or to rule out coronary artery disease of low or intermediate probability following pretest. Based on risk stratification, patients with suspected coronary artery disease without unstable characteristics (e.g., those who are free of symptoms, without primary or secondary risk indicators) may be discharged, but a system that guarantees re-admission for further investigation within three business days (or any time earlier in case of symptom relapse) must be in place. This system may also be implemented in cooperation with external private or public walk-in clinics (see [fig_ref] Table 2: Technical requirements TTE transthoracic echocardiography, POCT Point-of-Care Testing, CT computed tomography [/fig_ref].
## Diagnostic procedures
National and international guidelines for the diagnosis of acute chest pain must be implemented and observed [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] [bib_ref] SVM guidelines for the diagnosis and management of patients with Thoracic Aortic..., Hiratzka [/bib_ref] [bib_ref] Guidelines on the diagnosis and management of acute pulmonary embolism: the Task..., Torbicki [/bib_ref] [bib_ref] ESC Guidelines for the management of acute myocardial infarction in patients presenting..., Steg [/bib_ref].
A 15-lead ECG (including standard and posterior leads V7 to V9) must be recorded immediately upon admission of each patient [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] , and this ECG must be evaluated by a physician within 10 min [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref]. It is reasonable to record right precordial leads in each patient with inferior myocardial infarction, as this may have prognostic and therapeutic implications. An ECG must be recorded again after 6 h or upon symptom recurrence [bib_ref] Sensitive troponin I assay in early diagnosis of acute myocardial infarction, Keller [/bib_ref] [bib_ref] Comparison of the new high sensitive cardiac troponin T with myoglobin, h-FABP..., Kurz [/bib_ref]. An additional ECG 3 h after admission is recommended in order bridge the 6-h gap between recordings, and this is also useful for patients who can be discharged early in an accelerated ''rule-out protocol'' using high-sensitivity troponin measurements. In addition to the clinical assessment and ECG, the diagnosis of acute coronary syndrome always includes the assessment of cardiac markers. Cardiac troponins, ideally high-sensitivity troponin T or I, should be preferred as they have the highest sensitivity and can show an irreversible myocardial necrosis [bib_ref] Sensitive troponin I assay in early diagnosis of acute myocardial infarction, Keller [/bib_ref] [bib_ref] Comparison of the new high sensitive cardiac troponin T with myoglobin, h-FABP..., Kurz [/bib_ref]. It is recommended that troponin levels be checked at admission and 6-9 h thereafter [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] (this interval can be reduced to 3 h if high-sensitivity troponin is used) [bib_ref] Sensitive troponin I assay in early diagnosis of acute myocardial infarction, Keller [/bib_ref] [bib_ref] Comparison of the new high sensitive cardiac troponin T with myoglobin, h-FABP..., Kurz [/bib_ref]. An increasing number of studies show that strategies such as the use of a threshold for troponin below the 99th percentile [bib_ref] Undetectable high sensitivity cardiac troponin T level in the emergency department and..., Bandstein [/bib_ref] [bib_ref] Rapid exclusion of acute myocardial infarction in patients with undetectable troponin using..., Body [/bib_ref] , the shortening of the intervals between tests to 60-120 min [bib_ref] One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin..., Reichlin [/bib_ref] [bib_ref] Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess..., Cullen [/bib_ref] , or the use of other biomarkers such as copeptin in combination with troponin allow an earlier diagnosis of acute coronary syndrome [bib_ref] Copeptin helps in the early detection of patients with acute myocardial infarction:..., Maisel [/bib_ref] and a safe early discharge in case these biomarkers are negative [bib_ref] Early discharge using single cardiac troponin and copeptin testing in patients with..., Mockel [/bib_ref]. CPUs exposed to a high volume of patients might particularly profit from such strategies. In addition, an early diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI) has clinical implications for patients and allocation of resources [bib_ref] Chest pain unit concept: rationale and diagnostic strategies, Blomkalns [/bib_ref]. The determination of other biomarkers may be useful depending on the clinical diagnosis. Determination of D-dimer levels can be used to rule out acute pulmonary embolism or acute aortic syndrome in patients with unexplained chest pain [bib_ref] SVM guidelines for the diagnosis and management of patients with Thoracic Aortic..., Hiratzka [/bib_ref] [bib_ref] Guidelines on the diagnosis and management of acute pulmonary embolism: the Task..., Torbicki [/bib_ref].
Non-cardiac baseline parameters must be recorded upon admission, including a full blood count, electrolytes, creatinine, CRP, glucose, and coagulation status. Thyroid function parameters (particularly basal TSH) are optional but may be important in case there is a need for subsequent contrast media exposure or in patients with known or suspected thyroid disease. Arterial blood gas analysis should be carried out only if there is explicit clinical indication.
A transthoracic echocardiography is performed as clinically indicated; this includes all patients with suspected acute coronary syndrome or suspected aortic dissection [in the latter case transesophageal echocardiography (TEE), computed tomography, (CT), or magnetic resonance imaging (MRI) should be employed] [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] [bib_ref] Chest pain unit concept: rationale and diagnostic strategies, Blomkalns [/bib_ref]. An ultrasound machine equipped with an appropriate probe and staff trained in performing an ultrasound of the abdomen should be available at all times.
In line with the indications of the ESC and the DGK, scoring systems, e.g. the GRACE score [32], should be used to improve and standardize the risk stratification of the patients [bib_ref] Kommentar zu den Leitlinien der European Society of Cardiology (ESC) zur Diagnose..., Hamm [/bib_ref]. Accordingly, high-risk patients (GRACE score [140 points) should undergo coronary angiography within 24 h; those patients who are at moderate or lower risk should undergo angiography within 72 h [bib_ref] Early versus delayed invasive intervention in acute coronary syndromes, Mehta [/bib_ref]. The GRACE score is determined using eight independent risk parameters that include age, heart rate, and ST-segment abnormalities. If the GRACE score is below 108 points, the risk of patients dying in the hospital is less than 1 %. A moderate score of 109-140 points is associated with medium risk (1-3 %). Patients with 141-372 points show an in-hospital mortality rate of more than 3 % [bib_ref] Early versus delayed invasive intervention in acute coronary syndromes, Mehta [/bib_ref]. The use of alternative or additional scoring systems is advisable [bib_ref] Comparison of the Wells score with the simplified revised Geneva score for..., Penaloza [/bib_ref] [bib_ref] Diagnostic score to differentiate acute aortic dissection in the emergency room, Shirakabe [/bib_ref] [bib_ref] SCORE-and SMART-risk score for predicting cardiovascular morbidity and mortality in patients with..., Uthoff [/bib_ref] (see [fig_ref] Table 3: Diagnostic strategies in the CPU [/fig_ref].
## Therapy
A CPU is designed to optimize the diagnostic processes and therapeutic options in patients with chest pain. Each CPU must establish and implement strict standard operating procedures (SOPs) for the following diseases:
- ST-elevation myocardial infarction (STEMI) Use of different SOPs based on patient presentation (e.g., hemodynamic stability/instability, referral from emergency services or self-referral)
[formula] - NSTEMI - unstable angina pectoris - stable angina pectoris - hypertensive crisis - acute pulmonary embolism - acute aortic diseases - cardiogenic shock - decompensated heart failure - resuscitation - ICD discharge - pacemaker dysfunction - atrial fibrillation [/formula]
These treatment recommendations do not necessarily dictate that ACS patients should undergo triage to be treated exclusively in the CPU. Especially in cases of STEMI and cardiogenic shock, patients should be transferred directly from the ambulance to the catheterization laboratory [bib_ref] ESC Guidelines for the management of acute myocardial infarction in patients presenting..., Steg [/bib_ref]. These SOPs must nonetheless be well structured and defined.
Transfer times from CPU to catheterization laboratory in the case of high-risk patients should never exceed 15 min.
At the time of discharge, patients must receive a discharge letter including recommendations for therapy, especially in case of symptom relapse [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] [bib_ref] Guidelines on the diagnosis and management of acute pulmonary embolism: the Task..., Torbicki [/bib_ref] [bib_ref] ESC Guidelines for the management of acute myocardial infarction in patients presenting..., Steg [/bib_ref]. In addition, every patient should participate in a documented and structured consultation concerning lifestyle modifications (smoking cessation, exercise, and diet) and risk factors of medical therapy (LDL-cholesterol target values) (see [fig_ref] Table 4: Therapeutic strategies in the CPU [/fig_ref].
## Diagnostic algorithms for patients with suspected acute coronary syndrome and low risk
An early risk stratification is of paramount importance to triage patients into groups requiring immediate (\120 min), early (\24 h), or delayed (\72 h) invasive diagnostics or to allocate them to more conservative therapy. Patients without primary or secondary risk characteristics that remain free of symptoms during the course of admission and examination can be discharged early. A previous meta-analysis of eight studies showed that use of early invasive diagnostics leads to a 22 % reduction in the composite endpoint of death, myocardial infarction, or In the CPU CK creatine kinase, BNP B-type natriuretic peptide, hs-Troponin T high-sensitivity troponin T, TTE transthoracic echocardiography, ACS acute coronary syndrome hospitalization for ACS [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref]. Patients who are positive for biomarkers (cTn, hsTn), i.e. NSTEMI patients, profit particularly from this invasive approach [bib_ref] Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of..., Bavry [/bib_ref] , while patients with negative biomarkers do not profit from it, and women with negative biomarkers actually show a worse prognosis when exposed to unnecessary invasive exams [bib_ref] Early invasive vs conservative treatment strategies in women and men with unstable..., O'donoghue [/bib_ref]. The discharge of a patient after an accelerated diagnostic process based on the assessment of both cardiac troponin and copeptin appears to be as safe as the standard protocol with a repeated troponin assessment after 6 h [bib_ref] Early discharge using single cardiac troponin and copeptin testing in patients with..., Mockel [/bib_ref]. In patients at low risk (GRACE score \108 or TIMI 0-1) such accelerated diagnostic algorithms allow the ruling out of NSTEMI with two troponin assessments in the normal range within 60-120 min. As long as both values remain below the 99th percentile, the negative predictive value of such an approach is greater than 99 % [bib_ref] Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess..., Cullen [/bib_ref]. The ESC Guidelines also recommend against performing routine cardiac catheterization in asymptomatic patients without risk characteristics, especially changes in high-sensitivity troponin T values or an ischemic ECG (level of evidence IIIC). Therefore, the decision to direct a patient to invasive investigations should be based on the results of laboratory tests, ECG, and exercise (stress) tests. Stress tests should be carried out either before discharge or shortly thereafter (B3 working days).
In patients with low or intermediate pre-test probability for the presence of acute coronary syndrome, multi-slice CT angiography is recommended to rule out coronary artery disease [bib_ref] ESC Guidelines for the management of acute coronary syndromes in patients presenting..., Hamm [/bib_ref] , level of evidence IC).
Primary risk criteria
## Cooperations
A cardiac catheterization laboratory with permanent personnel available for acute intervention is an indispensable prerequisite for a CPU. The catheterization laboratory must be on duty 24/7; the only allowed exception is unexpected technical failure, in which case the facility may be temporarily logged out of the emergency care program. The reasons for such lapses must be recorded and a fail-safe concept must be present. Permanent staff availability must be guaranteed and should be documented by means of service plans; here also a fail-safe concept is required.
Of central importance is a close cooperation with the regional emergency care facilities and emergency structures, and these should not be negatively affected by the establishment of a CPU. For patients with STEMI who are diagnosed prior to arrival at the hospital, a fast-track protocol should be defined that bypasses the CPU and leads directly to the catheterization laboratory. Referring and emergency physicians should be offered the opportunity of a telemedical ECG transmission online or via fax [bib_ref] Validity of telephone ECG multichannel transmission, Dirschedl [/bib_ref].
An important in-hospital interface must exist with an intensive care unit or an intermediate care ward. The transfer time must not exceed 15 min.
Facilities must be in place to allow conventional X-ray diagnoses and CT scans, and it should be possible to consult with specialists in other disciplines in-house or in cooperation with external partners.
In addition, a strong link to external walk-in clinics must be established. This cooperation should also be extended to prevention and awareness campaigns. If an outpatient chest pain clinic exists, a collaboration should be sought (see [fig_ref] Table 5: Cooperations und partners of a CPU [/fig_ref].
## Education
The nursing staff must undergo special training. A specific training program for ''Chest Pain Unit Nurse'', certified by the DGK, has been established. Standard emergency training is also obligatory and should be repeated at least twice per year [bib_ref] The role of nurses in a chest pain unit, Siebens [/bib_ref].
Members of the medical staff should be able to demonstrate 2 years of professional experience in internal medicine, echocardiographic knowledge, and sufficient experience in internal intensive care medicine. CPU doctors are not necessarily allocated exclusively to this unit, but their shift must be organized in a way so as to guarantee the presence of a physician within 10 min of patientś admission and in case of need (e.g. parallel work in the emergency service ward is not allowed). A consultant specialized in cardiology must be on call with a maximum response time of 30 min. Each patient must be seen by a specialist before discharge. These requirements must be met at any time of the day or night, including holidays.
Each employee must be thoroughly informed about the standard operating procedures and trained in dealing with patients with acute chest pain. The local operating procedures must be based on international guidelines and must be documented in writing. All employees must undergo regular resuscitation training (Advanced Life Support). It may be useful to integrate local emergency services in the training programs to improve the entire chain of lifesaving procedures for acute or new-onset chest pain.
A report must be made at regular intervals (preferably quarterly), the results of which should be documented in team meetings and case conferences. Feedback mechanisms should also be introduced that reflect the results and the quality of treatment and diagnosis. Every patient should be informed in a structured manner about the necessary lifestyle changes (quitting smoking, performing regular exercise, engaging in healthy eating) and the importance of a medical therapy in preventing future cardiovascular events (see [fig_ref] Table 6: Education and training of the CPU [/fig_ref].
## Organization
A CPU is part of a cardiology department or clinic that provides for the possibility to administer invasive coronary therapy. If the beds of a CPU are associated with an emergency department, they must be expressly designated as CPU beds that are part of a cardiological facility. A cardiologist must be responsible for the management of the CPU, and his/her response time shall not exceed 30 min. One physician (or physician-in-training) must be constantly present in the CPU. The ratio between patients and nurses should not exceed 4:1, so that at least two nurses must be present if the number of monitored patients exceeds four.
Since a CPU is an emergency unit, it cannot be closed at any time (see [fig_ref] Table 7: Organization of a CPU Integration in the regional plan for ACS Integration... [/fig_ref].
## The certification process
Application for certification may be made at the office of the DGK. An invoice for the certification fee will be sent to the applying institution; payment of the first half of the amount is due 14 days after the invoice is sent and is a prerequisite for further action by the DGK. The application process begins formally with the mailing of the invoice.
After payment, the applicant receives an electronic data entry form saved on a CD-Rom. This is to be completed by the applicant and returned.
The DGK then informs the committee for the certification of CPU, which suggests the names of two independent, trained referees for the assessment of the application; if they are approved they are invited by the committee to review the application.
The expert referees next contact the applicant and arrange an appointment for an audit. After the audit, the experts write a report and a recommendation, which are sent to the DGK. The committee decides on the basis of these documents whether or not to grant the CPU certification.
Based on the evaluation, the DGK issues either a certification (''CPU-DGK certified'' logo), a rejection (with justification), or a certification pending fulfillment of conditions [bib_ref] Acute thoracic pain: Chest Pain Unit-the certification campaign of the German Society..., Breuckmann [/bib_ref].
A certification is valid for 3 years, after which the CPU needs to be re-certified for another 5 years. The Changes are highlighted in italic re-certification process is similar to the initial certification process but only involves one expert referee.
## Perspective
An overview of the current changes in the criteria of the DGK for the certification and re-certification process of CPUs is provided in [fig_ref] Table 8 continued: Criterium 2008 Minimal requirementsAdditional cooperations Gastroenterology, heart surgery, outpatient clinics Psychosomatic medicine... [/fig_ref].
To date, 200 CPUs have been certified in Germany and more than 134 CPUs re-certified. This rapid growth underscores the interest in the advantages that this structure offers. The number of CPUs in Germany already far exceeds that of the rest of Europe. The objective of our initiative remains to achieve nationwide coverage through a network of certified CPUs throughout the country. To meet this goal, it will be necessary to certify as many as 300 CPUs, as to date there are significant regional differences in cardiological care. Furthermore, we aim to export the concept to a European level, a process that has already begun. The criteria for certification will need to be updated constantly following technical developments and innovations, and they must be based on the most current guidelines. The German CPU registry will also have a central importance in evaluating standards of care and treatment strategies , while single-center experiences already demonstrate the benefit associated with the establishment of a CPU. To date, 30,087 patients have been enrolled in the CPU registry since December 2008, and the first data have already been published [bib_ref] Pre-and early inhospital procedures in patients with acute coronary syndromes: first results..., Post [/bib_ref] [bib_ref] The German CPU Registry: comparison of troponin positive to troponin negative patients, Maier [/bib_ref] [bib_ref] Disease distribution and outcome in troponin-positive patients with or without revascularization in..., Illmann [/bib_ref] [bib_ref] Self-referral to chest pain units: results of the German CPU-registry, Nowak [/bib_ref] [bib_ref] Establishment and progress of the chest pain unit certification process in Germany..., Post [/bib_ref].
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
[fig] Figure 1: Certified CPUs, CPUs in certification process and potential CPU sites in [/fig]
[table] Table 1: Spatial requirements for the establishment of a CPU [/table]
[table] Table 2: Technical requirements TTE transthoracic echocardiography, POCT Point-of-Care Testing, CT computed tomography [/table]
[table] Table 3: Diagnostic strategies in the CPU [/table]
[table] Table 4: Therapeutic strategies in the CPU [/table]
[table] Table 5: Cooperations und partners of a CPU [/table]
[table] Table 6: Education and training of the CPU [/table]
[table] Table 7: Organization of a CPU Integration in the regional plan for ACS Integration in the existing emergency system Integrated structures for the therapy of ACS at a regional and nationwideCatheterization laboratory Available 365 days/24 h, transfer time \15 min, with at least four interventional cardiologists Available 365 days/24 h, transfer time \15 min (the criterion of at least four cardiologists is deleted) [/table]
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An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0
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An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0
Background: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. Methods: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. Results: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. Conclusion: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.
# Background
Cutaneous melanoma continues to be a serious public health threat with a slow, but steady increase in annual incidence over the past four decades. In 2017, there were an estimated 87,110 new cases and 9730 deaths due to melanoma in the United States. While melanomas detected early can often be treated by complete surgical excision with good outcomes, the development of metastatic disease, which is associated with reduced survival, is correlated with increasing stage and other high-risk features of the primary tumor [bib_ref] Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up..., Hayes [/bib_ref]. Contemporary systemic therapeutic options for patients with metastatic melanoma include cytotoxic chemotherapy, molecularly targeted therapy, and immunotherapy. Since 2011, the treatment landscape for patients with melanoma has changed considerably with regulatory approval of 11 new drugs and/or combination regimens [bib_ref] Targeted agents and immunotherapies: optimizing outcomes in melanoma, Luke [/bib_ref]. Immunotherapy agents in particular have been associated with durable long-term survival in responding patients and have emerged as first-line treatment in most melanoma populations [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref].
The immunotherapy agents approved for melanoma include cytokines, such as interferon α2b/pegylated interferon α2b for high-risk adjuvant therapy and high-dose interleukin-2 (IL-2) for metastatic disease; ipilimumab and nivolumab, immune checkpoint inhibitors targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), respectively for high-risk adjuvant melanoma, and four T cell checkpoint inhibitors for metastatic melanoma, including ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), nivolumab (anti-PD-1) and the combination of ipilimumab/ nivolumab; finally, one gene-modified oncolytic virus, talimogene laherparepvec (T-VEC), has been approved for intralesional therapy [bib_ref] Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the eastern cooperative..., Kirkwood [/bib_ref] [bib_ref] Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage..., Eggermont [/bib_ref] [bib_ref] High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of..., Atkins [/bib_ref] [bib_ref] Improved survival with ipilimumab in patients with metastatic melanoma, Hodi [/bib_ref] [bib_ref] Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma, Hamid [/bib_ref] [bib_ref] Nivolumab in previously untreated melanoma without BRAF mutation, Robert [/bib_ref] [bib_ref] Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma, Larkin [/bib_ref] [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref]. While the clinical trials supporting regulatory approvals have dramatically changed the melanoma treatment landscape and provided patients and providers with several new options, there is relatively little data for evidence-based decisions in regard to optimal sequencing of these agents, methods or biomarkers to select the right treatment for individual patients, or rigorous information on how best to manage potential adverse events or indicators for optimal duration of therapy. The availability of other therapeutic options, in particular targeted therapy for patients whose melanoma harbors a mutation in BRAF, highlight the importance of having data or consensus agreement from experts in the field on how best to manage patients while waiting for new clinical and clinical trial data to help inform decision-making.
To address the gap in evidence-based data, the Society for Immunotherapy of Cancer (SITC) established a Melanoma Task Force to provide consensus recommendations for clinical decision making for patients with melanoma. SITC is a non-profit professional organization dedicated to improving cancer patient outcomes through the use of cancer immunotherapy. The Task Force consisted of melanoma experts, including physicians, nurses and patient advocates who met in person and communicated through email to consider major issues and provide recommendations related to patient selection, toxicity management, treatment cessation and treatment sequencing. The panel published the first consensus statement in 2013 [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref] , and this publication represents an update based on more recent assessment of the peer-reviewed literature and clinical experience of the expert Task Force participants. These recommendations are not intended to supplant sound clinical judgment but to provide clinicians who care for melanoma patients the most current thinking on how experts integrate immunotherapy into the treatment armamentarium for patients with advanced cutaneous melanoma.
# Methods
# Consensus statement policy
SITC utilized the National Academy of Medicine (formerly Institute of Medicine) March 2011 Standards for Developing Trustworthy Clinical Guidelines as a model for organizing and preparing this consensus statement. These standards include a transparent process for guideline development and funding, managing and reporting conflicts of interest, maintaining a multidisciplinary and balanced group composition, establishing an evidence-based foundation for recommendations and rating system to assess the strength of the evidence, reporting the results through a peer-reviewed publication and publicly available website, and updating the statement as changes in the field warrant revisions.
The Melanoma Task Force was established through SITC in 2011, with additional panel members added as necessary (Additional file 1). A Steering Committee led a panel discussion to develop clinical treatment guidelines considering four basic issues for each immunotherapy agent in current clinical practice: patient selection, toxicity management, assessment of response, and therapy sequencing and combinations. The in-person meeting was supplemented by email voting on several issues due to the rapid development of new findings and drug approvals for melanoma over the last 2 years. Full consensus recommendations can be found on the SITC website. Owing to disparities in drug approval and availability in some countries, this panel focused solely on drugs approved by the U.S. Food and Drug Administration (FDA). An advance copy of this manuscript was submitted to the FDA for comment before submission for publication. The panel also recognized that the AJCC Cancer Staging Manual, 8th Edition has been released but the clinical trial data reviewed utilized earlier versions of AJCC staging; as such, the recommendations presented in this manuscript were largely based on 7th edition staging criteria. However, recommendations that extrapolate clinical trial data using 7th edition staging criteria in the setting of completion lymph node dissection (CLND), are made to the current era using the 8th edition staging system in the non-CLND era where appropriate.
## Consensus panel and conflicts of interest
Potential panel members were solicited from the SITC membership and supplemented with non-member melanoma multidisciplinary experts, clinicians and groups in the U.S. expected to be affected by the development of any recommendations, including patients, patient advocates and nurses. Panel members were screened for conflicts of interest using the SITC disclosure form, which mandates full financial and other disclosures including relationships with commercial entities that might reasonably be expected to have direct regulatory or commercial impact resulting from the publication of this statement. Disclosures of potential conflicts of interest are noted in this manuscript. No commercial funding was used to support the consensus panel, literature review or preparation of the manuscript.
The consensus panel convened in June 2016 in accordance with the National Academy of Medicine and SITC guidelines to review results from a previously distributed questionnaire collecting information on the participants' role in the care of patients with melanoma, primary clinical focus, experience with FDA-approved agents used for immunotherapy treatments, and current practices in the use or recommendation for use of such agents. Additional questionnaires were distributed electronically after the meeting to collect further information, including a final questionnaire in the late summer of 2017. The final consensus statement was made available to the entire SITC membership for open comment and these comments were considered for the final manuscript and are available in supplementary materials (see Additional file 2) and online at the SITC website.
## Literature review and rating system
A search of the scientific literature (using the MEDLINE database) was conducted focusing on current therapeutic approaches in humans. The search terms included "melanoma" and "interferon", "interleukin-2", "ipilimumab", "vemurafenib," "BRAF," "dabrafenib, dacarbazine, temozolomide", "pembrolizumab", "nivolumab", "PD-1/PD-L1", "combination", "talimogene laherparepvec", "adverse event", and "toxicity". The search resulted in retrieval of nearly 2400 manuscripts, which were screened by Task Force members to include only papers with clinically relevant information and removing duplicates from independent searches, resulting in a final bibliography of 1643 manuscripts (see Additional file 3) catalogued using EndNote X5.0.1. The bibliography was supplemented with additional literature identified by the panel, as appropriate. Literature was graded into three levels of evidence, as previously described [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref]. Level A evidence is based on strong supporting evidence, such as data derived from appropriately powered prospective, randomized clinical trials or meta-analyses; Level B is based on moderate supporting data, such as uncontrolled, prospective clinical trials; and Level C is based on weaker supporting data, such as retrospective reviews and case reports.
## Consensus recommendations
The Task Force considered individual melanoma stages independently and provided the following consensus recommendations described by stage of disease. These recommendations were based on data available for AJCC version 7 staging guidelines; where appropriate, modifications relevant for AJCC version 8, which became active in January 2018, are noted. The majority of the immunotherapy trials on which the following recommendations are based included patients with ECOG Performance Status 0 or 1. These guidelines are intended to assist clinicians in critical decision-making for patients with melanoma and should not supplant clinical judgment for individual patient management.
## Immunotherapy for stage ii melanoma initial assessment
Patients with stage II melanoma have an excellent overall survival (OS) of 80% or better provided the primary tumor is completely excised [bib_ref] Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up..., Hayes [/bib_ref]. A subset of tumors, characterized as deep (Breslow thickness > 4 mm), and/ or with ulceration, and possibly those with a high tumor mitotic rate (≥1 per mm 2 ), are considered at higher risk for recurrence [bib_ref] Prediction of survival in patients with thin melanoma: results from a multi-institution..., Maurichi [/bib_ref]. Practically speaking, using both AJCC 7th and 8th additions, Stage IIB and IIC are considered higher risk. The panel discussed at length the changing landscape with respect to how to define high risk and when to consider further intervention with the goal of preventing tumor relapse. There was unanimous agreement that all stage II patients should have a comprehensive diagnostic workup and be reviewed by a multidisciplinary team, including physicians with expertise in surgical oncology, medical oncology, dermatology and dermatopathology to accurately determine tumor stage and estimate the risk of melanoma recurrence for individual patients. This workup should include sentinel lymph node biopsy information, as appropriate [bib_ref] of Surgical Oncology joint clinical practice guideline, Wong [/bib_ref].
## Consensus management of stage ii melanoma
The panel considered the therapeutic approach to stage II melanoma should be based on an assessment of risk for tumor recurrence or metastatic spread but recognized that there is considerable controversy in how to determine risk stratification. Further, changes in the AJCC staging system and emerging data using a variety of histologic and molecular assays for risk assessment have made firm recommendations challenging. For the purposes of our discussions, we defined high risk stage II as patients with tumors > 4 mm in depth (with or without ulceration) or tumors > 2-4 mm with ulceration. While this definition may change with further prospective data, the general approach to patient management can be considered based on clinical assessment of higher versus lower risk.
There was general agreement that patients with lower risk stage I and IIA melanoma can be observed and that there is no evidence that currently warrants treatment of these patients . The panel, however, was divided on the role of immunotherapy for patients with higher-risk stage IIB-C melanoma (see and recognized the limited Level A data available to inform clinical decision-making. The panel did consider emerging Level B data suggesting new recommendations are needed for high-risk stage II melanoma patients. Whereas before the majority of the panel recommended that high-risk patients be treated with standard 1-year high dose interferon-α2b, now a small majority (55%) recommend enrollment onto a clinical trial -either unselected or selected by a biomarker known to be associated with either risk (prognostic) or responsiveness to the therapy (predictive) -as a preferred option for these patients. Among panel members who did not recommend a clinical trial, twice as many recommended observation (20%) as did the pursuit of standard of care adjuvant interferon α-2b (10%). This is a reflection of a number of factors including: 1) improved systemic therapy for recurrent, metastatic disease [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref] ; 2) acknowledgment of the limitations of the AJCC staging system to identify those at high and low risk of recurrence (e.g., a significant number of patients with low risk [by currently available methods] melanoma will still die of disease [bib_ref] Prediction of survival in patients with thin melanoma: results from a multi-institution..., Maurichi [/bib_ref] ; and 3) emerging, as yet non-validated biomarkers, which may better identify patients at greatest risk of recurrence (e.g., ulceration, gene expression profile, circulating tumor DNA) [bib_ref] Prediction of survival in patients with thin melanoma: results from a multi-institution..., Maurichi [/bib_ref] [bib_ref] Development of a prognostic genetic signature to predict the metastatic risk associated..., Gerami [/bib_ref] [bib_ref] Use of circulating tumor DNA to predict survival in patients with resected..., Lee [/bib_ref]. None of the panel members recommended treatment with pegylated interferon-α2b for patients with stage II disease.
Patients with stage IIB or IIC melanoma who are treated with interferon-α2b should have a good Stage II melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate, and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician's discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) High-risk disease is defined as tumors > 4 mm in depth (with or without ulceration) or > 2-4 mm with ulceration. There is limited consensus on adjuvant therapy for this group with 10% of the panel recommending interferon-α2b, 20% recommending observation, 45 and 15% recommending therapeutic and/or biomarker-based clinical trial participation, respectively, and no panelists recommending pegylated-interferon-α2. [bib_ref] Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up..., Hayes [/bib_ref] There is no evidence that immunotherapy is useful in patients with lower risk stage II melanoma, although the panel did recommend clinical trial participation, if available. Protocol-specific eligibility would need to be followed to select appropriate study candidates. (3) Patients should have a good performance status without evidence of significant depression, psychiatric history or underlying autoimmune disease to be considered for interferon-α2b. There are limited data available on interferon-α2b as treatment for stage II disease. (4) Clinical trials were the preferred treatment recommendation for patients with stage II disease associated with higher risk of tumor recurrence performance status without evidence of significant depression or psychiatric history or underlying autoimmune disease [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref]. The data to support the use of adjuvant, high-dose interferon-α2b are controversial and many studies did not incorporate required sentinel lymph node biopsy into the study eligibility complicating the interpretation. In a prospective study, 499 patients with melanoma Breslow thickness > 1.5 mm, and without clinically detectable lymph node metastases, were randomly assigned to 18 months of subcutaneous interferon-α2b or observation [bib_ref] Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma..., Grob [/bib_ref]. Patients treated with interferon-α2b demonstrated a significant improvement in relapse-free survival (RFS) (P = 0.038) and a trend toward improved OS (P = 0.059). In another trial, 855 patients were randomly assigned to observation or 4 weeks induction interferon-α2b followed by 1 or 2 years of interferon-α2b maintenance therapy [bib_ref] Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients..., Hansson [/bib_ref]. The study investigators reported an improvement in RFS for patients who received 1 year of maintenance interferon-α2b (hazard ratio [HR] 0.77, 95% Confidence interval [CI]: 0.63-0.96; P = 0.034), but no benefit in OS (HR 0.91, 95% CI: 0.74-1.10; P = 0.642). Several other prospective randomized trials examined interferon-α2b at a variety of doses and treatment schedules in patients with stage II melanoma, but none has demonstrated a survival benefit [bib_ref] Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the eastern cooperative..., Kirkwood [/bib_ref] [bib_ref] Prospective randomized trial of interferon alfa-2b and interleukin-2 as adjuvant treatment for..., Hauschild [/bib_ref] [bib_ref] Adjuvant interferon in high-risk melanoma: the AIM HIGH study-United Kingdom coordinating committee..., Hancock [/bib_ref] [bib_ref] Prospective randomized multicenter adjuvant dermatologic cooperative oncology group trial of lowdose interferon..., Hauschild [/bib_ref] [bib_ref] Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in..., Hauschild [/bib_ref] [bib_ref] High-and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial..., Kirkwood [/bib_ref]. A recently reported phase 3 randomized study in 1150 patients with resectable melanoma (T2bN0, T3a-bN0, T4a-bN0, and T1-4N1a-2a) who were randomly assigned to receive intravenous (IV) high-dose interferon-α2b for 5 days every week for 4 weeks or observation, produced equivalent 5-year RFS rates between groups. Moreover, 4 weeks of IV interferon-α2b resulted in higher rates of treatment-related grade 3 and higher toxicities (57.9% vs. 4.6%; P < .001) and worsened quality of life [bib_ref] Phase III randomized study of 4 weeks of high-dose interferon-α-2b in stage..., Agarwala [/bib_ref]. These studies are complicated by a lack of a standardized definition of 'high risk for relapse' , 23 different interferon-α2b dosages/formulations/schedules were evaluated, and in some cases, the inclusion of other drugs in combination. Thus, the efficacy of interferon in sentinel node negative stage II melanoma patients remains unresolved. To date, there are no data with ipilimumab, nivolumab, pembrolizumab, or BRAF-targeted therapy (either single-agent BRAF inhibitors or combined BRAF/MEK inhibitor therapy) to justify the use of these agents/regimens in patients with stage II melanoma. However, data from planned clinical trials may provide additional information to guide the use of the anti-PD1 agent pembrolizumab in this setting.
## Immunotherapy for stage iii melanoma
Stage III comprises a heterogeneous group of patients with 5-year survival rates ranging from 30 to 80% [bib_ref] Prediction of survival in patients with thin melanoma: results from a multi-institution..., Maurichi [/bib_ref]. While the previous consensus statement considered stage III patients as a single group, the Task Force strongly believed that, in patients with microscopic metastasis to a single lymph node (stage N1a), especially when the node has been excised by sentinel lymphadenectomy, cancer behaves differently than in patients with more extensive lymph node involvement (stages N1b-3). In the updated recommendations, patients with N1a disease, in accordance with the AJCC 7th edition were considered as a distinct subset; management recommendations by nodal staging are shown in [fig_ref] Figure 2: Stage III N1a [/fig_ref]. With the recent publication and adoption of the 8th edition of AJCC, which strived to identify a group of Stage III patients with significantly lower risk, the Task Force considered Stage IIIA (per AJJC 8th Ed.) to have lower risk of tumor recurrence compared to Stage IIIB-D. The management of stage III disease has also been complicated by recent data showing that, while immediate completion lymph node dissection was associated with a decreased rate of lymph node basin recurrence and increased disease-free survival in sentinel node-positive patients, there was no improvement in melanoma-specific survival [bib_ref] Completion dissection or observation for sentinel-node metastasis in melanoma, Faries [/bib_ref]. These findings along with the availability of more effective systemic treatment will change the management for sentinel node-positive patients, although all of the reported clinical trials of adjuvant therapy mandated completion lymph node dissection as a key eligibility criterion for study participation. Thus, the recommendations for stage III management should be considered carefully in light of these recent developments.
## Initial assessment
In all patients with stage lll melanoma, a diagnostic workup should be performed and reviewed by a multidisciplinary team for patient and tumor characteristics. Complete tumor staging information should be assessed, including pathological features of the primary tumor and any involved lymph nodes, as well as BRAF mutation testing. In addition, whole-body imaging (see [fig_ref] Table 1: Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma At present there are... [/fig_ref] and performance status assessment should be completed prior to making treatment decisions. Nodal status should be determined based on physical examination and sentinel lymph node biopsy (SNB) with or without subsequent completion lymphadenectomy if SNB is positive. The consensus panel identified five potential immunotherapy agents with potential clinical benefit in the adjuvant therapy of patients with stage III melanoma: interferon-α2b, pegylated interferon-α2b, ipilimumab, pembrolizumab, and nivolumab [bib_ref] Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage..., Eggermont [/bib_ref] [bib_ref] A pooled analysis of eastern cooperative oncology group and intergroup trials of..., Kirkwood [/bib_ref] [bib_ref] Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III..., Bottomley [/bib_ref] [bib_ref] Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy, Eggermont [/bib_ref] [bib_ref] Adjuvant Nivolumab versus Ipilimumab in resected stage III or IV melanoma, Weber [/bib_ref]. Furthermore, the consensus panel noted that the combination of the BRAF and MEK inhibitors, dabrafenib and trametinib, respectively, was recently shown to be superior to placebo in patients with stage III melanoma with BRAF V600E/K mutations; these data provide the first evidence for significant RFS and OS benefit of a targeted antitumor therapy that does not fit the putative immunotherapy approach and can be considered for patients with tumors harboring BRAF mutations [bib_ref] Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma, Long [/bib_ref].
Consensus management of microscopic single node disease (stage N1a -AJCC 7th; stage IIIA -AJCC 8th)
The majority of the panel (70%) recognized that patients with microscopically involved lymph nodes (N1a disease) represents a different population from those with macroscopic nodal disease (N1b and N2-N3 disease) and agreed that the AJCC 8th edition takes this into account by redefining Stage IIIA as being associated with a lower risk than in the AJCC 7th edition. However, whereas the majority (52%) of the former panel in 2014 recommended a standard 1-year course of interferon-α2b for adjuvant therapy of patients with microscopic nodal disease, only a small number recommended this therapy in this update. Rather, the majority of the panel (58%) recommended a clinical trial, 10% recommended observation, 5% ipilimumab (10 mg/kg), and 10% adjuvant interferon-α2b, if a clinical trial was not available. No panelists recommend pegylated interferon-α2b or ipilimumab given at 3 mg/kg (see [fig_ref] Figure 2: Stage III N1a [/fig_ref].
There is one prospective randomized clinical trial demonstrating a benefit in RFS for patients with microscopic nodal disease treated with pegylated interferon-α2b [bib_ref] Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage..., Eggermont [/bib_ref]. A post-hoc analysis of that trial also suggested patients with ulcerated primary tumors might derive more clinical benefit from pegylated interferon-α2b [bib_ref] Long term follow up of the EORTC 18952 trial of adjuvant therapy..., Eggermont [/bib_ref]. In this analysis, patients with ulceration of their primary melanoma (n = 849) were compared to patients without ulceration of their primary melanoma (n = 1336), and patients with ulceration demonstrated a significant improvement in RFS (P = 0.02), distant metastasis-free survival (P < 0.001) and OS (P < 0.001). The analysis also found that the greatest reduction in risk was seen in patients with ulcerated primary melanomas who were classified as stage IIb-IIIN1, demonstrating a HR of 0.58 for OS benefit (P < 0.0001) [bib_ref] Ulceration and stage are predictive of interferon efficacy in melanoma: results of..., Eggermont [/bib_ref]. Thus, patients with ulcerated primary tumors and those with microscopic nodal disease could consider pegylated interferon-α2b based on this Level B data, although further evaluation of this regimen is ongoing in an EORTC trial. Stage III N1a (7th)/Stage IIIA (8th) melanoma immunotherapy treatment algorithm. The consensus of the panel was to separate Stage III N1a (based on AJCC 7th edition) and Stage IIIA (AJCC 8th) from other Stage III subsets based on lower risk of metastatic potential. However, a minority (30%) felt that all Stage III patients should be treated similarly. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician's discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) There are limited data on the role of adjuvant therapy following sentinel lymphadenectomy alone, which is anticipated to become more common. (2) There is Level A evidence to support the use the combination of dabrafenib and trametinib in patients with BRAF V600E/K mutant, Stage III melanoma independent of the volume of lymph node involvement or the number of lymph nodes involved. (3) Level A data supporting the use of nivolumab over ipilimumab was demonstrated in patients with Stage IIIB to IV resected melanoma and did not include patients with Stage IIIA (based on 7th) disease. Ipilimumab 10 mg/kg dosing was supported by a minority of panelists (10%), however, subset analysis suggests that the risk: benefit ratio for patients with Stage IIIA melanoma does not support its use in Stage IIIA patients at this time. (4) There are level A data that 1 year interferon-α2b is associated with improvement in RFS and, while this therapy was generally recommended by the consensus panel previously, only two panelists recommended considering this therapy. There are level B data to support a benefit in RFS for pegylated-interferon-α2b in patients with N1a disease and in patients with ulceration of the primary tumor site; however, no panelists considered this a reasonable option for these patients. Abbreviations: LDH, lactate dehydrogenase; NCCN, National Comprehensive Cancer Network; RFS, recurrence-free survival Ipilimumab has been studied in patients with stage III melanoma in a prospective clinical trial (EORTC 18071), which randomized 951 patients to either placebo or ipilimumab, given at 10 mg/kg induction (4 doses every 3 weeks) followed by maintenance (every 12 weeks for up to 3 years) [bib_ref] Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy, Eggermont [/bib_ref]. With a median follow up of over 5 years, ipilimumab was associated with improved RFS compared to patients treated with placebo (median 27.6 vs. 17.1 months, HR 0.76, 95% CI: 0.64-0.89; P = 0.0008) and OS (5-year 65% vs. 54%, HR 0.72, 95% CI: 0.58-0.88; P = 0.001). However, in subgroup analysis, patients with stage IIIA disease, despite being required to have one or more nodal metastases at least 1 mm in size, had no evidence of benefit (HR 0.98, 95% CI: 0.46-2.09) [bib_ref] Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy, Eggermont [/bib_ref]. Thus, there was hesitation in considering adjuvant ipilimumab for patients with lower risk, stage III disease in light of known toxicity, although adjuvant ipilimumab was recommended by a minority of the panel (10%).
In an older trial, which included patients with completely resected stage IV or high-risk stage III melanoma, adjuvant granulocyte-macrophage colony stimulating factor (GM-CSF) did not demonstrate improvements in RFS response to individual therapeutic agents - There is considerable interest in PD-L1 expression, mutation burden, lymphocyte infiltration, interferon-γ and related cytokine gene signatures as potential biomarkers - There are data suggesting higher response rates to monotherapy, but not combination therapy, with T cell checkpoint inhibitors when PD-L1 expression is increased but the panel does not recommend PD-L1 status be used outside of clinical trials Laboratory Assessment - Immunotherapy is associated with significant irAEs that require laboratory monitoring before and during active treatment - Clinicians should be alert for irAEs during therapy and for several months after stopping treatment - All panelists agreed that baseline and routine labs should include complete blood count, liver enzymes, metabolic panel, serum LDH and thyroid function studies (free T4, TSH) - Additional hormone levels should be assessed in patient with suspected treatment-related hypophysitis (free T4, TSH, ACTH, morning cortisol, cosyntropin stimulation test, LH, FSH, testosterone, prolactin) and early endocrinology referral - The frequency of laboratory testing was more controversial with most panelists recommending testing prior to each infusion for most drugs and less frequent surveillance during follow-up Imaging Guidelines - Confirming disease response/progression may be challenging with immunotherapy due to the delayed kinetics of response and induction of local inflammation - The panel (100%) recommends whole body imaging for melanoma patients treated with immunotherapy prior to starting and at regular intervals no more than 12 weeks apart while disease persists - A majority of the panel recommends imaging with CT scans of the chest, abdomen and pelvis and MRI of the brain - A minority recommend initial imaging with PET scans - Imaging should continue after complete responses at regular intervals for five years to identify recurrence Treatment Cessation - Since the kinetics of response to immunotherapy may be delayed decisions to stop treatment can be challenging - The panel recommended stopping treatment for any unresolved or recurrent high grade adverse event or when disease progression is confirmed by two independent imaging scans or clinical deterioration - Pseudo-progression has been reported for checkpoint inhibitors and T-VEC but is rare for interferon and IL-2; most panelists suggested that treatment with interferon or IL-2 should be stopped with any sign of disease progression - Repeat imaging within 1-2 months was recommended to confirm response or progression when pseudo-progression is suspected - Minority opinions included considering surgical resection for incomplete responses and tumor biopsy for equivocal cases Abbreviations: ACTH adrenocorticotropic hormone, CT computed tomography, FSH follicle stimulating hormone, LH luteinizing hormone, MRI magnetic resonance imaging, PD-L1 programmed cell death 1 ligand, PET positron emission tomography, TSH thyroid stimulating hormone or OS in a randomized, placebo-controlled phase 3 study [bib_ref] Randomized, placebocontrolled, phase III trial of yeast-derived granulocyte-macrophage Colonystimulating factor (GM-CSF) versus..., Lawson [/bib_ref]. GM-CSF, an immunomodulatory agent with pleiotropic and sometimes opposing effects on antitumor immunity, remains investigational for any stage of melanoma, although its incorporation into an oncolytic virotherapy for intratumoral administration is approved for advanced melanoma, and its role in combination immunotherapy appears promising [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref] [bib_ref] Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a..., Hodi [/bib_ref]. Although immunomodulatory therapy is the only intervention that had ever shown promise in the adjuvant therapy of melanoma, there is now evidence that molecularly-targeted therapies can benefit patients with resected high-risk melanoma whose tumor cells carry an activating BRAF mutation. A trial of dabrafenib and trametinib given at standard doses (CombiAD), randomized 870 patients (1:1) to either the combination of dabrafenib and trametinib (D/T) or placebo for 1 year. This trial excluded patients with stage IIIA (N1) with a < 1 mm metastatic nodal deposit. With a median follow up of 2.8 years, D/T was associated with improved RFS (HR 0.47; 95% CI: 0.39-0.58, P < 0.001) and OS (HR 0.57; 95% CI: 0.42-0.79, P < 0.001) compared to placebo. Moreover, there were no additional safety concerns that arose with D/T that had not previously been seen in patients with unresectable or stage IV melanoma [bib_ref] Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma, Long [/bib_ref]. While this combination is not considered immunotherapy, inhibitors of BRAF and associated pathways in the tumor cell have been shown to have immunomodulatory properties that contribute to their activity. For these patients, the choice between molecularly targeted and immune checkpoint-based adjuvant therapy remains unclear, as direct comparisons have not yet been made. However, benefit was seen across all AJCC 7th (and by extrapolation 8th) edition stage III subgroups, and this combination can be considered for any patient with stage III, BRAF V600E/K -mutant melanoma. Stage III N1a (based on AJCC 7th edition) and Stage IIIA (AJCC 8th) from other Stage III subsets based on lower risk of metastatic potential. However, a minority (30%) felt that all Stage III subsets should be treated similarly. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician's discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) There are limited data on the role of adjuvant therapy following sentinel lymphadenectomy alone. (2) After evaluation by multi-disciplinary team with surgical oncology, if complete resection is possible patients should undergo resection followed by adjuvant therapy listed. If the tumor is considered unresectable, a different treatment paradigm should be followed. (3) In patients with Stage IIIB-IV resected melanoma, there is Level A evidence supporting the use of nivolumab over ipilimumab and pembrolizumab over placebo for stage IIIB-C and IIA patients with micrometastases > 1 mm. Accordingly, nivolumab or pembrolizumab were supported by 46% of the panel. (4) Ipilimumab at 3 mg/kg was supported by a minority of panelists (8.3%). (5) There is Level A evidence to support the use the combination of dabrafenib and trametinib in patients with BRAF V600E/K mutant, Stage III melanoma. (6) While there are Level A data that 1 year interferon-α2b is associated with improvement in RFS, no panelists recommended considering this therapy for this patient population. (7) Overall, the majority of panelists recommended a clinical trial, if available. [bib_ref] Improved survival with ipilimumab in patients with metastatic melanoma, Hodi [/bib_ref] The majority of the panelists have had experience with T-VEC, and half of respondents said they would recommend T-VEC for first-line treatment for limited disease burden, and a significant minority (39%) would consider T-VEC for patients with locoregional disease. (9) Unresectable disease could be managed by options available for stage IV patients (see [fig_ref] Figure 4: See legend on next page [/fig_ref]. Abbreviations: CR, complete response; LDH, lactate dehydrogenase; NCCN, National Comprehensive Cancer Network; PD, progressive disease; RFS, recurrence-free survival, TVEC, talimogene laherparepvec Consensus management of macroscopic nodal disease (stage N1b/c, N2b/c, N3b/c in 7th edition or stage IIIB-IIID in 8th edition)
Patients with macroscopic involvement of a single or multiple lymph nodes (stage N1b and N2b-N3 disease per AJCC 7th Edition; or Stages IIIB-IIID in AJCC 8th Edition) are at significant risk for melanoma recurrence. The panel recommendations for these melanoma patients are detailed in [fig_ref] Figure 3: Stage III N1b-3 [/fig_ref]. Whereas the majority of the panel in 2014 recommended that these patients consider 1 year of interferon-α2b treatment (73%) [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref] , in the current setting, the majority of panelists recommended either a clinical trial (56%), or if a trial is not available then adjuvant nivolumab based on the results of the CheckMate 238 trial, or adjuvant pembrolizumab based on the results of the recent phase III clinical trial (46% of panelists) [bib_ref] Adjuvant Nivolumab versus Ipilimumab in resected stage III or IV melanoma, Weber [/bib_ref] [bib_ref] Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma, Long [/bib_ref] [bib_ref] Adjuvant Pembrolizumab versus placebo in resected stage III melanoma, Eggermont [/bib_ref]. A minority of panelists would consider adjuvant ipilimumab (8%) based on the results of the EORTC 18071 trial [bib_ref] Long term follow up of the EORTC 18952 trial of adjuvant therapy..., Eggermont [/bib_ref]. For patients whose tumor harbors a BRAF V600E/K mutation, combination dabrafenib/trametinib may be preferred over immunotherapy since the impact of adjuvant checkpoint inhibitors on the management of subsequent disease progression is not known. Of note, no panelists recommend pegylated interferon-α2b for patients with resected macroscopic nodal disease, and only one panelist considered high-dose interferon-α2b as an option if a clinical trial was not available.
CheckMate 238 is a phase 3 trial that randomized 906 patients with resected stage IIIB-IV melanoma to either 1 year of nivolumab (3 mg/kg every 2 weeks) or ipilimumab (10 mg/kg every 3 weeks for 4 doses, followed by every 12 weeks). With minimum follow-up of 18 months, the trial met its primary endpoint showing that nivolumab was associated with an improved RFS compared with ipilimumab (RFS at 12 months 70.5% vs. 60.8% for nivolumab and ipilimumab, respectively; HR 0.65; CI: 0.51-0.83; P < 0.001). Furthermore, the rate of treatment-related grade 3-4 toxicity was 14.4% with nivolumab vs. 42.6% in patients treated with ipilimumab [bib_ref] Adjuvant Nivolumab versus Ipilimumab in resected stage III or IV melanoma, Weber [/bib_ref]. OS data were immature and not reported. The data from this trial led to the FDA-approval of nivolumab in patients with resected Stage III melanoma.
More recently, a prospective, double-blind phase III clinical trial was conducted in patients with resected, high-risk stage III melanoma. In this study patients were eligble if they had stage IIIB or IIIC, while a subset of patients with stage IIIA were also included if they had at least one micrometastasis measuring > 1 mm. The trial randomly assigned 514 patients to treatment with 200 mg of pembrolizumab and 505 patients to placebo every 3 weeks for 1 year [bib_ref] Adjuvant Pembrolizumab versus placebo in resected stage III melanoma, Eggermont [/bib_ref]. In this study, patients were stratified by cancer stage and geographic location. At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival compared to placebo in the intention-to-treat population . In a cohort of 853 patients with PD-L1-positive tumors, the 1-year rate of recurrence-free survival was 77.1% in the pembrolizumab treated group compared to 62.6% in the placebo group (HR 0.54; 95% CI: 0.42-0.69). Grade 3 or greater adverse events were observed in 14.7% of patients treated with pembrolizumab -with one treatment-related death attributed to myositis -versus 3.4% in patients treated with placebo.
In light of these newer data, patients with resected stage IIIB, IIIC, and IV melanoma could consider several options, and the panel considered anti-PD-1 antibody therapy with either nivolumab or pembrolizumab (46%), ipilimumab at 3 mg/kg (8%), D/T in BRAF mutant patients 1 (13%), or high-dose interferon (4%) as acceptable recommendations. Almost one third of the panel members (29%) were unable to make a specific recommendation. These members suggested using either anti-PD-1 therapy or D/T, while others preferred the use of D/T if the tumor was BRAF mutant or enrollment onto a clinical trial incorporating ipilimumab at 3 mg/kg. The recommendation to use low dose ipilimumab is supported by data from the phase III U.S. Intergroup E1609 study in which patients with resected high-risk melanoma were treated with interferon-α, ipilimumab at 10 mg/kg or ipilimumab at 3 mg/kg; while there was no obvious difference in recurrence-free survival between the two ipilimumab cohorts (although no formal statistical comparison was performed), there was a significant increase in toxicity reported for the 10 mg/kg cohort compared with 3 mg/kg [bib_ref] A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg)..., Tarhini [/bib_ref]. No panelists endorsed observation as a clinical option.
## Consensus management of unresectable stage iii/iv melanoma with injectable lesions
In patients with unresectable stage III disease, the use of T-VEC, an oncolytic herpes virus engineered to express GM-CSF, was felt to be appropriate by a significant minority of panelists (39%). This recommendation was based on results from a prospective, randomized trial in which 436 patients with unresectable stage IIIB-IV melanoma were randomized in a 2:1 fashion to treatment with T-VEC or recombinant GM-CSF [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref]. The primary endpoint of the study was durable response rate (DRR), which was significantly better for T-VEC treated patients compared to control subjects (16.3% vs. 2.1%, odds ratio [OR] 8.9; P < 0.001). T-VEC was also associated with improved objective response rate (ORR 26.4% vs. 5.7%) and OS (median OS 23.3 months for T-VEC vs. 18.9 months for control, HR 0.79, P = 0.051). On a pre-specified subset analysis, however, a particularly strong effect was seen in patients with stage IIIB-IVM1a disease, where the DRR was 33% vs. 0% in stage III patients and 16% vs. 2% for stage IVM1a patients. A similar effect on OS was seen in the stage III-IVM1a patients with a 43% improvement in survival for patients treated with T-VEC [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref]. Thus, there is Level A data supporting T-VEC in these patients, and T-VEC may be more appropriate for patients with limited visceral disease. Other options for this patient population would be enrollment onto a clinical trial or treatment as stage IV melanoma (see [fig_ref] Figure 4: See legend on next page [/fig_ref]. Of particular interest are the multiple emerging trials of neo-adjuvant/pre-operative therapy for patients with melanoma of borderline resectability, who may be better served by initial cytoreduction and possibly a scenario, if significant response is seen, where the patient may not require resection.
## Immunotherapy for stage iv melanoma initial assessment
In patients with stage lV melanoma, a diagnostic workup that includes a multidisciplinary team review of clinical and tumor data should be conducted. Staging should be confirmed via pathological evaluation, whole body imaging, and serum LDH analysis. Genetic mutation analysis of the tumor should also be performed with special emphasis on identifying mutations in BRAF. In addition, careful attention should be paid to central nervous system (CNS) assessment since melanoma patients are at high risk of CNS metastasis. Thus, in addition to computed tomography (CT) imaging of the chest, abdomen and pelvis, an MRI of the brain should be obtained to fully stage potential metastatic melanoma patients. Surgical evaluation by a multi-disciplinary team that includes an experienced surgical oncologist for possible metastectomy is important, especially in patients with solitary pulmonary metastasis where complete extirpation is possible. If complete resection of all metastatic disease is likely, metastasectomy can be considered based on Level B retrospective outcome studies, but the panel agreed that this operative management is less compelling as systemic therapy improves [bib_ref] Metastasectomy for stage IV melanoma, Deutsch [/bib_ref] [bib_ref] Metastasectomy for stage IV melanoma in the era of effective systemic agents, Ollila [/bib_ref] [bib_ref] Association of Surgical Treatment, systemic therapy, and survival in patients with abdominal..., Deutsch [/bib_ref]. Patients who achieve partial response (PR) or stable disease (SD) following immunotherapy should also be reassessed for possible resection [bib_ref] Metastasectomy following immunotherapy with adoptive cell transfer for patients with advanced melanoma, Klemen [/bib_ref] [bib_ref] Treatment of oligometastases after successful immunotherapy, Yang [/bib_ref]. The panel recognizes several systemic treatment options for patients with unresectable stage IV melanoma, including immunotherapy with high-dose IL-2 (where available), ipilimumab, nivolumab, pembrolizumab, T-VEC (if accessible lesions are present), combination ipilimumab and nivolumab, clinical trial participation, and cytotoxic chemotherapy [bib_ref] High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of..., Atkins [/bib_ref] [bib_ref] Improved survival with ipilimumab in patients with metastatic melanoma, Hodi [/bib_ref] [bib_ref] Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma, Hamid [/bib_ref] [bib_ref] Nivolumab in previously untreated melanoma without BRAF mutation, Robert [/bib_ref] [bib_ref] Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma, Larkin [/bib_ref] [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref]. Additionally, vemurafenib, dabrafenib, trametinib, and the combinations of either dabrafenib and trametinib or vemurafenib and cobimetinib are options for patients with BRAF-mutated tumors [bib_ref] Improved survival with vemurafenib in melanoma with BRAF V600E mutation, Chapman [/bib_ref] [bib_ref] Dabrafenib in BRAFmutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled..., Hauschild [/bib_ref] [bib_ref] Improved survival with MEK inhibition in BRAF-mutated melanoma, Flaherty [/bib_ref] [bib_ref] Improved overall survival in melanoma with combined dabrafenib and trametinib, Robert [/bib_ref] [bib_ref] Combined vemurafenib and cobimetinib in BRAF-mutated melanoma, Larkin [/bib_ref]. An additional combination regimen of potent BRAF and MEK inhibitors (encorafenib and binimetinib) is anticipated to receive regulatory approval in the future.
The panel considered the overall approach to the patient with stage IV melanoma and, while previous recommendations suggested that BRAF mutation status and performance status be considered as critical elements in the decision-making process, all Task Force participants agreed that immunotherapy should be considered prior to targeted therapy in patients with good performance status, based on the potential for durable responses with immunotherapy. There is little data available to support optimal sequencing of targeted therapy and immunotherapy in this setting. However, two retrospective studies have suggested enhanced clinical benefit from immunotherapy administered prior to BRAF-targeted therapy in those patients who required both (those who did not achieve durable or curative responses to the first line of therapy) [bib_ref] Metastasectomy for stage IV melanoma in the era of effective systemic agents, Ollila [/bib_ref] [bib_ref] Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma:..., Ascierto [/bib_ref]. A data series of 274 patients with BRAF-mutated melanoma who sequentially received BRAF inhibitors and immunotherapy (high-dose IL-2, ipilimumab, or PD-1 inhibitors) illustrated that ipilimumab therapy after BRAF inhibitors was associated with no tumor response and poor survival [bib_ref] Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or..., Ackerman [/bib_ref]. In another study of 93 patients with BRAF-mutated melanoma who received BRAF inhibitors (vemurafenib or dabrafenib) before or after ipilimumab, longer OS was found in the cohort of patients receiving ipilimumab prior to BRAF inhibitor therapy (14.5 vs. 9.9 months, P = 0.04) [bib_ref] Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma:..., Ascierto [/bib_ref]. In both studies, the response rates to BRAF-targeted therapy was similar regardless of prior immunotherapy. Thus, starting with immunotherapy may provide patients with an opportunity for long-term benefit without negatively affecting the activity of BRAF inhibitor therapy. In order to determine optimal sequencing, the ECOG-ACRIN-led intergroup randomized protocol EA6134 (NCT02224781) has been initiated to compare the sequential administration of ipilimumab/ nivolumab and dabrafenib/trametinib. OS at the 2-year landmark, the primary endpoint of this randomized phase 3 trial, is expected to be reported in 2019 or 2020.
In this edition of the guidelines, the panel suggested that key elements to consider for individual patients should include clinical performance status, tumor burden, and presence of visceral metastases (compared to M1a patients with cutaneous, soft tissue or nodal only metastatic disease), and the tempo of disease progression. While there is limited evidence, where available, most immunotherapy agents do appear to be effective against CNS metastases from melanoma [bib_ref] Safety and clinical activity of ipilimumab in melanoma patients with brain metastases:..., Weber [/bib_ref] [bib_ref] Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases, Guirguis [/bib_ref] [bib_ref] Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases, Parakh [/bib_ref]. Data recently reported from two studies also show evidence that combination nivolumab/ipilimumab has clinical activity in patients with asymptomatic brain metastases [bib_ref] Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases, Parakh [/bib_ref] [bib_ref] Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with..., Tawbi [/bib_ref]. In 75 patients with > 1 measurable brain metastasis who received combination ipilimumab/nivolumab, the intracranial response rate (IRR) was 56% (95% CI: ; in addition, 19% of patients had a complete response (CR) [bib_ref] Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with..., Tawbi [/bib_ref]. Moreover, in 50 patients with untreated brain metastases, both nivolumab monotherapy (ICR 20% [95% CI: 7-41]) and combination ipilimumab/nivolumab (ICR 44% [95% CI: 24-65]) were found to be active [bib_ref] A randomized phase II study of nivolumab or nivolumab combined with ipilimumab..., Long [/bib_ref]. Based on the discussion, recommendations for the management of stage IV melanoma were considered independently for patients with a good performance status, generally low disease burden and slow tempo of disease progression versus patients with a declining performance status, widespread visceral metastases and/or rapid disease progression [fig_ref] Figure 4: See legend on next page [/fig_ref]. Extent of CNS involvement, mass effect, cerebral edema and steroid requirements and symptoms will also factor into treatment decisions.
## Consensus management of stage iv melanoma patients with a good clinical performance status
The treatment approach for patients with good performance status stage IV melanoma who are not surgical candidates should include an assessment of BRAF mutation status, history and physical examination, serum LDH, baseline laboratory evaluation and whole body imaging (see [fig_ref] Table 1: Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma At present there are... [/fig_ref] , and assessment of tempo of disease, tumor burden, and presence or absence of CNS disease before treatment selection. Only a minority of panelists felt that PD-L1 expression status (15%) or tumor cell mutation burden (10%) was important for treatment planning. For a typical patient with a good performance status, regardless of BRAF status, a majority of the panel members recommended enrollment onto a clinical trial (75%) as a first-line option, followed by treatment with combination ipilimumab and nivolumab, which was favored over single-agent PD-1 inhibitor therapy (pembrolizumab or nivolumab) by three of the five members who did not favor clinical trial. This ratio of support for combined ipilimumab and nivolumab versus single-agent anti-PD-1 therapy held up by the panel when a clinical trial was not an option (12 of 20 respondents). Half of the panelists felt that the selection of the combination of ipilimumab and nivolumab should mandate transfer of the patient to a physician or center with more immunotherapy experience due to the higher toxicity incidence and complexity associated with combination immunotherapy. Panel members (83%) also suggested that T-VEC be considered if accessible lesions for injection are present in patients whose disease has progressed after combination or monotherapy checkpoint inhibitors and who still maintain a good performance status.
Participation in clinical trials is dependent on having access to appropriate studies and ensuring that patients meet protocol-specific eligibility requirements. In addition, patients must be willing to participate in a clinical trial and provide written, informed consent. The high priority placed (See figure on previous page.) [fig_ref] Figure 4: See legend on next page [/fig_ref] Stage IV melanoma immunotherapy treatment algorithm. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician's discretion. These algorithms represent consensus sequencing suggestions by the panel. The panel recommended all patients be evaluated with full body imaging, histopathology review, serum LDH, and tumor mutation analysis with emphasis on BRAF mutations. Other factors to be considered in selecting appropriate treatment should include performance status, burden and tempo of disease and presence of CNS metastases. (1) All patients should be evaluated for resection by a multi-disciplinary team including surgical oncology before and after immunotherapy treatment, although the role of surgery is changing and may be appropriate for patients with solitary pulmonary lesions where complete extirpation is possible; each case must be individualized.
(2) All patients should have an MRI of the brain prior to treatment to rule out or manage CNS metastasis. (3) There was level B data for a clinical benefit with surgical resection when complete excision of all disease is possible although first-line surgical resection was a minority opinion of the panel. (4) As determined by an experienced surgical oncologist, patient is eligible to receive surgical intervention as first-line treatment. (5) Immunotherapy was recommended for any patient with a good performance status regardless of BRAF mutation status and provided that any CNS disease was treated and controlled. Clinical trial was the favored first line approach by the panel. 6) In the absence of an appropriate clinical trial, the panel recommended combination ipilimumab and nivolumab based on the high response rates reported. This may also be preferred for patients with CNS disease with a minority of panelists (33.3%) recommending stereotactic radiation prior to systemic therapy for CNS lesions (7) Next, the panel recommended single agent anti-PD-1 therapy (pembrolizumab or nivolumab). The panel considered these agents to have the same therapeutic efficacy and treatment selection could be based on physician experience and patient preference. [bib_ref] Improved survival with ipilimumab in patients with metastatic melanoma, Hodi [/bib_ref] The panel also recommended T-VEC in patients with accessible tumor for injection and limited visceral tumor burden. This option may be especially appropriate for elderly patients and those not eligible for checkpoint inhibitors. (9) Patients with poor performance status were not considered good candidates for combination immunotherapy and BRAF mutation was an important factor for determining therapeutic planning. Most panelists considered clinical trials to be the most important option in these patients, if available. In those patients without a BRAF mutation, the next option should be single agent anti-PD-1 therapy (pembrolizumab or nivolumab). (10) In patients with poor performance status and a BRAF mutation who are not eligible or whose tumors progress after a clinical trial, treatment with a BRAF and/or MEK inhibitor therapy is indicated. This option was also considered appropriate for patients with uncontrolled CNS disease. Single agent anti-PD-1 treatment could be considered if disease progression occurs after targeted therapy. [bib_ref] Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma, Larkin [/bib_ref] In patients with disease progression following the recommendations, management should be carefully considered. If patients can tolerate treatment, ipilimumab/ nivolumab should be considered. If patients have a BRAF mutation and have not been treated with BRAF/MEK inhibitors previously these can be considered. Ipilimimab monotherapy and high-dose IL-2 can also be considered in these patients. [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref] Patients should have a good PS and otherwise qualify for IL-2 administration per local institutional guidelines.Dacarbazine is the only approved chemotherapy agent but temozolomide and carboplatin/paclitaxel are often used as well depending on patient preference and physician experience. Abbreviations: BRAF+, positive for actionable BRAF mutations; BRAF-, negative for actionable BRAF mutations; CNS, central nervous system; IL, interleukin; LDH, lactate dehydrogenase; PS, performance status on clinical trials is a reflection of the progress being made in clinical drug development in melanoma and interest in defining more effective regimens with acceptable toxicity. If such clinical trials are not readily available or patients are not willing or do not qualify for participation, combination ipilimumab and nivolumab was considered the treatment of choice for patients with good performance status. This recommendation was based on a series of prospective clinical trials demonstrating improved response rates with the combination, although increased incidence of immune-related adverse events (irAEs) was also reported. In a phase 1 study, 53 melanoma patients were treated with concurrent nivolumab (doses ranged from 0.3-10 mg/kg) and ipilimumab (dose ranged from 1 to 10 mg/kg) IV every 3 weeks for four doses followed by nivolumab alone every 3 weeks for another four doses [bib_ref] Nivolumab plus ipilimumab in advanced melanoma, Wolchok [/bib_ref]. The ORR was 40% based on World Health Organization (WHO) criteria with a disease control rate of 65% [bib_ref] Nivolumab plus ipilimumab in advanced melanoma, Wolchok [/bib_ref]. Treatment-related adverse events (TRAEs) were seen in 93% of patients with grade 3 or greater events from all causes observed in 72%; 53% were considered treatment-related. The authors concluded that the maximum doses with an acceptable safety profile were nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg, with objective responses seen in 53% of patients treated with this dosing regimen [bib_ref] Nivolumab plus ipilimumab in advanced melanoma, Wolchok [/bib_ref].
Following the phase 1 data, a double-blind study was conducted in 142 treatment-naïve, metastatic melanoma patients and enrolled in a 2:1 manner to treatment with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) or ipilimumab (3 mg/kg) and placebo every 3 weeks for four doses [bib_ref] Nivolumab and ipilimumab versus ipilimumab in untreated melanoma, Postow [/bib_ref]. Patients in the combination group were able to receive additional maintenance nivolumab and at a median follow-up of 24.5 months, 2-year OS was 63.8% for those in the combination treatment arm vs. 53.6% in the ipilimumab arm [bib_ref] Nivolumab and ipilimumab versus ipilimumab in untreated melanoma, Postow [/bib_ref]. Of note, patients in the ipilimumab arm were permitted to cross over to nivolumab monotherapy at time of disease progression, making this trial a study of combination ipilimumab and nivolumab vs. sequential ipilimumab followed by nivolumab. Interestingly, there was a 22% CR rate and improvement in progression-free survival (PFS) for the combination although median OS was not reached in either treatment group. Similar to other trials, the grade 3 or greater TRAE rate was 54% in the combination cohort compared to 20% in the ipilimumab alone cohort.
These data led to a randomized phase 3 trial in which 945 treatment-naïve patients with unresectable stage III or IV melanoma were randomized in a 1:1:1 ratio to treatment with ipilimumab and nivolumab, nivolumab alone or ipilimumab alone [bib_ref] Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma, Larkin [/bib_ref]. The study was designed with two primary endpoints, PFS and OS, with a significant improvement seen in PFS (11.5 months for the combination treated patients vs. 2.9 months for ipilimumab alone [HR 0.42, P < 0.001] and 6.9 months for nivolumab alone [HR 0.57, P < 0.001]). In this study, patients whose tumors exhibited > 5% PD-L1 expression had a median PFS of 14 months in both combination and nivolumab alone arms; however, in patients with PD-L1 negative tumors, the median PFS was 11.2 months for combination treated subjects compared to 5.3 months in patients treated with nivolumab alone. TRAEs of grade 3 or greater were reported in 55% of the combination treated patients, 16.3% in those receiving nivolumab alone and 27.3% in the ipilimumab alone cohort. At a minimum follow-up of 37 months, the median OS has not been reached for patients on the combination arm compared to 37.6 months and 19.9 months in patients receiving nivolumab or ipilimumab alone, respectively [bib_ref] Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma, Wolchok [/bib_ref]. The three-year OS was 58% for combination therapy patients compared to 52% in nivolumab alone (HR 0.85, 95% CI: 0.68-1.07; non-significant P-value) and 34% in patients treated with ipilimumab alone (HR for ipilimumab/nivolumab vs. ipilimumab 0.55, 95% CI: 0.45-0.69; P < 0.0001; HR for nivolumab vs. ipilimumab 0.65, 95% CI: 0.53-0.80; P < 0.0001) [bib_ref] Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma, Wolchok [/bib_ref].
The above described studies collectively provide Level A evidence supporting the role of combination ipilimumab and nivolumab for first-line treatment in patients with melanoma. However, the lack of a significant OS benefit for the combination over nivolumab alone, particularly in patients with BRAF WT or PD-L1-expressing tumors [bib_ref] Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma, Wolchok [/bib_ref] , suggests it is reasonable to consider anti-PD-1 agents alone at this time. In CheckMate 067, a sub-group analysis showed significant improvement in PFS and numerical improvement in OS with combination therapy only in patients with low (< 5 and < 1%) PD-L1 staining; however, the panel did not consider there to be sufficient data to support a role for PD-L1 expression in clinical decision-making at this time [bib_ref] Nivolumab plus ipilimumab in advanced melanoma, Wolchok [/bib_ref] [bib_ref] Nivolumab and ipilimumab versus ipilimumab in untreated melanoma, Postow [/bib_ref] [bib_ref] Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma, Wolchok [/bib_ref]. While adverse events are significantly greater with combination ipilimumab/nivolumab treatment compared to monotherapy, there is some evidence that health-related quality of life may not be significantly impacted by concurrent combination treatment [bib_ref] Health-related quality of life results from the phase III CheckMate 067 study, Schadendorf [/bib_ref] due to a greater time without disease related symptoms or treatment toxicity (as measure by QTWIST) [bib_ref] Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with stage III/IV melanoma, Sherrill [/bib_ref].
The panel went on to recommend monotherapy with anti-PD-1 agents as another option for patients who are not able to participate in a clinical trial or are not eligible for combination ipilimumab/nivolumab. There are two agents available, pembrolizumab, which is administered at 200 mg IV every 3 weeks, and nivolumab administered at 240 mg IV every 2 weeks or 480 mg IV every 4 weeks (per a recent change to non-weight-based dosing). The panel considered these drugs equally effective, with indistinguishable toxicities, and advised that selection can be based on physician experience or patient preference.
Pembrolizumab and nivolumab are monoclonal antibodies that block the PD-1 T cell checkpoint, and there are considerable data supporting their use in the treatment of metastatic melanoma. In a clinical dose-finding study, patients with advanced melanoma were treated with pembrolizumab (initially called lambrolizumab) at a dose of 10 mg/kg every two or three weeks or 2 mg/kg every 3 weeks [bib_ref] Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma, Hamid [/bib_ref]. Patients were allowed, but not required, to have had prior ipilimumab therapy to be eligible for study participation. The study enrolled 135 patients and the response rate assessed by standard Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was 38% without significant differences between doses or by prior ipilimumab exposure. The responses were durable with 81% of patients still in response at a median follow-up of 11 months. The most frequent adverse events were fatigue, rash, pruritus and diarrhea, and these were generally grade 2 or less [bib_ref] Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma, Hamid [/bib_ref]. Pembrolizumab was also evaluated in a separate multi-institutional phase 1 study evaluating doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma [bib_ref] Anti-programmed-deathreceptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort..., Robert [/bib_ref]. In this study, 173 patients received 2 mg/kg (n = 89) or 10 mg/ kg (n = 84) pembrolizumab and data were reported at a median follow-up of 8 months. The response rate by RECIST was 26% at both doses. Treatment was considered tolerable with the most frequent TRAEs being fatigue, pruritus, and rash; all were grade 2 or less except for five patients (3%) who reported grade 3 fatigue [bib_ref] Anti-programmed-deathreceptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort..., Robert [/bib_ref]. These studies led to the regulatory approval of pembrolizumab, at a dose of 2 mg/kg every 3 weeks, for the treatment of patients with metastatic melanoma. The approved dose and schedule was subsequently changed to 200 mg IV every 3 weeks.
In a multi-institutional phase 2 study, 540 melanoma patients with disease that had progressed following ipilimumab and BRAF/MEK inhibitor therapy, if their tumors harbored a BRAF (V600) mutation, were randomized 1:1:1 to treatment with pembrolizumab at 2 mg/kg every 3 weeks (N = 180), 10 mg/kg every 3weeks (N = 181) or investigator-choice chemotherapy (N = 179) [bib_ref] Pembrolizumab versus investigatorchoice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase..., Ribas [/bib_ref]. Patients were stratified for performance status, LDH level and BRAF mutation status. The PFS was significantly better for patients in both pembrolizumab treatment arms compared to chemotherapy (HR 0.57, P < 0.0001 for 2 mg/kg and HR 0.50, P < 0.0001 for 10 mg/kg). The 6-month PFS was 34% in patients treated with pembrolizumab at 2 mg/kg, 38% at 10 mg/ kg and 16% for chemotherapy. The toxicity profile was similar to previous pembrolizumab trials with an incidence of grade 3-4 adverse events of 11 and 14% in the pembrolizumab 2 mg/kg and 10 mg/kg cohorts, compared to 26% for patients receiving chemotherapy. These data were also similar to another global phase 1b clinical study in which 655 melanoma patients were treated with pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks until disease progression, intolerable toxicity, or investigator decision to stop treatment [bib_ref] Association of Pembrolizumab with Tumor Response and Survival among Patients with Advanced..., Ribas [/bib_ref]. In this study, investigators evaluated the impact of pembrolizumab based on prior exposure to ipilimumab. To address this, 135 patients (48 with prior ipilimumab and 87 without) were enrolled without randomization and 520 patients were prospectively randomized (294 with prior ipilimumab and 226 without). Response rates were reported at a median follow-up of 21 months; response rates were 33% in patients with prior ipilimumab exposure and 45% in treatment-naïve patients. The 12-month PFS was 35% overall and 52% in treatment-naïve patients, and the median OS was 23 months overall and 31 months in treatment-naïve subjects. Overall, 14% of patients reported at least one grade 3 or greater TRAE. These results confirmed response rates seen in the phase 1 trials and also supported the 2 mg/kg dosing schedule.
These initial studies were followed by a randomized phase 3 clinical trial in which 834 patients with advanced melanoma were randomized 1:1:1 to pembrolizumab (10 mg/kg) every 2 weeks or every 3 weeks or four doses of ipilimumab (3 mg/kg) every 3 weeks [bib_ref] Pembrolizumab versus Ipilimumab in Advanced Melanoma, Robert [/bib_ref]. The study was powered for primary endpoints of PFS and OS. In this study, the estimated 6-month PFS was 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks and 26.5% for ipilimumab (HR, 0.58; P < 0.001). The response rate was higher with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), vs. ipilimumab (11.9%) (P < 0.001 for both comparisons) and responses were durable in 89.4, 96.7, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Grade 3 or greater TRAEs were lower in the pembrolizumab cohorts (13.3 and 10.1%) compared to ipilimumab alone (19.9%).
The panel was queried about when single-agent anti-PD-1, as opposed to combination immunotherapy, was most appropriate. In considering BRAF mutation, LDH, PD-L1 expression status and mucosal histology, 42% of panelists stated that PD-L1 expression was the most important discriminating factor supporting single agent anti-PD-1 treatment, despite lack of level A evidence. One each said mucosal melanoma or PD-L1 negative status should prompt combination therapy, two stated that single-agent PD-1 therapy should always be favored, and 10 panelists felt that a number of other factors should be considered, including medical co-morbidities (e.g. autoimmune disease, history of organ transplantation, etc.), disease volume/tumor burden, site of disease, performance status, functional status, and patient preference.
Pembrolizumab has also been tested in a non-randomized phase 2 study in 52 patients with CNS metastases; eighteen patients with melanoma and 34 with non-small cell lung cancer (NSCLC) presented with untreated brain metastases and were treated with 10 mg/kg every 2 weeks until disease progression [bib_ref] Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain..., Goldberg [/bib_ref]. Eligible patients had metastatic lesions measuring 5-20 mm, had no neurologic symptoms, did not require corticosteroids, and for the NSCLC cohort were required to have positive tumor PD-L1 expression. A preliminary analysis was reported with evidence of CNS disease response in 4 of the 18 (22%) patients with melanoma and 6 of 18 (33%) patients with NSCLC. The responses appeared to be durable and TRAEs were typical of pembrolizumab toxicity in other studies and only 3 patients (17%) with melanoma had neurologic toxicities, including grade 3 cognitive dysfunction and grade 1-2 seizures. The authors concluded that pembrolizumab was safe in patients with CNS metastasis and might be associated with therapeutic responses.
Finally, a minority of panel members (46%) who were familiar with T-VEC recommended T-VEC be considered in patients with good performance status stage IV melanoma based on the results of the previously mentioned randomized phase 3 clinical trial [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref]. This requires that tumors be clinically visible or palpable for injection or be accessible by ultrasound guidance. This option may be especially appropriate for patients who are not candidates for T cell checkpoint inhibitors, such as patients with significant co-morbid conditions, or older patients unable to tolerate significant systemic toxicity [fig_ref] Figure 4: See legend on next page [/fig_ref].
Patients with tumors that do not respond to ipilimumab and nivolumab, monotherapy with anti-PD-1 agents, or T-VEC should be treated according to the guidelines for poor performance status patients (see [fig_ref] Figure 4: See legend on next page [/fig_ref] and treatment selection will depend on BRAF mutation status and which drug(s) an individual patient has already received. In general, panel members recommended targeted therapy (if BRAF mutation is present), combination immunotherapy (if not previously received and performance status is good), ipilimumab monotherapy (if the patient has not been previously exposed to the agent), high-dose IL-2, clinical trial participation, or chemotherapy.
There is considerable evidence supporting a role for high-dose IL-2 in the treatment of patients with stage IV melanoma, and the drug has been approved since 1998. A fairly consistent ORR of 16-17%, including 6-7% CRs, has been reported [bib_ref] High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of..., Atkins [/bib_ref]. Further analysis of the original 270 patients treated in the regulatory trials at a median follow-up at 7 years demonstrated a median duration of response that was unchanged in patients achieving an initial CR or PR at 8.9 and 5.9 months, respectively [bib_ref] High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update, Atkins [/bib_ref]. The benefits of IL-2 and contemporary management of IL-2-related toxicity has been previously reported [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref] [bib_ref] High dose interleukin-2 (Aldesleukin) -expert consensus on best management practices-2014, Dutcher [/bib_ref]. Treatment generally requires referral to centers with experience in management of high-dose IL-2 and patients should have a good performance status when starting treatment.
## Consensus management of patients with stage iv melanoma and poor clinical performance status
The panel considered that patients with a poor or declining performance status, those with extensive disease burden, rapid tempo of progression, presence of active CNS disease and those that have documented disease progression after T cell checkpoint inhibitors or T-VEC should be treated differently than those with overall good performance status, limited disease burden, slow tempo of progression and without active CNS metastasis. Patients with poor performance status should have BRAF mutation analysis to determine if there is a V600 or other targetable mutation, for which targeted therapy regimens are available [bib_ref] Improved survival with vemurafenib in melanoma with BRAF V600E mutation, Chapman [/bib_ref] [bib_ref] Dabrafenib in BRAFmutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled..., Hauschild [/bib_ref] [bib_ref] Improved survival with MEK inhibition in BRAF-mutated melanoma, Flaherty [/bib_ref] [bib_ref] Improved overall survival in melanoma with combined dabrafenib and trametinib, Robert [/bib_ref] [bib_ref] Combined vemurafenib and cobimetinib in BRAF-mutated melanoma, Larkin [/bib_ref]. Noting that clinical trial participation in patients with poor performance status is challenging due to protocol restrictions, the panel applauded efforts by the ASCO-Friends of Cancer Research working group, which is taking steps to broaden clinical trial eligibility and recommended that, whenever feasible, these patients be considered for clinical trial participation whether or not their tumor harbors a BRAF mutation (see [fig_ref] Figure 4: See legend on next page [/fig_ref]. In the absence of a BRAF mutation, and if clinical trials are not an option, the panel recommended treatment with single agent anti-PD-1 therapy, such as pembrolizumab or nivolumab based on the Level A data described above. In patients whose tumor harbors a BRAF mutation and who are not eligible for clinical trial participation, treatment with BRAF/MEK targeted therapy should be considered, and readers are referred elsewhere for guidance on administration of these agents [bib_ref] Systemic therapy for previously untreated advanced BRAF-mutated melanoma: a systematic review and..., Devji [/bib_ref]. If patients progress on targeted therapy or are not eligible for such agents, monotherapy with pembrolizumab or nivolumab is recommended. There is evidence for activity with both BRAF/MEK inhibitors and anti-PD-1 agents alone or with ipilimumab in the treatment of CNS metastasis [bib_ref] Targeted therapies for melanoma brain metastases, Berghoff [/bib_ref]. Combination ipilimumab/nivolumab could also be considered in selected patients where they have not previously received such treatment, the performance status decline is not related to significant medical co-morbidities and the patients is clinically able to tolerate therapy. While response rates are notably higher with combination ipilimumab/nivolumab, the incidence of serious adverse events is also higher, and the risk/ benefit ratio must be considered on an individual basis. The majority of the panel (67%) recommended combination ipilimumab/nivolumab for treatment of CNS melanoma, while a minority of the panel (33%) would treat individual CNS lesions with stereotactic radiation prior to systemic immunotherapy, and this may require consultation/coordination with neurosurgery and/or radiation oncology specialists [bib_ref] Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain..., Goldberg [/bib_ref] [bib_ref] Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase..., Mcarthur [/bib_ref]. As always, disease symptomatology and corticosteroid requirements will influence treatment decisions.
In patients who have failed the above treatments, regardless of performance status, other therapeutic options should include renewed consideration of targeted therapy in patients with BRAF mutated tumors if this has not been previously used. Other options include clinical trial participation, single agent ipilimumab, high-dose IL-2, T-VEC, and cytotoxic chemotherapy [fig_ref] Figure 4: See legend on next page [/fig_ref].
Ipilimumab was initially approved for the treatment of metastatic melanoma based on several clinical trials that demonstrated durable responses and improvement in OS [bib_ref] Improved survival with ipilimumab in patients with metastatic melanoma, Hodi [/bib_ref] [bib_ref] Ipilimumab plus dacarbazine for previously untreated metastatic melanoma, Robert [/bib_ref]. Further follow-up studies have confirmed the potential for durable responses and long-term survival providing Level A data supporting a role for ipilimumab in melanoma [bib_ref] Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab..., Maio [/bib_ref] [bib_ref] Pooled analysis of longterm survival data from phase II and phase III..., Schadendorf [/bib_ref]. Here we summarize key data from ipilimumab trials that support the rationale for its use in the second-line setting in patients with advanced melanoma. The first important study was a multi-institutional, double-blind, randomized phase 3 trial in which 676 patients with advanced melanoma expressing human leukocyte antigen (HLA)-A2 were randomized to treatment with ipilimumab (3 mg/kg every 3 weeks for four doses), ipilimumab (same dose and schedule) given with an HLA-A2-restricted modified gp100 peptide vaccine, or vaccine alone [bib_ref] Improved survival with ipilimumab in patients with metastatic melanoma, Hodi [/bib_ref]. Overall, patients treated with ipilimumab demonstrated improved OS compared to patients receiving vaccine alone (10 months vs. 6 months; P = 0.0026). This study led to FDA approval for ipilimumab as single agent therapy for melanoma in 2011. Another prospective, randomized clinical trial was subsequently reported in which 502 patients with treatment-naive melanoma were randomized to ipilimumab at 10 mg/kg every 3 weeks for four doses and dacarbazine (850 mg/m 2 ) or dacarbazine (850 mg/m 2 ) and placebo [bib_ref] Ipilimumab plus dacarbazine for previously untreated metastatic melanoma, Robert [/bib_ref]. This trial reported improved OS in patients treated with ipilimumab and dacarbazine (11.2 months vs. 9.1 months; P < 0.001). The study also reported improved 3-year survival of 20.8% for ipilimumab-dacarbazine-treated patients compared to 12.2% for dacarbazine alone (HR 0.72; P < 0.001). An update of this study population demonstrated 5-year survival rate of 18.2% in patients in the ipilimumab and dacarbazine cohort compared to 8.8% in the dacarbazine alone arm (P = 0.002) [bib_ref] Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab..., Maio [/bib_ref]. A plateau in the survival curve was observed around 3 years and persisted out to 5 years. The authors also reported safety and found the only persistent grade 3 or greater irAEs involved the skin. In order to better estimate the survival benefit in patients treated with ipilimumab, a retrospective, pooled analysis of 1861 patients treated in 10 prospective and 2 retrospective trials was performed [bib_ref] Pooled analysis of longterm survival data from phase II and phase III..., Schadendorf [/bib_ref]. Across all studies included in the analysis, median OS was 11.4 months (range 10.7-12.1 months) and the investigators saw a similar plateau in the survival curve at approximately 3 years. A 3-year survival rate of 22% was seen in all patients with 26% in treatment-naïve subjects and 20% in previously treated patients. Ipilimumab has also been shown to have activity against CNS metastases in a single arm phase 2 clinical trial [bib_ref] Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2..., Margolin [/bib_ref]. A randomized clinical study in 245 unresectable stage III-IV melanoma patients evaluated ipilimumab at 10 mg/kg intravenously on day 1 and GM-CSF at 250 μg subcutaneously on days 1-14 of each 21-day cycle [bib_ref] Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a..., Hodi [/bib_ref]. In this study, an improvement in overall survival for the combination treatment was observed (17.5 vs. 12.7 months) and, unexpectedly, the incidence of serious grade 3 or greater adverse events was lower in the combination group compared to ipilimumab alone (44.9% vs. 58.3%). Although promising, further validation of this combination in a larger sample size and at ipilimumab doses of 3 mg/ kg are needed.
Some panel members also recommended T-VEC in this setting. There is limited evidence supporting this recommendation. In the randomized phase 3 study, a subset analysis found that durable response was higher than control therapy in treatment-naïve patients (24% vs. 0%) when compared to those receiving T-VEC as second-line or later therapy (10 vs. 4%), and a similar trend toward better OS was seen when T-VEC was used in the first-line setting [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref]. As mentioned, T-VEC treatment requires accessible lesions for direct injection. Thus, while IL-2 and T-VEC are good options to consider, careful patient selection is required to optimize therapeutic benefit.
## Special issues in tumor immunotherapy for melanoma
The panel recognized that there are several unique issues related to clinical management of patients with melanoma opting for immunotherapy. These include issues related to the clinical integration of biomarkers, laboratory assessment, and imaging in the management of patients before and during treatment. There are also concerns over management of irAEs that are unique to immunotherapy treatment and guidelines for when to stop therapy given the potential for delayed regression. While the panel largely acknowledged that there is only Level C data to inform decision-making with respect to these issues, consensus recommendations were made and are summarized in [fig_ref] Table 1: Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma At present there are... [/fig_ref].
## Consensus management of immune-related adverse events
Immunotherapy is associated with irAEs that manifest as autoimmune-like phenomenon involving lymphocytic infiltration and inflammation of various tissues and organ systems. These events may range from vitiligo not requiring intervention to more serious episodes of immune-related colitis, pneumonitis, hepatitis and hypophysitis [bib_ref] Management of toxicities of immune checkpoint inhibitors, Spain [/bib_ref]. More recently, there have been rare case reports of immune-related myocarditis associated with mortality [bib_ref] Fulminant myocarditis with combination immune checkpoint blockade, Johnson [/bib_ref] [bib_ref] Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic..., Laubli [/bib_ref] [bib_ref] Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy, Heinzerling [/bib_ref]. These events are problematic and may occur early in the treatment course or weeks to even months after stopping therapy, and a high level of clinical suspicion must be maintained in patients treated with immunotherapy. The panel did not specifically address toxicity management in detail but endorsed current clinical recommendations to educate patients and caregivers about toxicities, monitor patients carefully for emergence of potential irAEs, rapidly rule out other causes and initiate corticosteroid management once a high-grade immune-mediated event is identified. There is currently some controversy as to whether there is an association between irAEs and improved therapeutic responses [bib_ref] Nivolumab in resected and Unresectable metastatic melanoma: characteristics of immune-related adverse events..., Freeman-Keller [/bib_ref]. The panel, however, felt the data were strong enough to demonstrate prolonged responses even after treatment was stopped due to toxicity, and with the use of steroids; thus, the panel did not recommend continued treatment through significant toxicity for the purpose of enhancing clinical response.
In patients who experience grade 2 or greater adverse events, treatment may be withheld during acute management and resumed upon resolution, but treatment will likely need to be permanently discontinued in the face of a high grade or recurrent immune-mediate adverse event. Additional management guidelines are widely anticipated in the near future and clinicians should monitor the literature for new guidance in this area. Several groups, including the SITC Toxicity Management Working Group, have recently published guidelines to address the management of adverse events from immune checkpoint inhibition [bib_ref] on behalf of the Society for Immunotherapy of Cancer Toxicity Management Working..., Puzanov [/bib_ref] [bib_ref] Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment..., Haanen [/bib_ref] [bib_ref] Management of Immune-Related Adverse Events in patients treated with immune checkpoint inhibitor..., Brahmer [/bib_ref]. We have previously reported on the management of acute IL-2 and interferon-related side effects, including interferon-associated depression in the first consensus statement on melanoma [bib_ref] The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for..., Kaufman [/bib_ref].
## Consensus statement on predictive biomarkers for melanoma immunotherapy
The panel acknowledged the importance of identifying predictive biomarkers to help inform clinical decision-making in melanoma immunotherapy. Preliminary reports of higher response rates in patients treated with T cell checkpoint inhibitors who have high tumor-infiltrating lymphocytes and PD-L1 expression in the tumor microenvironment suggested these factors might serve as biomarkers [bib_ref] Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict..., Vilain [/bib_ref]. In fact, PD-L1 expression has been used for patient selection and is associated with improved outcomes with anti-PD-1 therapy in NSCLC [bib_ref] Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung Cancer, Reck [/bib_ref]. Nonetheless, PD-L1 expression has not been validated for melanoma patient selection or therapeutic monitoring, and this may relate to differences in the assay sensitivity or reliability, the dynamic regulation of PD-L1 expression and sampling error [bib_ref] PD-L1 expression in melanoma: a quantitative Immunohistochemical antibody comparison, Sunshine [/bib_ref]. At this time, PD-L1 expression is not considered valuable in clinical management of patients with melanoma by the majority (58%) of the consensus panel. However, some panelists did consider PD-L1 expression as important in clinical decision-making in special situations, such as in patients with co-morbid medical conditions that might preclude combination immunotherapy (25% of panelists), patients older than 65 years of age (8%), patients less than 65 years of age (4%) or in the presence of BRAF mutation (4%). In these settings, high PD-L1 expression would support using single agent PD-1 blockade and reserve combination therapy for those without PD-L1 expression since these patients are less likely to respond to monotherapy [bib_ref] Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma, Wolchok [/bib_ref].
Mutation burden in the tumor has also recently been recognized as a potential predictor of response to immunotherapy with T cell checkpoint inhibitors [bib_ref] Genetic basis for clinical response to CTLA-4 blockade in melanoma, Snyder [/bib_ref] [bib_ref] Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade, Mcgranahan [/bib_ref]. Thus, it is interesting to note that melanoma, NSCLC and other tumors where these agents have shown clinical activity appear to be associated with higher levels of mutations within the tumor genome [bib_ref] Genetic basis for clinical response to CTLA-4 blockade in melanoma, Snyder [/bib_ref] [bib_ref] Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer, Rizvi [/bib_ref] [bib_ref] PD-1 blockade in tumors with mismatchrepair deficiency, Le [/bib_ref]. The biologic basis of this finding may be due to the emergence of neoantigens derived from the mutations resulting in abnormal proteins and peptide fragments within the tumor cells allowing recognition by T cells that might not recognize the native peptide [bib_ref] Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment..., Haanen [/bib_ref]. Thus, mutation burden could be an important predictor of benefit for treatment with immunotherapy. In its first tissue-agnostic approval based on a biomarker, the FDA recently granted accelerated approval to pembrolizumab for the treatment of patients with unresectable or metastatic mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) solid tumors that have progressed after prior treatment and have no alternative treatment options. This approval was based on data from 149 patients across 5 single-arm clinical trials in which pembrolizumab illustrated an ORR of 39.6%, including 11 CRs and 48 PRs. Similar results led to approval of nivolumab in this population based on results from the CheckMate 142 clinical trial [bib_ref] Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal..., Overman [/bib_ref]. Another area of intense investigation is the association between therapeutic effectiveness of immunotherapy regimens and the presence of IFN-γ-related gene signatures within the tumor microenvironment [bib_ref] IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade, Ayers [/bib_ref]. While the Task Force agreed with the importance of emerging data in this area, there are not sufficient prospective validation studies to recommend use of these parameters for clinical decision-making for patients with melanoma at this time (see [fig_ref] Table 1: Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma At present there are... [/fig_ref].
## Consensus statement on laboratory assessment for melanoma patients on immunotherapy
The panel strongly recommended routine baseline and surveillance laboratory assessments be performed on patients undergoing treatment with tumor immunotherapy.
While panelists acknowledged a lack of evidence-based data in this area, serum LDH is considered an important prognostic marker as it is part of the current AJCC (v7 and v8) staging for melanoma, and toxicity management is supported by careful laboratory analysis with baseline values for comparison. Clinicians should be alert for signs and symptoms of irAEs, which can present with isolated laboratory abnormalities, such as elevated hepatic enzymes, serum creatinine, amylase, lipase, glucose and others. A baseline complete blood count, serum chemistry panel to evaluate hepatic, renal and electrolyte parameters, and a thyroid function panel that includes at least free T4 and thyroid stimulating hormone (TSH) should be obtained on all patients. With increasing awareness of the risk of myocarditis, monitoring of creatine kinase and troponin I or T should also be considered. The panel also unanimously agreed that these same laboratory assays should be repeated during therapy but there was no agreement on the frequency of assessment. Some panel members suggested obtaining lab work prior to each infusion, whereas others suggested early monitoring and then limiting collection to periodic assessment or as clinically indicated. Patients who present with signs or symptoms of possible hypophysitis should have additional hormone levels monitored prior to starting corticosteroid intervention (see [fig_ref] Table 1: Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma At present there are... [/fig_ref] for recommended panel).
## Consensus statement on imaging for melanoma patients on immunotherapy
The type and frequency of imaging for patients with melanoma treated with immunotherapy continues to be controversial and there are no prospective, randomized clinical trials to guide clinical decision-making. Since tumor regression may be delayed with immunotherapy, appropriate imaging becomes increasingly important to ensure patients achieve optimal therapeutic benefit. Thus, all panel members recommended that whole body imaging be performed prior to and at regular intervals during immunotherapy. The majority of the panel use computed tomography (CT) scans of the chest, abdomen and pelvis and magnetic resonance imaging (MRI) of the brain. Additional imaging may also be necessary in some patients with suspected disease in locations not imaged with these scans, such as the neck or extremities. A minority of panel members recommended whole body positron emission tomography (PET) or PET-CT scans as the preferred imaging modality. The false-positive rate for PET imaging and difficulty providing definitive lesion measurements were reasons cited for preferring CT and MRI imaging by the majority of panel participants. Although the panel recognized the absence of Level A data to support post-treatment imaging, the consensus recommendation was that patients should be followed every 3-12 months with whole body CT imaging and selective brain imaging depending on tumor stage and location, the disease-free period from initial diagnosis and as clinically indicated (see [fig_ref] Table 1: Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma At present there are... [/fig_ref]. A minority opinion suggested that imaging could be individualized for each patient.
## Consensus statement on clinical endpoints and treatment cessation
The panel considered the issue of when to stop treatment, which is complicated in patients receiving immunotherapy since "pseudo-progression" has been reported and is thought to be related to delayed response kinetics and/or tumor immune infiltration. This possibility has suggested that additional criteria may be needed to assess response optimally and avoid discontinuing treatment in patients who might experience delayed regression; these criteria have been termed immune-related response criteria (irRC) or iRECIST [bib_ref] Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related..., Wolchok [/bib_ref] [bib_ref] iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics, Seymour [/bib_ref]. While pseudo-progression has been reported with ipilimumab [bib_ref] Improved survival with ipilimumab in patients with metastatic melanoma, Hodi [/bib_ref] and T-VEC [bib_ref] Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma, Andtbacka [/bib_ref] , there is some evidence that this phenomenon may also occur with anti-PD-1 agents [bib_ref] Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced..., Hodi [/bib_ref]. In a review of 655 patients treated with pembrolizumab, 24 (7%) had atypical responses defined as "early pseudo-progression" in 15 (5%) and "delayed pseudo-progression" in 9 (3%) by the investigators [bib_ref] Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced..., Hodi [/bib_ref]. This study also found 14% of patients had progression by RECIST criteria but did not meet the definition for disease progression by the irRC and suggested that clinical benefit may be underestimated if standard RECIST criteria are used in monitoring clinical endpoints for immunotherapy studies. There are also case reports of pseudoprogression of melanoma brain metastases in patients treated with pembrolizumab [bib_ref] Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment, Cohen [/bib_ref].
The panel generally agreed that new lesions or an increase in tumor burden in patients treated with interferon or IL-2 is cause for treatment cessation. The assessment of response in patients receiving T cell checkpoint inhibitors or T-VEC is more challenging. The majority of the panel recommends that patients with disease progression by imaging and who are clinically asymptomatic without a decline in performance status can be safely continued on treatment and re-imaged in 1-2 months to evaluate response. There is limited Level B evidence to support this position. In a retrospective study using pooled data of 526 randomized patients from two phase 3 trials of nivolumab in treatment-naïve melanoma patients, those who received continued treatment beyond first disease progression (N = 85) were compared to those patients who immediately discontinued nivolumab at first signs of disease progression (N = 221). The authors reported that 24 of the 85 (28%) patients treated beyond progression went on to experience greater than 30% regression after further therapy [bib_ref] Nivolumab for patients with advanced melanoma treated beyond progression: analysis of 2..., Long [/bib_ref]. The authors concluded that selected patients might derive further clinical benefit from continued treatment beyond progression. The panel also recommended that patients with unacceptable toxicity or clinical deterioration should be promptly removed from treatment and only if disease progression is documented should they move on to another therapeutic regimen.
In addition, it is critical that clinicians monitoring melanoma patients on immunotherapy be able to confirm clinical responses and stop therapy at an appropriate timepoint. The panel recognized that there is considerable controversy on how best to define when to stop therapy and agreed that there may be limited evidence to support continued treatment beyond disease progression. Because of this uncertainty, the panel considered confirmation of objective responses to be important for optimal clinical decision making, and suggested that patients achieving CR, PR or SD, should be re-imaged within 2-3 months to confirm response. A minority of the panel suggested that patients with incomplete responses, and where all remaining sites of disease can be completely excised, could be considered for surgical management or biopsy to confirm existence of viable tumor in these areas and/or identify other potential treatment options (e.g., through mutational burden analysis). Finally, the panel was asked about scenarios in which it would be appropriate to stop therapy in a patient with SD or better response. Of the panelists responding, 4% would be comfortable stopping therapy once a patient achieves a radiographic complete response, 8% would stop after achieving PET-CT-based complete response, and 29% would stop after completing 2 years of therapy. A further 38% would consider any of these endpoints appropriate to prompt treatment discontinuation. Five panelists had alternative suggestions as to when to stop treatment: after 1-2 years of therapy if disease remains stable, 1 year after documentation of a CR, or after a radiographic CR or 2 years of therapy. None of the panelists felt that pathologic CR was necessary to halt treatment.
The data to support these recommendations are, to be fair, premature. With that said, the above recommendations are made based on the anecdotal experience of each panel member who have seen the maintenance of prolonged clinical benefit off therapy, appreciating that the risks of continuing therapy indefinitely are legitimate, and the available data from melanoma clinical trials are premature. The existing published data come from the Keynote 001 study, which enrolled 655 patients with melanoma, 105 of whom developed a CR. With a median follow up of 30 months from first identification of CR, the chance of maintaining a CR was 91% in the 105 patients treated beyond response and 90% in the 67 patients who discontinued therapy for observation after CR, which was allowable per protocol [bib_ref] Durable complete response after discontinuation of Pembrolizumab in patients with metastatic melanoma, Robert [/bib_ref]. In presented data at ASCO 2017, Robert and colleagues presented data from the Keynote 006 (described above) showing that in the 104 patients with SD, PR, or CR who completed 2 years of therapy with a median follow up off pembrolizumab of 9.7 months, 23 of 24 CRs and 60 of 64 PRs remained in response, while 8 of 10 patients with SD remained with stable disease.
Further, a recent pooled retrospective analysis of 2624 melanoma patients treated with PD-1 blockade from eight multi-center clinical trials submitted to the FDA, identified 692 of 1361 patients (51%) who had continued PD-1-directed treatment after documentation of RECIST-defined progressive disease [bib_ref] Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a..., Beaver [/bib_ref]. The authors pooled data from all patients and found 19% of patients treated beyond progression had a 30% or greater decrease in tumor burden and this represented 4% of the entire 2624 patient population. The median overall survival was also greater in patients treated beyond progression compared to patients who did not receive treatment beyond progression (24.2 vs. 11.2 months). In this study, the rate of serious adverse events was slightly lower in the patients treated beyond progression compared to patients who stopped treatment at progression (43% vs. 54%), and immune-related adverse events were similar in incidence in both groups. The authors concluded that treatment beyond progression with anti-PD-1 therapy in might be appropriate in selected melanoma patients but clinical benefit remains to be proven.
# Conclusions
The approval of six new immunotherapy agents since 2011 has led to the emergence of cancer immunotherapy as the standard of care for patients with high-risk and advanced melanoma. However, limited data are available to guide optimal patient selection, treatment sequencing and clinical monitoring during therapy. Immunotherapy differs from standard chemotherapy in its mode of action, in being associated with a higher likelihood of durable response when response occurs, and in the potential for delayed response and appearance of irAEs that require clinical diligence to detect and treat. Further progress in the field is anticipated to focus on combination immunotherapy strategies between two or more immunotherapy agents and with targeted therapies, metabolic (e.g., indoleamine 2,3-dioxygenase [IDO], vascular endothelial growth factor [VEGF]) inhibitors and adoptively transferred T cells. This updated SITC consensus statement provides recommendations by an expert panel of melanoma specialists to assist in the clinical management of melanoma patients treated with immunotherapy, the use of which provides a beneficial therapeutic option for patients with melanoma.
[fig] Figure 2: Stage III N1a (7th)/Stage IIIA (8th) melanoma immunotherapy treatment algorithm. The consensus of the panel was to separate Stage III N1a (based on AJCC 7th edition) and Stage IIIA (AJCC 8th) from other Stage III subsets based on lower risk of metastatic potential. However, a minority (30%) felt that all Stage III patients should be treated similarly. All treatment options shown may be appropriate and final selection of therapy should be individualized based on patient eligibility and treatment availability at the physician's discretion. These algorithms represent consensus sequencing suggestions by the panel. (1) There are limited data on the role of adjuvant therapy following sentinel lymphadenectomy alone, which is anticipated to become more common. (2) There is Level A evidence to support the use the combination of dabrafenib and trametinib in patients with BRAF V600E/K mutant, Stage III melanoma independent of the volume of lymph node involvement or the number of lymph nodes involved. (3) Level A data supporting the use of nivolumab over ipilimumab was demonstrated in patients with Stage IIIB to IV resected melanoma and did not include patients with Stage IIIA (based on 7th) disease. Ipilimumab 10 mg/kg dosing was supported by a minority of panelists (10%), however, subset analysis suggests that the risk: benefit ratio for patients with Stage IIIA melanoma does not support its use in Stage IIIA patients at this time. (4) There are level A data that 1 year interferon-α2b is associated with improvement in RFS and, while this therapy was generally recommended by the consensus panel previously, only two panelists recommended considering this therapy. There are level B data to support a benefit in RFS for pegylated-interferon-α2b in patients with N1a disease and in patients with ulceration of the primary tumor site; however, no panelists considered this a reasonable option for these patients. Abbreviations: LDH, lactate dehydrogenase; NCCN, National Comprehensive Cancer Network; RFS, recurrence-free survival [/fig]
[fig] Figure 3: Stage III N1b-3 (AJCC 7th)/Stage IIIB-D (AJCC 8th) melanoma immunotherapy treatment algorithm. The consensus of the panel was to separate [/fig]
[fig] Figure 4: See legend on next page.) [/fig]
[table] Table 1: Clinical Issues in Tumor Immunotherapy for Cutaneous Melanoma At present there are no validated biomarkers that reliably predict [/table]
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Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: An evidence-based clinical practice guideline (updated version)
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Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: An evidence-based clinical practice guideline (updated version)
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 , affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the (Continued on next page) management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID-19 patients.
# Background
On March 11th 2020, the World Health Organization (WHO) declared Corona Virus Disease 2019 (COVID-19) a pandemic. There has been 17,106,007confirmed cases of COVID-19 globally, including 668,910 deaths, reported to WHO as of 4:39 pm CEST, 31 July 2020. Given the current global public health threat and economic impact, chemoprophylaxis, fast diagnosis, therapeutic measures, and discharge management are all-important. Early in the COVID-19 outbreak, we published a rapid advice guidelinefor the diagnosis and treatment of COVID-19 following the WHO Rapid Advice Guideline Handbook. In the absence of direct published evidence, our recommendations were primarily based on clinical expert evidence and indirect evidence (such as Severe Acute Respiratory Syndrome or Middle East Respiratory Syndrome [MERS]) up to the end of January 2020. Recently, a number of research papers are being published both in China and abroad providing research evidence for managing COVID-19 that can change some of our previous recommendations and motivate us to update our guideline.
This updated guideline includes four sections: Chemoprophylaxis, Diagnosis, Treatments, and Discharge Management.
# Methods
## Target users
Frontline clinicians and policymakers involve in the care of patients with COVID-19. The guideline applies to all income settings.
## Target population
Adult patients (≥18 years) with any clinical types of COVID-19 (pregnant women were not included).
## Composition of the guideline development group
The guideline panel was composed of a steering group, working group, and an evidence synthesis group, which included 27 clinical experts (expertise in respiratory medicine, infectious disease, critical care medicine, cardiology, emergency medicine, pediatrics, oncology, gerontology, laboratory medicine, medical imaging, clinical immunology, and clinical pharmacy), six methodologists, and 18 clinical research assistants with evidence searching and assessment. The external review group included 9 clinical experts and one methodologist. (See the Authors' Contributions).
## Conflict of interest policy
All guideline panel members signed a confidentiality agreement and disclosed all potential conflicts of interest (Survey form see Additional file 1).
## Question generation
The initial "Structural Overview and Research Questions for Diagnosis and Treatment of COVID-19" were developed by the steering group members and were discussed in detail by the working group members. Eventually, 29 research questions were finalized after an online discussion, and guideline protocol has been published in New Medicine (Chinese name: Yixue Xinzhi Zazhi; http:// www.jnewmed.com/) in China.
## Evidence review and development of clinical recommendations
We searched the bibliographic databases: PubMed, Embase, Cochrane library, CNKI (China National Knowledge Infrastructure) and Wanfang Databases. In addition, we searched recently up-to-date medical journals, preprint platforms, and platforms of clinical trial registry (search resources and websites see Additional file 2). The methodologists designed search strategies (Additional file 3) using medical subject heading keywords and text words in Chinese and English for all direct evidence defined as systematic review or meta-analysis, original studies with no language limitation. For questions of chemoprophylaxis and treatments, we excluded single-arm study and case reports. The first search was from December 1, 2019 to June6, 2020. Search for systematic reviews and primary articles were updated daily until July 8, 2020.
The risk of bias or quality assessment was based on the international evaluation standards of the corresponding literature, ROB 2.0 for randomized controlled trial (RCT); QUADAS-2 for diagnostic accuracy study; ROBINS-I for non-randomized comparative intervention studies. Before the literature search, outcomes of treatment were ranked by the guideline panel classifying their importance as critical, important, and less important according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. For treatment questions, the critical outcomes prioritized for this guideline were mortality, critical conversion rate, incidence rate or time of intensive care unit (ICU) admission, and sequential organ failure assessment (SOFA). The important outcomes were oxygenation index/oxyhemoglobin saturation, time/rate positive-to-negative conversion of RT-PCR test for SARS coronavirus 2 (SARS-CoV-2), chest or lung imaging improvement or lesion absorption time or ratio, time to clinical improvement, clinical cure time or rate, pneumonia severity index (PSI), body temperature/time for body temperature to return to normal, duration of hospital stay, incidence rate or time of mechanical ventilation, and viral load. For diagnostic questions, the diagnostic accuracy outcomes (such as sensitivity, specificity, and AUC [area under curve]) were regarded as important outcomes.
Following the GRADE principles, the guideline panel rated the certainty of evidence for each outcome as "high," "moderate," "low," or "very low". Recommendations were graded based on the GRADE approach.
The simplified Evidence to Decision framework was considered in recommendation development: quality of the evidence, balance of desirable and undesirable consequences, acceptability of intervention to stakeholders, and feasibility of implementation.
Based on these rules, the guideline panel members formulated the clinical recommendations establishing their strength by online discussion, reaching consensus where required by voting. For a recommendation to be graded as strong or weak, at least 70% of participants were required to endorse it. The guideline was reported using the AGREE Reporting Checklistand Reporting Items for practice Guidelines in Healthcare (RIGHT) Reporting Checklist.
# Results
We finally used evidence of 75 original articles (included 12 RCTs), 33 systematic reviews or meta-analyses (See flow chart in literature searching in Additional files 4 and 5). We issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement.
Patients with COVID-19 were classified into four categories according to their clinical presentations: 1) Mild Type, the clinical symptoms are mild with no pneumonia manifestations found in imaging. 2) Moderate Type, patients have symptoms such as fever and respiratory tract symptoms with pneumonia manifestations seen on imaging. 3) Severe Type, adults who meet any of the following criteria: respiratory rate ≥ 30 breaths/min; oxygen saturations ≤93% in resting state; arterial partial pressure of oxygen (PaO 2 )/oxygen concentration (FiO 2 ) ≤300 mmHg. Patients with > 50% lesions progression within 24 to 48 h in lung imaging should be treated as severe cases. 4) Critical Type, meeting any of the following criteria: occurrence of respiratory failure requiring mechanical ventilation; presence of shock; other organ failure that requires monitoring and treatment in the ICU.
The traditional GRADE summary tables for each outcome only presented in evidence body with pooled effect because of different disease types, interventions, doses, medication courses, and reported time of outcome as stated in some questions. We excluded single-arm study and case reports except for question of lung transplantation. Quality of evidence assessed by GRADE for pooled effect of outcomes of interest see Additional file 6. Recommendations list see Additional file 7. Results of methodological quality assessment of included studies and report of the external review panel will provide when for request.
## Chemoprophylaxis
Question 1: Which kind of agents can prevent COVID-19 in pre-exposure population to reduce SARS-CoV-2 infection?
Recommendation There is insufficient evidence to for or against any agents to pre-exposure population (Grade2C). Guideline panels determine the overall quality of evidence across all the critical outcomes essential based on: 1) If the quality of evidence is the same for all critical outcomes, then this becomes the overall quality of the evidence supporting the answer to the question; 2) If the quality of evidence differs and there is inconsistent results across critical outcomes, the interval quality of evidence is supplied; 3) If the quality of evidence differs and there is consistent results across critical outcomes, the lowest quality of evidence for any of the critical outcomes determines the overall quality of evidence
Evidence summary A retrospective cohort study including 106 healthcare workers indicated that as for 54 health care personnel before being exposed to their first COVID-19 patients, taking pre-exposure hydroxychloroquine prophylaxis was associated with an 80.7% reduction in the risk of acquiring a SARS-CoV-2 infection (RR = 0.193; 95% CI = 0.071-0.526; P = 0.001) compared with those who were not on it. Adverse effects, mostly mild, were recorded in 29.8% of those on hydroxychloroquine prophylaxis (gastrointestinal upset: 19.1%; skin rash: 6.4%; headache: 4.3%). The quality of evidence was very low due to lack of adequate information relevant to study design, for example, co-interventions balanced across intervention groups, start time of follow-up and start of intervention for most participants and imprecision of evidence quality.
Justification Based on very low quality evidence, the panel did not suggest for or against hydroxychloroquine to prevent COVID-19 in pre-exposure population to reduce SARS-CoV-2 infection. Recommendation There is insufficient evidence to for or against any agents to post-exposure population (Grade2C).
Evidence summary A randomized trial included 821 participants who had household or occupational exposure to a person with confirmed COVID-19 at a distance of less than 6 ft. for more than 10 min while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). The incidence of COVID-19 did not differ significantly between participants receiving hydroxychloroquine within 4 days after exposure. In addition, a retrospective cohort study including a total of 66 members in 27 families and 124 health care workers had evidence of close exposure to patients with confirmed COVID-19 revealed that compared with health care workers in Wuhan Union Hospital initially exposed to a cluster of COVID-19 infected colleagues without standard respiratory protection, as for the participants, Arbidol was a protective factor against the development of COVID-19 (HR 0.025, 95% CI 0.003-0.209, P = 0.0006 for family members and HR 0.056, 95% CI 0.005-0.662, P = 0.0221 for health care workers). However, the quality of evidence was low due to lack of adequate information relevant to study design, for example, co-interventions balanced across intervention groups, start time of follow-up and start of intervention for most participants and limited sample size, although large magnitude of an effect of decreasing incidence rate was observed.
Justification We downgraded quality of evidence based on risk of bias and imprecision and did not upgrade evidence quality. Based on low quality evidence, the panel did not draw any recommendations for or against Arbidol or hydroxychloroquine to prevent COVID-19 in post-exposure population to reduce SARS-CoV-2 infection. Recommendation There is no evidence to for or against using any TCM agents for preventing COVID-19 in in post-exposure populations (Ungraded Consensus-Based Statement).
## Diagnosis
Question 5: What are the typical clinical manifestations that can assist clinicians to differentiate SARS-CoV-2 infection from other viral infection in people with suspicious COVID-19?
Recommendations The initial symptoms of COVID-19 in ordinary adult patients are most commonly fever and cough (mainly dry cough), often accompanied by fatigue, muscle soreness, dyspnea, expectoration and chest distress. In addition, some patients may present with ocular symptoms, cutaneous symptoms and gastrointestinal symptoms such as diarrhea, nausea, vomiting, olfactory and gustatory dysfunctions. From the perspective of Traditional Chinese Medicine clinical characteristics, the most common tongue body, tongue coating and pulse patterns were red tongue, greasy coating and deep pulse, respectively. If clinicians find that the patient has abovementioned symptoms during the initial diagnosis, further examination (e.g. CT examination, nucleic acid test etc.) is required to confirm the diagnosis (Grade1A).
Asymptomatic patients generally remain asymptomatic or develop mild symptoms after admission, and clinicians should be cautious about the aggravation of symptoms in these patients. Critical-type patients have severe clinical manifestations and are more prone to fever, dyspnea and abdominal pain, and clinicians should identify the specific manifestations of critical patients as early as possible. (Grade2C).
Evidence summary Common clinical manifestations: Ten systematic reviews/meta-analyses (134,222 patients from China, Australia, Italy, Japan, Korea, Netherlands, Singapore, UK, USA, Nepal, South Korea and Vietnam) showed that the most common symptoms of COVID-19 patients were fever (78.0-91.3%), cough (52.0-72.2%), myalgia or fatigue (16.7-51.0%), dyspnea (10.4-45.6%), expectoration (21.3-41.8%)and chest distress (31.2%).
Gastrointestinal symptoms: Four systematic reviews/ meta-analyses (19,007 patients from China, USA, South Korea, Singapore, UK, Australia, Belgium, Cambodia, France, Germany, Italy, Japan, Malaysia, Nepal, Philippines, Russia, Thailand and Vietnam) showed that the pooled prevalence of digestive symptoms was 9.8-17.6%, with diarrhea (7.8-10.4%), nausea or vomiting (5.5-7.7%), abdominal discomfort/pain (3.0-6.9%)and loss of appetite (11%)being the most common symptoms.
Severe-type patients: Two systematic review and meta-analysis (7827 patients from China) showed that the severe group had a higher risk of fever (OR = 1.67, 95% CI 1.15-2.42, P = 0.007, I 2 = 38.8%), dyspnea (OR = 4.17, 95% CI 2.04-8.53, P < 0.001, I 2 = 71.3% / OR = 5.50, 95% CI 2.45-12.33, P < 0.001, I 2 = 61%)and gastrointestinal symptoms (OR = 1.86, 95% CI 1.19-2.89, P = 0.006, I 2 = 0%)than non-severe group, while another systematic review and meta-analysis (2477 patients from China, Singapore, and Australia) found that there was no significant difference in the incidence of diarrhea (OR = 1.32, 95% CI 0.8-2.18, Z = 1.07, P = 0.28, I 2 = 17%) or nausea and/or vomiting (OR = 0.96, 95% CI 0.42-2.19, Z = 0.10, P = 0.92, I 2 = 55%) between either group. However, there was seven times higher odds of having abdominal pain in patients with severe illness when compared with non-severe patients (OR = 7.17, 95% CI 1.95-26.34, Z = 2.97, P = 0.003, I 2 = 0%).
TCM clinical symptoms: A systematic review and meta-analysis (484 patients from China) showed that the most common symptoms of COVID-19 patients were fever (74.0%), poor appetite (61.3%), fatigue (53.5%) and cough (50.4%). The most common tongue body, tongue coating and pulse patterns were red tongue (39.1%), greasy coating (65.3%) and deep pulse (44.4%) respectively.
Asymptomatic patients: A systematic review and metaanalysis (506 patients from China, Japan and USA) showed that the majority of asymptomatic patients (92.6%) remained asymptomatic during follow-up. Five patients developed symptoms, with mild fever (< 38°C) recorded in all of them. Other symptoms such as cough, fatigue, arthralgia, dizziness, and nasal congestion were noted only in single cases.
Olfactory and gustatory dysfunctions: Two systematic review and meta-analysis (26,602 patients from 18 different countries) found that the overall prevalence of alteration of the sense of smell or taste was 47-52%. The loss of smell and taste preceded other symptoms in 20% (95% CI 13-29%) of cases and it was concomitant in 28% (95% CI 22-36%). A total of 21,515 patients were assessed in a systematic review and meta-analysis..
Ocular symptoms: A cross-sectional study (535 patients from China) showed that conjunctival congestion (5.0%) was one of the COVID-19-related ocular symptoms, which could occur as the initial symptoms. The other ocular symptoms, including increased conjunctival secretion (29.6%), ocular pain (18.5%), photophobia (11.1%), dry eye (37.0%) and tearing , were also found in patients with conjunctival congestion. A cross-sectional study of 121 patients demonstrated that ocular symptoms including itching, redness, tearing, discharge, and foreign body sensation were among the symptoms of covid-19(5.0%). A cross-sectional study showed that ocular symptoms (27%) are relatively common in COVID-19 disease and may appear just before the onset of respiratory symptoms. Another cross-sectional study found that one-third (31.6%) of patients with COVID-19 had ocular abnormalities, which frequently occurred in patients with more severe COVID-19 (66.7%).
Cutaneous symptoms: A systematic review including 507 patients from China, Spain, Italy, France, USA, Canada, Belgium, Thailand, Indonesia and Japan found that the skin symptoms of COVID-19 patients were multiformity. The most common skin lesion was erythema, which was observed in 224 patients and distributed on patients' trunk, extremities, flexural regions, face, and mucous membranes. Moreover, the erythema lesions were also confined to specific sites, such as the heels without other triggers such as exposure. Chilblainlike lesions were described in 100 (19.7%) patients. Urticaria-like lesions were presented in 83 patients (16.4%) and distributed on patients' trunks or dispersed widely on their bodies. Two hundred twenty-seven patients (44.8%) complained of significant pruritus at the skin lesions. In addition, other manifestations such as vesicular.0%), livedo/necrosis (31, 6.1%) and petechiae (8, 1.6%) were described. and it was noteworthy that 13 patients (14.8%) had skin lesions as the first symptom.
Justification The evidence quality for each outcome ranged from very low to high. All this evidence focusing on clinical manifestations is crucial for the initial diagnosis of patients with COVID-19. After considering the certainty of evidence, patient preference, health equity, acceptability, feasibility, and generalizability, the guideline panel gave a strong recommendation for general clinical manifestations and weak recommendation for clinical manifestations of asymptomatic patients mostly based on low certainty of evidence. High-quality contemporaneous case-control studies are barrier to confirm that if some typical symptoms can assist clinicians to differentiate SARS-CoV-2 infection from other viral infection in people with suspicious COVID-19. However, the current included literatures were mainly systematic reviews/meta-analyses of included cross-sectional studies. Recommendations If the patient's condition allows (expectorating sputum spontaneously or receiving mechanical ventilation), lower respiratory tract specimens (sputum or broncho-alveolar lavage fluid) can be preferred for testing (Grade2C).
Sampling specimens from lower respiratory tract may result in a higher positive detection rate than those from upper respiratory tract specimens (Ungraded Consensus-Based Statement).
## Implementation consideration
(1) When collecting lower respiratory tract specimens, special attention should be paid to the infection protection of patients and collectors, and airborne precautions should be taken. (2) Nasal or pharyngeal swabs are preferred for patients without sputum. The results supported sputum sampling as a primary method of COVID-19 diagnosis and monitoring, and highlight the importance of early testing after symptom onset to increase the rates of COVID-19 diagnosis. However, different target genes were used for RT-PCR detection and asymptomatic infection or mild symptom patients were not included in the systematic review and meta-analysis may reduce the credibility of the pooled results.
## Evidence summary
In addition, there were two cross-sectional studies that evaluated the positive rate of RT-PCR detection of SARS-CoV-2 in respiratory samples. One study including 4880 respiratory samples from suspected patients showed the positive rate of RT-PCR test were 80% (4/5) in alveolar lavage fluid, 49.12% (28/57) in sputum, and 38.25% (1843/4818) in nasal and pharyngeal swabs. The positive rate of lower respiratory tract specimens (51.6%, 32/62) was higher than upper respiratory tract specimens (38.25%, 1843/4818). Another study including 8274 respiratory samples from suspected patients found the positive rate of RT-PCR test were 60% (3/5) in alveolar lavage fluid, 24.51% (25/102) in sputum, 47.92% (23/48) in oropharynx, 41.01% (2047/4992) in nasopharynx, and 20.69% (647/3127) in oropharynx combined with nasopharynx. The positive rate of upper respiratory tract specimens (33.3%, 2717/8167) was higher than lower respiratory tract specimens (26.2%, 28/107). Moreover, due to the small sample size of the lower respiratory tract from suspected patients in these two cross-sectional studies, the results should be interpreted with caution.
Justification Considering the controversy and uncertainty between the evidence, and because the lower respiratory tract specimen collection may bring the risk of occupational exposure, but expert opinion believed sampling specimens from lower respiratory tract may result in a higher positive detection rate, the guideline panel finally gave a weak recommendation and an ungraded consensus-based statement.
Question 7: Should IgM and IgG antibody tests be added on to nucleic acid RT-PCR test to have better diagnostic outcomes (i.e., sensitivity, specificity, PPV, NPV) than nucleic acid RT-PCR test alone in people with suspicious COVID-19?
Recommendation Clinically diagnosed patients should be tested for SARS-CoV-2 specific IgM and IgG antibodies at 10-14 days after onset of symptoms. IgM and IgG antibodies combined test is better than using IgM or IgG antibody alone (Grade1C).
Implementation consideration Clinically diagnosed patients are those with epidemiological history, typical clinical symptoms and imaging characteristics of COVID-19, but having negative RT-PCR test. It can confirm the diagnosis of COVID-19 if the SARS-CoV-2 specific IgG antibody changes from negative to positive or the IgG level in the recovery phase is more than 4 times higher than in the acute phase. Justification It's important to confirm the clinically diagnosed patients. Nearly all expert evidence showed that patients should be tested for SARS-CoV-2 specific IgM and IgG antibodies no matter the results of RT-PCR. Generally speaking, for the diagnosis of infectious diseases, it is ideal if the pathogen can be directly detected from the specimen. However, due to the high conditions required for the growth of some pathogens, the long growth time and the low positive rate of detection, it is usually difficult. The detection of specific antibodies can make up for the above shortcomings to a certain extent. Based on evidence, considering health equity, acceptability, feasibility, and generalizability, the guideline panel gave a strong recommendation. Although the quality of evidence is very low, considering the rapid spread, high contagion of the virus, and urgent need for diagnosis confirmation the guideline panel gave a strong recommendation.
## Evidence summary
Question 8: Can chest computed tomography (CT) or x-ray be useful for diagnosing COVID-19 in suspicious people when their nucleic acid RT-PCR tests are negative? If so, which one is more useful?
Recommendation Chest CT or x-ray is important alternative tests for RT-PCR test. Suspected COVID-19 patients with typical chest CT and x-ray presentation should be isolated and treated as clinically diagnosed patients (Grade1C).
Implementation consideration In a low prevalence region, chest CT or x-ray should not be the primary screening or diagnosis method.
Evidence summary A meta-analysis (n = 6218) evaluated diagnostic performance measures of chest CT. For chest CT, the results of initial or repeated RT-PCR as the reference standard. The pooled sensitivity and specificity of chest CT were 94% (95% CI 91-96%; I 2 = 95%) and 37% (95% CI 26-50%; I 2 = 83%), respectively. In sensitivity analysis, the pooled sensitivity of chest CT for the studies with repeated RT-PCR as the reference standard was 93% (95% CI 88-96%; I 2 = 87%). The pooled specificity was 35% (95% CI 23-48%; I 2 = 86%). The pooled prevalence in China was 39% (95% CI 23-59%; I 2 = 92%). The estimated PPV and NPV of chest CT were 1.5 and 99.8% at a disease prevalence of 1, 14.2 and 98.2% at a prevalence of 10, and 48.8% and 90.6% at a prevalence of 39%, respectively. The prevalence of COVID-19 outside China ranged from 1.0 to 22.9%. For chest CT scans, the PPV ranged from 1.5 to 30.7%, and the NPV ranged from 95.4 to 99.8%. In short, chest CT scans for the primary screening or diagnosis of COVID-19 would not be beneficial in a low prevalence region due to the substantial rate of false-positives. We downgraded this meta-analysis to very low quality for high risk of bias and inconsistency.
Besides, two diagnostic accuracy studies (n = 1122) met our study selection criteria. For chest CT and xray, RT-PCR was as the reference standard. The sensitivity and specificity of CT were 97.7 and 53.9%, the sensitivity and specificity of chest x-ray were 89.0% (95% CI 85.5-91.8%) and 60.6% (95% CI 51.6-69.2%), respectively. The PPV and NPV of CT were 85.6 and 89.2% respectively. The PPV and NPV of x-ray were 87.9% (95% CI 84.4-90.9%) and 63.1% (95% CI 53.9-71.7%), respectively. The positive likelihood ratio (LR) and negative LR of CT were 2.12 and 0.04, respectively. There was not enough available information to assess the interval time between chest CT, x-ray and RT-PCR in the two studies and thus may reduce the reliability of the evidence.
Justification The evidence indicated that chest CT has high sensitivity for detecting patients with SARS-CoV-2 pneumonia but low specificity, which may lead to high false positive rate. We downgraded quality of evidence based on high risk of included studies. But some of the reasons leading to high risk of evidence was from that some of included studies were not for diagnostic performance of CT and RT-PCR, but for other research purpose, so relevant information about the diagnostic test was unclear. Facing the epidemic outbreak, suspected COVID-19 patients with typical chest CT and xray presentation should be diagnosed, cared and isolated as soon as possible. Although the quality of evidence is very low, considering the rapid spread, high contagion of the virus, and urgent need for early diagnosis the guideline panel gave a strong recommendation.
Question 9: What are the CT imaging manifestations that can assist clinicians to differentiate SARS-CoV-2 pneumonia patients from other viral pneumonia patients?
Recommendation The lesions in patients with COVID-19 are mainly distributed either unilaterally or bilaterally in the lower lobes, mostly in peripheral areas. The common imaging findings for COVID-19 are as follows: ground-glass opacities (GGO), interlobular septal thickening, vascular enlargement, crazy paving pattern, subpleural bands, consolidation, and air bronchogram sign. Predominantly GGO pattern is more common than other viral pneumonias, while a mixed pattern of GGO and consolidation is less frequent than other viral pneumonias. COVID-19 pneumonia presented a higher prevalence of peripheral distribution, and involvement of upper and middle lobes than non-COVID pneumonia. Compared to moderate patients, some CT manifestations were more frequent in severe and critical type patients, such as traction bronchiectasis, interlobular septal thickening, consolidation, crazy-paving pattern, reticulation, pleural effusion, and lymphadenopathy (Grade1A).
## Evidence summary a systemic review and metaanalysis (included 2451 covid-19 patients from
China) regarded the chest CT manifestations of COVID-19 pneumonia in common and severe patients. In the research, the common group included moderate type patients. Severe group included severe and critical type patients. In moderate patients, pooled results indicated that the CT features of vascular enlargement were 79% (95% CI 0.74-0.84), GGOs were 78% (95% CI 0.64-0.89), subpleural bands were 58% (95% CI 0.12-0.97), and interlobular septal thickening were 51% (95% CI 0.26-0.76). Among severe patients, CT features of vascular enlargement were 93% (95% CI 0.75-1.00), GGOs were 82% (95% CI 0.68-0.92), interlobular septal thickening were 80% (95% CI 0.64-0.93), air bronchogram were 67% (95% CI 0.57-0.78), consolidation were 61% (95% CI 0.42-0.78), subpleural bands were 61% (95% CI 0.10-1.00), crazy-paving pattern were 59% (95% CI 0.42-0.79), and traction bronchiectasis were 52% (95% CI 0.30-0.73). The pooled incidences of 1 lobe affected, 2 lobes affected and over 2 lobes affected in moderate patients were 26% (95% CI 0.07-0.52), 21% (95% CI 0.01-0.54), and 57% (95% CI 0.23-0.87). The pooled incidences in severe group were 1% (95% CI 0.00-0.05), 4% (95% CI 0.00-0.10), and 94% (95% CI 0.88-0.99). The pooled incidences of unilateral pneumonia, right upper lobe involved, right middle lobe involved, right lower lobe involved, left upper lobe, left lower lobe, peripheral distribution and central distribution in moderate patients were 22% (95% CI 0.12-0.33), 49% (95% CI 0.A systemic review and meta-analysis (included 52,251 COVID-19 confirmed patients from China) showed that 84% (95% CI 0.78-0.85) of COVID-19 patients had abnormal radiological findings on chest X-ray and CT scans. The radiological abnormalities of bilateral involvement were 76.8% (95% CI 0.63-0.87), consolidation were 75.5% (95% CI 0.51-0.91), GGOs were 71% (95% CI 0.4-0.9), unilateral involvement were 16.5% (95% CI 0.85-0.30).
A systemic review and meta-analysis (included 934 COVID-19 patients from China, Japan and Italy, and 977 non-COVID patients from China, Japan, Australia, Italy Justification Based on the above evidence and expert evidence, the guideline panel gave strong recommendations. Recommendation We do not suggest offering lopinavir-ritonavir to treat any type patients with COVID-19 (Grade2 (C-B)).
Evidence summary One RCT(n = 199) showed that there was no difference in the time to clinical improvement between the lopinavir-ritonavir group and standardcare group (HR = 1.31, 95% CI 0.95-1.85, P = 0.09) in patients with severe COVID-19. In terms of clinical deterioration, no difference was observed (HR = 1.01, 95% CI 0.76-1.34). In addition, gastrointestinal adverse events were more common in the lopinavir-ritonavir group.
The other RCTrandomly assigned 21 patients with mild or moderate COVID-19 to receive lopinavirritonavir, 16 to umifenovir, and 7 to no antiviral medication as control. The median time of positive-to-negative conversion of RT-PCR test was 8.5 (interquartile range (IQR), 3-13) days in the lopinavir-ritonavir group, 7 (IQR 3-10.5) days in the umifenovir group and 4 (IQR, 3-10.5) days in the control group, with no statistical differences (P = 0.75). Five (23.8%) patients in the lopinavir-ritonavir group experienced adverse events including diarrhea (14.3%), loss of appetite (9.5%) and elevation of Alanine aminotransferase (ALT) (4.8%), but no apparent adverse events occurred in the umifenovir or control group.
One non-RCTreported 80 patients with COVID-19 who received lopinavir-ritonavir or favipiravir (all received interferon α2b atomized inhalation). The time of positiveto-negative conversion of RT-PCR test in lopinavir-ritonavir group (n = 45) was longer than that in favipiravir group (n = 35) (median, IQR, 11days vs. 4 [2.5-9] days, P < 0.001), but the rate of chest imaging improvement was faster in favipiravir group (91.4% vs. 62.2%, P = 0.004). The incidence of adverse reactions in the lopinavir-ritonavir group was higher than that in favipiravir group (55.6% vs. 11.4%, P < 0.001). The main adverse reactions were nausea, vomiting, diarrhea, rash, hepatic and renal injury. A retrospective cohort studyinvestigated 108 patients given lopinavir-ritonavir and 114 given other antiviral drugs (included recombinant human interferon α1b, ribavirin injection, Lianhuaqingwen capsules). The time of positive-to-negative conversion of RT-PCR test (7.13 ± 3.36 days vs. 8.53 ± 3.85 days, P = 0.04) and lung imaging improvement (6 (4-8.75) days vs. 8 (5-11) days, P = 0.047) was shorter in lopinavir-ritonavir group than that in control group, but there was no difference in clinical symptom improvement between the two groups (P > 0.05). The incidence of adverse reactions in lopinavir-ritonavir group were higher than that in control group (27.8% vs. 13.2%, P = 0.007). The main adverse reactions included increase transaminase and bilirubin, nausea, vomiting, diarrhea, rash and so on.
One retrospective studyincluded 78 patients with COVID-19 infection with lopinavir-ritonavir and 42 without lopinavir-ritonavir (non-critical patients). The median time of positive-to-negative conversion of RT-PCR test in the lopinavir-ritonavir group was shorter than the control group (22 (IQR, 18-29) days vs. 28.5 (IQR, 19.5-38) days, P = 0.02) within 10 days, and did not show a significant difference > 10 days (median27.5 days vs. 28.5 days, P = 0.86). The study did not report adverse effects.
The other retrospective cohort studyrecruited 42 patients with COVID-19 infection with lopinavirritonavir and 5 without lopinavir-ritonavir. All the patients received adjuvant drugs (included interferon aerosol inhalation and umifenovir). Although the two groups showed no significant difference (P > 0.05) in the body temperature of patients over 10 days, the patients in the lopinavir-ritonavir group returned to normal body temperature in a shorter time than control group (4.8 ± 1.94 days vs. 7.3 ± 1.53 days, P = 0.04). The time of positive-to-negative conversion of RT-PCR test in lopinavir-ritonavir group was shorter than control group (7.8 ± 3.09 days vs. 12.0 ± 0.82 days, P = 0.02). The study showed that compared to control group the abnormal percentage of ALT (9.5% vs. 25%) and AST (19% vs. 25%) in the lopinavir-ritonavir group was lower.
Another retrospective cohort studyinvolved 50 patients compared lopinavir-ritonavir group (n = 34) with umifenovir group (n = 16). Patients in the umifenovir group had a shorter duration of positive-to-negative conversion of RT-PCR test compared to those in The last retrospective cohort studycompared 52 patients with lopinavir-ritonavir, 34 with umifenovir, and 48 without antiviral medication. All the patients received interferon α2b atomized inhalation. The median time of temperature (P = 0.31) normalization and positive-to-negative conversion of RT-PCR test were not significantly different between the three groups (P = 0.79). Although the rate of adverse effect was no statistical difference between three groups, the common rate of gastrointestinal adverse reactions in lopinavir-ritonavir group, umifenovir group and control group (17.3% vs. 8.8% vs. 8.3%, respectively).
Justification The two RCT studies did not find benefit from lopinavir-ritonavir group. Some cohort studies have shown benefit in lopinavir-ritonavir group, however the conventional treatment group included other antiviral drugs, which made difficult to ascertain lopinavirritonavir work. After balanced benefit and harms, more than 70% of working group members in the guideline panel gave a weak recommendation against using lopinavir-ritonavir. There are some ongoing trials.
Question 11: Should umifenovir be used to treat patients with COVID-19 to improve clinical outcomes?
Recommendation Umifenovir may be considered in COVID-19 treatment (Ungraded Consensus-Based Statement).
## Implementation considerations
(1) Umifenovir 200 mg three times a day for no longer than 10 days. (2) It should be noted that some patients taking umifenovir had diarrhea and elevated serum transaminase, with occasional bradycardia. The cohort studyinvolved 134 COVID-19 patients (96% moderate cases), all received interferon α2b atomized inhalation, and 52 cases were allocated to receive lopinavir-ritonavir, 34 to umifenovir and 48 to no antiviral medication. This measured median time of temperature normalization (P = 0.31) and positive-tonegative conversion of RT-PCR test (P = 0.79) with no statistical differences between groups. Adverse effects: there were 3 cases (8.8%) with diarrhea and 2 cases with mild liver function injury in the umifenovir group, with no significant difference between groups. In addition, all the adverse reactions improved after withdrawal of drugs.
One cohort studyinvolved 49 in the umifenovir plus conventional therapy group and 62 in the conventional therapy group (defined as treatment based on clinician's experiences and judgements). Results showed that umifenovir could accelerate and enhance the process of virus clearance (59.2% vs. 40.3%, P = 0.048), improve the local absorption of lung lesions (55.1% vs. 32.2%, P = 0.02), and reduce the demand of high flow nasal catheterization oxygen (P = 0.002). Adverse effects: this study showed bradycardia in one case which was alleviated after withdrawal of umifenovir.
The other retrospectively cohort studyinvolving 50 cases, compared lopinavir-ritonavir group (n = 34) with umifenovir group (n = 16). Patients in the umifenovir group had a shorter duration of positive-to-negative conversion of RT-PCR test compared to those in the lopinavir-ritonavir group (11.5(8.8-17.0) vs. 9.5(5.3-11.0), P < 0.01). Adverse effects: 3 patients in the lopinavir-ritonavir group and 4 patients in the umifenovir group showed an elevated ALT.
Another cohort studyincluded 62 patients with COVID-19, 42 received umifenovir combined with adjuvant therapy, and 20 received adjuvant therapy alone (included aerosol inhalation of interferon). The time of temperature normalization (4.98 ± 1.79 days vs. 6.01 ± 1.80 days, P = 0.02) and positive-to-negative conversion in the test group were shorter than that in the control group. While the hospitalization period in the test group was shorter, but there was no marked difference between the two groups in this aspect (16.5 ± 7.14 vs. 18.55 ± 7.52 days, P > 0.05). There were 7 cases (16.7%) with nausea and 2 cases (4.8%) with diarrhea and dizziness respectively in the umifenovir group, but with no significant difference between groups (P > 0.05).
The last retrospectively cohort studyincluded 81 moderate/severe patients with COVID-19, with 45 in the umifenovir group and 36 in the control group. Patients in the umifenovir group had a longer hospital stay than patients in the control group (13 days (IQR 9-17) vs. 11 days (IQR 9-14), P = 0.04). The median time of positive-tonegative conversion in the umifenovir group was longer than that in the control group (6 days (IQR 4-8) vs. 3 days (IQR 1-7) d, P < 0.05). As for security, 5/45 (11%) patients in the umifenovir group and 3/36 (8%) patients in the control group demonstrated digestive symptoms, including diarrhoea and nausea (P = 0.49), but with no significant difference between groups (P > 0.05).
Justification The evidence was based on one RCT study and five cohort studies. The results from evidence were still inconsistent. A RCT study included three groups showed no-benefit in patients with COVID-19 used umifenovir. However, due to the imbalances in baseline characteristics of three groups and insufficient sample size, which would decrease the probability of detecting umifenovir effectiveness. In addition, most cohort studies still support its using. More than 70% of working group members in the guideline panel thought that umifenovir was a potentially effective drug based on their clinical experience although it needs confirmation from the ongoing trials.
Question 12: Should favipiravir be used to treat patients with COVID-19 to improve clinical outcomes?
Recommendation We suggest that favipiravir can be used to treat patients with COVID-19 (Grade2B).
## Implementation consideration
(1) Favipiravir 1600 mg twice a day on day 1; then 600 mg twice a day. Treatment should generally not exceed 14 days. (2) It should be noted that the most common adverse reactions to favipiravir were digestive system reactions (nausea, acid regurgitation and flatulence), and elevated serum uric acid and ALT and/or AST.
Evidence summary One RCTthat enrolled 236 moderate or severe COVID-19 patients with hypertension or diabetes. In moderate COVID-19 patients, favipiravir had a higher clinical recovery rate for 7 days than umifenovir (71.4% vs. 55.9%, P = 0.02), and led to shorter time of cough relief and fever reduction (P < 0.0001), but there was no statistical difference in severe patients (5.6% vs. 0%, P = 0.47). The most common adverse event was raised serum uric acid in the favipiravir group (13.8% vs. 2.5%, P < 0.01). There were also other adverse effects with no statistical differences: abnormal liver function test (elevated ALT and/or AST), psychiatric symptom reactions and digestive tract reactions (nausea, anti-acid, flatulence) between two groups. A non-RCTreported 80 patients with COVID-19, 35 with favipiravir, and 45 with lopinavir-ritonavir, all the patients also received interferon α2b atomized inhalation. The time of positive-to-negative conversion of RT-PCR test in favipiravir group was lower than that in lopinavir-ritonavir group (median, IQR, 4 (2.5-9) days vs. 11days, P < 0.001), and chest imaging improvement rate was significantly faster compared to lopinavir-ritonavir group (91.4% vs. 62.2%, P = 0.004). The incidence of adverse reactions in favipiravir group was lower than that in the control group (11.4% vs. 55.6%, P < 0.001). The main adverse reactions were nausea, vomiting, diarrhea, rash, hepatic and renal injury, and so on.
Justification The evidence from a RCT and a non-RCT, the quality of the studies were medium risk because of the lack of allocation concealment, blind method and unadjusted confounding bias, which would affect uncertainty of evidence. In addition, the included research samples are all from China leading to uncertain whether they are suitable for other countries. We downgraded quality of evidence based on risk of bias, imprecision and indirectness. After balancing benefit and harms, more than 70% of working group members believed that favipiravir may have benefit for certain patients and voted a weak recommendation. There are still relevant trials in progress.
Question 13: Should interferon be used to treat patients with COVID-19 to improve clinical outcomes?
Recommendation Interferon may be considered in COVID-19 treatment (Ungraded Consensus-Based Statement).
Implementation consideration INF-α (5million U or equivalent), 2 ml sterile water for injection, twice a day, atomized inhalation. The treatment should generally not exceed 14 days. In addition, the use of interferon in different countries can be carried out according to the corresponding drug instructions.
Evidence summary One open-label randomized clinical trialenrolled 81 patients with COVID-19, 42 received interferon β-1a (12 million IU/ml of interferon β-1a was subcutaneously injected three times weekly for two consecutive weeks), 39 received only the standard of care (included other antiviral drugs). Compared with the control group, the IFN group had significantly increased discharge rate on day 14 (66.7% vs. 43.6%, OR = 2.5, 95% CI1.05-6.37) and decreased 28-day mortality (19% vs. 43.6%, P = 0.015). In addition, early administration significantly reduced mortality (OR = 13.5, 95% CI 1. . There was no difference in the time of clinical improvement (9.7 ± 5.8 vs. 8.3 ± 4.9 days, P = 0.95) and duration of mechanical ventilation (10.86 ± 5.38 vs. 7.82 ± 7.84, P = 0.47) between two groups. The rate of adverse effects was not different between the groups. But injection-related side effects still happened in 8 (19%) in IFN group.
A cohort studyenrolled 256 patients with COVID-19. One hundred six patients in interferon β1b group (subcutaneous injection at a dose of 250 μg on alternate days, for moderate-severe pneumonia, with a duration between 3 and 5 doses) and 150 patients in control group. All patients received conventional treatment (included other antiviral drugs). The study showed that the interferon β1b group was not associated to decrease in -hospital mortality (20.8% vs. 27.3%, P = 0.229). The study did not report any of adverse effects.
One prospective cohort studyenrolled 814 patients with COVID-19 in Cuba. Seven hundred sixty-one were treated with the IFN-α2b (intramuscular injection, 3 million IU 3 times per week, for 2 weeks) combined with the approved protocol (included lopinavir-ritonavir and chloroquine), 53 received the protocol without IFN treatment. The rate of discharged patients was higher in the IFN-treated compared with non-IFN treated group (95.4% vs. 26.1%, P < 0.01). The IFN group had significantly decreased mortality (0.9% vs. 32.1%, P < 0.01). The study did not report any of adverse effects.
The other retrospective cohort studyinvolved 77 moderate patients with COVID-19, 7 were treated with nebulized IFN-α2b, 24 with umifenovir, 46 with combined treatment of IFN-α2b plus umifenovir. The study showed that the time of positive-to-negative conversion of RT-PCR test using IFN-α2b was shorter than that in umifenovir group (P = 0.003). The study did not report any of adverse effects.
Justification Insufficient evidence for a graded recommendation. The current evidence came from one RCT study and three cohort studies. The results from evidence were inconsistent, only one cohort study showed no-benefit used interferonβ1b to patients with COVID-19. While the study selection and unmeasured confounding bias cannot be completely excluded. In addition, the conventional treatment group included other antiviral drugs, which would affect uncertainty about their effects. More than 70% of working group members believed that benefits outweigh risk of INF using, so we gave "Ungraded Consensus-Based Statement".
Question 14: Should remdesivir be used to treat COVID-19 patients to improve clinical outcomes?
Recommendation We suggest that remdesivir can be used to treat patients with COVID-19 (Grade2(C-B)).
## Implementation considerations
(1) Remdesivir 200 mg loading dose on day 1, followed by 100 mg daily for no longer than 10 days, intravenously. (2) The most common adverse reactions to remdesivir were anemia or decreased hemoglobin.
Evidence summary A systematic review and metaanalysisJustification There are only 2 studies comparing the efficacy of remdesivir group and placebo group which included in the meta-analysis above, and the results of these two studies were controversial. The report of a RCT in China demonstrates no benefit in clinical outcomes in using remdesivir for treatment of severe patients with COVID-19. However, the inability to recruit the predetermined study population resulted in study power reduction from 80 to 58%. Low study power and higher severity of illness in remdesivir group both decreases the probability of detecting remdesivir effectiveness. The large RCT study included 1059 patients (88.7% were severe) with COVID-19 has shown benefit in the time to recovery, but it did not have a statistically significant effect on deaths. In addition, remdesivir is also in short supply and is complex to administer (it must be given by injection over the course of several days). Those evidence were low risk of bias, and we downgraded quality of evidence just because of inconsistency. This systematic review and mate analysis included case series which we thought they were no benefit for adding more evidence for remdesivir based on that we already had RCTs with low risk of bias and case series has a very low ability to demonstrate causality. Although the effect of remdesivir on survival remains unknown, more than 70% of working group members believed that remdesiviris potentially effective in some ways, and its benefits outweigh risk of using remdesivir.
Results of some ongoing RCTs may provide strong evidence for this treatment option.
## Question 15: could a combination of antiviral drugs be used to treat patients with covid-19 to improve clinical outcomes?
Recommendations There is insufficient evidence to for or against using combination of antiviral drugs (Grade2C).
Three or more antiviral drugs should not be used at the same time (Ungraded Consensus-Based Statement).
Evidence summary One open-label, randomised, phase 2 trial studyrecruited 127 patients with COVID-19. 86 were randomly assigned to the combination group (included lopinavir-ritonavir, ribavirin and interferon beta-1b) and 41 were assigned to the control group (given lopinavir-ritonavir). All patients received conventional treatment. The study showed that the combination group had a shorter time in negative conversion of SARS-CoV-2 within 7 days (6.5 d (IQR 4-8) vs. 12.5d (8-14.8), P < 0.0010), clinical improvement within 7 days (4 d (3-5) vs. 8 d (6.5-9), P < 0.0010) and duration of hospital stay within 7 days (8 d (6.0-12.5) vs. 15 d (9-16.0), P = 0.003) than the control group in mild/moderate/severe patients with COVID-19. There was no significant difference in the rate of adverse reactions (48% vs. 49%) between two groups. No serious adverse events were reported in the combination group. No patients died during the study.
A non-RCT studyincluded 237 patients with COVID-19. One hundred ninety-six patients were received oral umifenovir, lopinavir-ritonavir and interferon α2b in the combined group and 41 were received lopinavir-ritonavir and interferon α2b in control group. All patients received conventional treatment. The study show that the combined group had a shorter time in negative conversion of SARS-CoV-2 (12.2 ± 4.7 d vs..0 ± 5.0 d, P < 0.01) and median length of hospital stay (12 d vs. 15 d, P < 0.05) than control group in patients with COVID-19. There was no difference in the rate of ARDS between two groups (11.7% vs. 19.5%, P < 0.05).
A cohort study (pre-print)included 73 patients with COVID-19. Thirty-four patients were treated with lopinavir-ritonavir, 39 with lopinavir-ritonavir plus umifenovir. All patients received conventional treatment. The study showed that treatment with lopinavirritonavir alone was not difference from lopinavirritonavir combined with umifenovir in negative conversion rate of SARS-CoV-2 (92.3% vs. 97.1%, P = 0.618), in negative conversion time of SARS-CoV-2 (11.5 ± 9.0 d vs. 9.9 ± 7.5 d, P = 0.585), in the rate of severe disease progression (5.1% vs. 0%, P = 0.495), in the rate of chest CT imaging improvement (84.6% vs. 91.1%, P = 0.489), in the length of hospital stay (14.4 ± 7.9 d vs..0 ± 9.0 d, P = 0.431) and in the rate of mortality (2.6% vs. 2.9%, P > 0.99) for moderate and severe patients with COVID-19. The study did not report adverse effects.
One cohort studyincluded 33 patients with COVID-19. Sixteen patients were received oral umifenovir and lopinavir-ritonavir in the combined group and 17 were received oral lopinavir-ritonavir only in the monotherapy group. All patients received conventional treatment. The study show that combined group had a higher rate in negative conversion of SARS-CoV-2 at 7 days (75% vs. 35%, P < 0.05) and rate of chest CT imaging improvement after 7 days (69% vs. 29%, P < 0.05) than the lopinavir-ritonavir group in patients with COVID-19. The study did not report adverse effects.
The other cohort studyinvolving 141 patients with COVID-19. Combined group patients were given Umifenovir and IFN-α2b (n = 71), monotherapy group patients inhaled IFN-α2b (n = 70). All patients received conventional treatment. The study show that the combined group had a faster time in chest CT imaging improvement (16.7 vs. 19.8 d, P = 0.037), but there were no difference in time of negative conversion of SARS-CoV-2 (27.4 d vs. 23.8 d, P = 0.057) and hospital stay (24.2 d vs. 27.1 d, P = 0.056) between two groups. There were no differences between the two groups in ALT, Aspartate aminotransterase (AST), or creatinine during or after treatment. But 13 patients (18.8%) in combined group demonstrated mild nausea, stomachache, and all patients could tolerate without giving up treatment.
The last cohort studyinvolving 109 non-critical patients with COVID-19, 58 received interferon α and 51 received interferon α combine lopinavir-ritonavir. All patients received conventional treatment. Patients in the combined group had a higher rate of clinical improvement than interferon α group at 7 days (70.6% vs. 48.3%, P < 0.05). Although the median time of positive-tonegative conversion in the combined group was shorter than that in the interferon α group, with no difference between two groups (16.43 vs. 21.79, P > 0.05). The combined group was higher than interferon α group in the rate of adverse effects (80.4% vs. 27.4%, P < 0.05). Although all the adverse reactions were treated with symptomatic treatment or the symptoms were improved after drug withdrawal.
Justification The current evidence from one RCT study, one non-RCT study and 4 cohort studies. The evidence for most comparisons was moderate because of risk of confounding (lack of appropriate statistical analysis) and the limited number of participants. The results from evidence were inconsistent, one RCT study and two cohort studies still support early administration. In addition, due to the lack of no-treatment group, the studies can only show that the combined group was better than the monotherapy group, but can not be extrapolated to the combined group was better than the no-treatment group. Based on the risk of bias and inconsistency of evidence, and inconclusive result of any antiviral drug alone, we did not draw any recommendation for combination of antiviral drugs. All experts believed that three or more antiviral drugs should not be used at the same time.
## Question 16: should hydroxychloroquine (hcq)/ chloroquine (cq) be used to treat patients with covid-19to improve clinical outcomes?
Recommendations There is inconsistent evidence to for or against using HCQ/CQ in COVID-19 treatment (Grade2C).
We do not suggest using the combination of HCQ and azithromycin (AZ) (Grade2C).
Evidence summary A systematic review and metaanalysis (n = 10,659) showed that HCQ cannot effectively reduce mortality (8 observational studies, RR = 0.98, 95% CI 0.66-1.46), or clinical deterioration of ARDS (6 observational studies, RR = 0.90, 95% CI 0.47-1.71). There was no statistically significant difference in virologic clearance (2 RCTs and 3 observational studies, RR = 1.03, 95% CI 0.83-1.28) and in time to fever remission (2 RCTs and 1 observational study, WMD = − 0.54 days, 95% CI -1.19-0.11) between HCQ and placebo. Compared with standard-of-care (SOC), HCQ increases the risk of ECG abnormalities/cardiac arrhythmias with or without azithromycin (2 observational studies, RR = 1.46, 95% CI 1.04-2.06). Two RCTs related to virologic clearance were all open labels. Most of the comparative studies were of poor methodologic quality and were subject to high risk of bias owing to the non-randomized study design and the lack of placebo control. A living systematic review came to a conclusion that evidence on the benefits and harms of using HCQ or CQ is very weak and conflicting.
Among the 4 RCTs included, 2 RCTs have a high risk of bias in selection of the reported result, and 2 RCTs have some concerns on the randomization process or selection of the reported result.
A multicenter, randomized, parallel, open-label, trial evaluated 150 (mild/moderate or severe) COVID-19 patients, 75 patients were assigned to HCQ (loading dose of 1200 mg daily for 3 days followed by a maintenance dose of 800 mg daily for the remaining days) plus SOC and 75 were assigned to SOC alone. Results showed that the positive-negative conversion rate of RT-PCR test at day 28 was similar for the two groups (85.4, 95% CI 73.8-93.8%) vs. (81.3, 95% CI 71.2-89.6%, P = 0.34). Significant efficacy of HCQ in alleviating symptoms was observed when the confounding effects of anti-viral agents were removed in the post-hoc analysis (HR = 8.83, 95% CI 1.09-71.3). Twenty-one adverse events were reported in HCQ patients, 1 with disease progression and 1 with upper respiratory tract infection, the others were nonserious adverse events, such as diarrhea and vomiting, which were significantly higher than those reported in the SOC group (P = 0.001).
A RCT was performed in Brazil to assess safety and efficacy of two different chloroquine diphosphate (CQ) dosages (high dose CQ: 41 patients, 600 mg CQ twice daily for 10 days or total dose 12 g; low dose CQ: 40 patients, 450 mg, twice daily only on the first day then daily for 5 days, total dose 2.7 g). Of the 81 cases, 61 cases were confirmed by RT-PCR, and 19 cases were unconfirmed cases but had clinical and epidemiological presentation. All patients received AZ. One patient developed rhabdomyolysis, which was attributed to CQ, and the drug was withdrawn. QTc interval corrected by the Fridericia method (QTcF) ≥ 500 ms was more frequent in the highdosage group than the low-dosage group (18.9% vs. 11.1%). Two of 37 patients (2.7%) in the high-dosage group experienced ventricular tachycardia before death, without torsade de pointes. Hemoglobin decrease was observed in both groups (high-dosage vs. low-dosage: 19.2% vs. 22.2% decrease respectively). Raised creatinine was observed in both groups (high-dosage vs. low-dosage: 39.1% vs. 46.7% increase respectively). No apparent differences in hematological or renal toxicity were seen between the groups. Mortality was 39.0% in the high-dosage group and 15.0% in the low-dosage group with no apparent differences despite more deaths in the high-dosage group.
A cohort study from the US evaluated 807 COVID-19 patients (HCQ, n = 198, the median age (IQR) was 71 years; HCQ + AZ, n = 214, the median age (IQR) was 68years; no HCQ, n = 395, the median age (IQR) was 70 (59-77) years). Rates of ventilation in the HCQ, HCQ + AZ, and no HCQ groups were 19.0, 20.5, 19.9%, respectively, P = 0.94. Compared to the no HCQ group, the risk of death from any cause was higher in the HCQ group (adjusted HR = 1.83, 95% CI 1.16-2.89, P = 0.009) but not in the HCQ + AZ group (adjusted HR = 1.31, 95% CI 0.80-2.15, P = 0.28). The propensity-score-adjusted risk of mechanical ventilation was similar in the HCQ group (adjusted HR = 1.19, 95% CI 0.78-1.82, P = 0.42) and in the HCQ + AZ group (adjusted HR = 1.09; 95% CI 0.72-1.66, P = 0.69), compared to the no HCQ group.
Justification More than 70% of working group members believed that there was inconsistent data to for or against using HCQ based on the above evidence and its quality, and clinicians' own experience. However, in different contexts, different countries can make their own consensus statements. For example, China made the consensus recommendation on CQ on March 42,020. There is also insufficient evidence to support the combination of HCQ and AZ leading to better clinical outcomes than HCQ alone, but we also know both of these drugs may cause Q-T prolongation. Hence, we do not recommend this combination at present. However, antibiotics therapy should be prescribed for patients having concurrent bacterial infection.
To date, at least 71 clinical trials of HCQ/CQ for COVID-19 have been registered. When new evidence that may change the current recommendation is available, we will update the recommendation.
## Question 17: should interleukin-6 inhibitors be used to treat covid-19 patients to improve clinical outcomes?
Recommendation There is insufficient evidence to support or against using interleukin-6 inhibitors (Grade2C).
Evidence summary A meta-analysis of 3641 patients including 16 studies (13 retrospective cohort studies and 3 prospective cohort studies) showed that adding tocilizumab (TCZ) to standard of care (SOC) may reduce the mortality of severe COVID-19 (Pooled OR = 0.57, 95% CI 0.36-0.92, P = 0.02), and it did not report any adverse effect. However, this evidence body was a lowquality evidence with degrading factors: more confounding factors (the difference in the age and comorbidities, variability in the follow-up period) and significant heterogeneity (I 2 = 80%) among the included studies.
The following studies were not included in the above meta-analysis:
A non-randomized controlled study showed that after adjusting for age and mechanical ventilation, use of TCZ (400 mg, iv., two doses) was not associated with mortality of COVID-19 patients in ICU (OR = 3.97, 95% CI 0.28-57.2, P = 0.3), and no adverse events were reported that could be directly related to TCZ. A propensity-score matched cohort study severe/critical patients) found TCZ use was associated with a better overall survival (HR = 0.499, 95% CI 0.262-0.952, P = 0.035), but the length of hospital stay with TCZ was longer (dose: 8 mg/kg, HR = 1.658, 95% CI 1.088-2.524, P = 0.019). Besides, infectious complications were observed in 32.4% of TCZ group, and 14.9% of TCZ patients were accompanied by severe events (sepsis cases, candidemia, lung abscess or epidural abscess). Another propensity-score matched cohort study (84 vs. 84 severe patients; 400 mg single-dose) came to similar conclusions in improving overall survival (adjusted HR = 0.26, 95% CI 0.135-0.51, P = 0.0001), and it did not report any adverse effect. A cohort study found TCZ therapy (dose: 8 mg/kg) in hyperglycaemic (n = 31) failed to attenuate risk of severe outcomes as it did in normoglycaemic patients (n = 47) (P < 0.009), and it did not report any adverse effect.
A small sample of open-label cohort study showed that overall clinical improvement, mortality, and the rate of adverse events (infections, neutropenia, increase in liver enzymes and thromboembolism) in severe COVID-19 patients were not significantly different between sarilumab and SOC at 28 days of follow-up (all P > 0.05). In addition, sarilumab (400 mg, iv.) was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline (P = 0.002). Another propensity-score matched cohort study showed that the 30-day mortality rate in patients with COVID-19 respiratory failure was significantly lower in the siltuximab (11 mg/kg, iv.) than in the control (HR = 0.462, 95% CI 0.221-0.965, P = 0.0399), and no adverse events were reported to be related to the study drug.
Since most of the evidence listed were retrospective cohort studies with fewer samples, they usually had more confounding factors, such as age, gender, disease severity, and comorbidities. Although most studies used methods/models to control measurable confounding, confounding factors still existed. The overall quality was medium or low, and no upgrade factors were found.
Justification Although meta-analysis as high-quality evidence has shown that tocilizumab can reduce mortality, its methodological quality is not high, so its strength of evidence needs to be downgraded. Tocilizumab is a representative of Interleukin-6 inhibitors, increasing evidence has shown that tocilizumab could decrease the mortality of COVID-19 patients, but due to the limitations of study type (mainly observational research) and small samples, high-quality studies are still needed to verify the effectiveness of tocilizumab.
## Question 18: should interleukin-1 inhibitors be used to treat covid-19 patients to improve clinical outcomes?
Recommendation There is insufficient evidence to support or against using interleukin-1 inhibitors (Grade2C).
Evidence summary A cohort study showed that severe COVID-19 patients who were treated with anakinra, administered subcutaneously at a dose of 100 mg twice daily for 3 days, then 100 mg daily for 7 days had a significant reduction on the need for invasive mechanical ventilation or death in the multivariate analysis (HR = 0.22, 95% CI 0.10-0.49, P = 0.0002). Besides, the frequency of elevated liver enzymes, coagulopathy was similar between patients in anakinra and control, and it is unlikely that anakinra might be caused.
A cohort study showed that moderatesevere COVID-19 patients who were treated with anakinra, administered subcutaneously at a high dose of5 mg/kg twice a day intravenously had a higher survival (90% vs. 56%, P = 0.009). Besides, the incidence of bacteremia, increased liver enzymes, and thromboembolism was similar in the two groups.
Since the evidence listed were retrospective cohort studies with fewer samples, they usually had more confounding factors. Although most studies used methods/ models to control measurable confounding, confounding factors still existed. The overall quality was medium or low, and no upgrade factors were found.
Justification To date, there is insufficient evidence to recommend for or against to use interleukin-1 inhibitors in COVID-19 patients. Additionally, working group members had no clinical experience of using Interleukin-1 inhibitors.
Question 19: Should glucocorticoid be used to treat COVID-19 patients to improve clinical outcomes?
Recommendations We do not suggest to use glucocorticoid for patients with COVID-19 in general (Grade 2B).
When sever or critical COVID-19 patients' condition deteriorates dramatically, low-dose glucocorticoid with a short course may be considered (Grade 2B).
## Implementation considerations
(1) Methylprednisolone (MP) can be considered to be used as a low dose of 1-2 mg/kg/day for a short course of about 3 days; (2) Dexamethasone can be considered to be added as a dose of 6 mg once daily (oral or intravenous) for up to 10 days.
Evidence summary A systematic review (including 11 retrospective studies, n = 4168 patients; 1 RCT, n = 6425 patients) showed that a common pattern evolving from the retrospective trials suggested more benefit with low dose steroids compared to the high dose steroids. Moreover, judicious use of corticosteroids had been shown to improve several parameters of severe and critical COVID-19, including reduction of duration of hospital stay, prevention of worsening of the ventilator parameters, progression to ARDS, and death, quicker normalization of pyrexia and improvement in the status of oxygenation, reduced incidence of intubation and subsequent ventilation, but the results from these retrospective studies were heterogenous and difficult to infer of a definitive protective benefit with corticosteroids. RE-COVERY trial (multicenter RCT conducted in 176 NHS hospitals, n = 6425 patients, 2104 for dexamethasone-6 mg once daily for up to 10 days and 4321 for usual care) found dexamethasone reduced 28-day mortality by 35% amongst the invasive mechanical ventilation patients (29.0% vs. 40.7%, RR = 0.65, 95% CI 0.51-0.82, P < 0.001) and by 20% amongst patients on supplemental oxygen therapy with or without noninvasive ventilation (21.5% vs. 25.0%, RR = 0.80, 95% CI 0.70-0.92, P = 0.002), although no benefit was observed in mild cases (17.0% vs. 13.2%, RR = 1.22, 95% CI 0.93-1.61, P = 0.14). It did not report any adverse effect. In this SR, most of included studies had a small cohort size and had a high degree of heterogeneity regarding the choice of steroids, the dose and timing of the steroids, and had a coprescription of broad-spectrum antibiotics and antivirals. However, this included multi-center, large-sample RCT clearly confirmed that the effectiveness of glucocorticoid therapy in reducing mortality, especially for severe patients.
The following studies were not included in the above systematic review:
A retrospective cohort (n = 115 patients, 73 for glucocorticoid group, 1-3 mg/kg per day for 3-10 days and 42 for control group) found that compared with conventional treatment, corticosteroid treatment was associated with a 2.155-fold increase in risk of either mortality or ICU admission in multivariate analysis (adjust for disease severity), although not statistically significant, and the corticosteroid group had more adverse outcomes (32.9% vs. 11.9%, P = 0.013).
Another retrospective cohort (n = 72 patients, 51 for glucocorticoid group: 0.75-1.50 mg/kg/d and 21 for control group) found that there was no significant difference between two groups in the median time from the onset to the negative detection of nucleic acid in sputum (P > 0.05), and it would cause some adverse reactions, such as transient hyperglycemia, hypokalemia, acne like skin rash and high blood pressure.
A retrospective cohort study based on propensity score analysis (n = 132 non-severe COVID-19 patients, matching 35 for corticosteroid group-initial MP dosage 40 mg/ d for 8-12 days, and 35 for control group) found that in corticosteroid group, the hospital stay and duration of viral shedding were prolonged, while fever time was shortened, however all these data had no statistically significant differences, and it did not report any adverse effect.
A multicentric, partially randomized, preference, open-label trial (n = 85 COVID-19 patients, 56 for MP and 29 for control) showed that a short course of MP had a beneficial effect on the clinical outcome of severe COVID-19, decreasing the risk of the composite end point of admission to ICU, NIV or death (RR = 0.55, 95% CI 0.33-0.91, P = 0.024). No major side effects were observed, but hyperglycemia was more frequent in the MP group.
A retrospective cohort (n = 202 non-ICU patients, 60 for corticosteroid group, and 145 for control group) found that patients who received corticosteroids were less likely to have had a primary outcome (composite of ICU transfer, intubation or death) than were patients who did not receive corticosteroids (adjusted HR = 0.15; 95% CI 0.07-0.33, P < 0.001), and it did not report any adverse effect.
A retrospective cohort study (n = 463 patients, 396 for steroids and 67 for control) showed that survival of COVID-19 patients was higher in glucocorticoids group than control (HR = 0.51, 95% CI 0.27-0.96, P = 0.044), especially among with moderate or severe ARDS (OR = 0.23, 95% CI 0.08-0.71, P = 0.014). In-hospital mortality was not different between initial regimens of 1 mg/kg/ day of MP and steroids pulses (OR = 0.880, 95% CI 0.449-1.726, P = 0.710), and it did not report any adverse effect.
A multicenter, observational, longitudinal study (n = 173 severe COVID-19 patients, 83 for MP and 90 for control) showed that early administration of prolonged MP treatment was associated with a significantly lower hazard of death (adjusted HR = 0.29, 95% CI 0.12-0.73, P = 0.005) and decreased ventilator dependence (24.0 ± 9.0 days vs. 17.5 ± 12.8 days; P = 0.001). The complication rate was similar for the two groups (P = 0.84).
A retrospective cohort (n = 72 patients, 56 for toci-lizumab+ MP group, and 16 for tocilizumab group) found that MP administered in patients treated with tocilizumab reduces the risk of death (RR = 0.20, 95% CI 0.08-0.47, P < 0.01), and it did not report any adverse effect.
Since most of the evidence listed were retrospective cohort studies with fewer samples, they usually had more confounding factors, such as age, gender, disease severity, and comorbidities. Although most studies used methods/models to control measurable confounding, confounding factors still existed. The overall quality was medium or low, and no upgrade factors were found.
Justification Although the results from retrospective studies are heterogeneous and difficult to infer a definitive protective benefit with corticosteroids, RECOVERY trial, as one of the world's largest RCT for COVID-19, found a significantly better outcome with dexamethasone, mostly in severe cases. Besides, dexamethasone and methylprednisolone are easily available in pharmacies, cost less, and have better economic benefits. In addition, there were limited drug-related adverse reactions during short-term use. After considering the desirable and undesirable effects, balancing the benefits and harms and based on their clinical opinion, more than 70% of working group members thought low-dose glucocorticoid may be considered for severe or critical patients when their condition deteriorates dramatically.
Question 20: Should QingfeiPaidu decoction (TCM) be used to treat patients with COVID-19 to improve clinical outcomes?
Recommendation QingfeiPaidu Decoction (QPD) may be considered to treat patients with mild or moderate COVID-19 (Ungraded Consensus-Based Statement).
## Implementation considerations
(1) Constituent parts: Ephedrae Herba 9 g, Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle 6 g, Armeniacae Semen Amarum 9 g, Gypsum Fibrosum 15-30 g (Decocted earlier), Cinnamomi Ramulus 9 g, Alismatis Rhizoma 9 g, Polyporus 9 g, Atractylodis Macrocephalae Rhizoma 9 g, Poria 15 g, Bupleuri Radix 16 g, Scutellariae Radix 6 g, Pinelliae Rhizoma Praeparatumcum Zingibere Et Alumine 9 g, Zingiberis RhizomaRecens 9 g, Asteris Radix Et Rhizoma 9 g, Farfarae Flos 9 g, Belamcandae Rhizoma 9 g, Asari Radix Et Rhizoma 6 g, Dioscoreae Rhizoma 12 g, Aurantii Fructus Immaturus 6 g, Citri Reticulatae Pericarpium 6 g, Pogostemonis Herba 9 g. (2) QPD, water decoction, 200 ml twice a day, 40 min after meal, warm-taken, 3 days a course, can be taken up to four courses based on patients' clinical manifestations.
Evidence summary A cohort study showed that compared with antiviral treatment (oseltamivir, abidor, lopinavir/ritonavir).
Justification The available evidence is very weak, but after balancing benefit and harms, considering patient preference, acceptability, feasibility, and more than 70% of working group members thought QPD may be a treatment option for patients with COVID-19, based on their clinical opinion. The results of three ongoing trials will provide evidence for this treatment option. But considering lacking of generalizability in some countries for TCM treatment and lacking of confident evidence, we finalized recommendation with "ungraded Consensus-Based Statement".
Question 21: Should Lianhua Qingwen granules/capsules (TCM) be used to treat patients with COVID-19 to improve clinical outcomes?
Recommendation We suggest that Lianhua Qingwen can be used to treat patients with mild or moderate COVID-19 with conventional therapy (defined as nutritional supportive therapy, symptomatic treatment, antiviral and antibacterial treatment if needed) (Grade2C).
## Implementation considerations lianhua qingwen
Granules/Capsules: 6 g/1.4 g by mouth, three times per day for 14 days.
Evidence summary One RCT of mild patients showed that, compared with arbidol treatment (148 patients), the TCM syndrome scores (based on the TCM syndrome rating scale) were significantly decreased (P < 0.05) after 7 days treatment with Lianhua Qingwen Granules (LQG) plus arbidol (147 patients),the total effective rate (excellent effective rate + effective rate) was increased (81.0% vs. 64.9%, P < 0.05), and lung CT images showed improvement (69.4% vs. 62.8%, P > 0.05) in the experimental group, no serious adverse reactions appeared in each group.
Another RCT showed that, compared with routine treatment (oxygen therapy, antiviral medications and symptomatic therapies) (142 patients), after 14 days treatment with LQG plus routine treatment(142 patients), the recovery rate was significantly higher (91.5% vs. 82.4%, P < 0.05),the median time to symptom recovery was markedly shorter (7 vs. 10 days, P < 0.001),time to recovery of fever was also significantly shorter (2 vs. 3 days, P < 0.001),the rate of improvement on lung CT images (83.8% vs. 64.1%, P < 0.001) and clinical cure (78.9% vs. 66.2%, P < 0.05) was higher in treatment group. However, the rate of conversion to severe cases or viral assay findings had no significant difference in both groups (P > 0.05). No serious adverse events appeared in each group.
One non-RCT reported that comparing with conventional therapy (nutritional supportive therapy, symptomatic therapy, antiviral therapy, and antibacterial therapy) (51 moderate patients), LQG plus conventional therapy (51 moderate patients) resulted in a higher rate of fever resolved (83.7% vs. 61.0%, P < 0.05) after 7 days treatment, less rate of change to severe types of COVID-19 (7.84% vs. 21.57%, P < 0.05), and higher rate of improvement on lung CT images (54.9% vs. 45.1%, P > 0.05).
Another non-RCT showed that, compared with conventional therapy (nutritional supportive therapy, symptomatic therapy, antiviral therapy, and antibacterial therapy) (21 moderate patients), the fever better resolved (85.7% vs. 57.1%, P < 0.05) after being treated by LQG plus conventional therapy (21 moderate cases) and the fever duration shortened (4.6 ± 3.2 days vs. 6.1 ± 3.1 days, P > 0.05).
The third non-RCT reported compared with conventional treatment (nutritional supportive therapy, symptomatic treatment, antiviral and antibacterial treatment) (38 suspected cases), the fever better resolved (86.7% vs. 67.7%, P < 0.05) and the disease condition less worsened (6.4% vs. 15.8%, P > 0.05) after being treated by LQG plus conventional therapy (63 suspected cases) for 10 days and showed no adverse reactions.
Among other four studies, important confounding information existed, the overall risk was judged as moderate or serious.
Justification After balancing benefit and harms, and considering the quality of evidence, patient preference, acceptability, and feasibility, the guideline panel gave a weak recommendation for Lianhua Qingwen Granules/ Capsules to treat COVID-19 with conventional therapy.
Question 22: Should convalescent plasma be used to treat COVID-19 patients to improve clinical outcomes?
Recommendation There is insufficient evidence to for or against using convalescent plasma to treat severe and critical COVID-19 patients (Grade2B).
Evidence summary A Cochrane's systematic review, which retrieved until June 4, 2020, explored the effectiveness of convalescent plasma for COVID-19 patients. Control groups received SOC. Results from 1 non-randomized studies of interventions (NRSIs) with 21 participants (6 received convalescent plasma) showed that convalescent plasma has no effect on all-cause mortality at hospital discharge (RR = 0.This systematic review included results from 1 RCT, 3 controlled NRSIs and 10 non-controlled NRSIs assessing safety of convalescent plasma. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. A non-controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first 4 h after convalescent plasma transfusion. This study reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Almost all included studies revealed a significant risk of bias, due to study design, type of participants, and other previous or concurrent treatments. The included RCT were unblinded for participants and personnel, selection of the reported result, and have bias in incomplete outcome data.
An in the Netherlands was halted prematurely after 86 patients were enrolled. Patients were randomly assigned via a web-based system to the convalescent plasma group (n = 43) and SOC group (n = 43). Results showed that convalescent plasma has no effect on overall mortality (OR = 0.95, 95% CI 0.20-4.67, P = 0.95) and was not associated with a shorter time to discharge from the hospital (HR = 0.88, 95% CI 0.49-1.60, P = 0.68). No plasma related serious adverse events were observed.
Another RCT(49 participants, of whom 21 received convalescent plasma) showed that convalescent plasma reduced duration of infection about 4 days (19.3 ± 6.9 days vs.23.42 ± 6.4 days, P < 0.05), and showed less death rate (1/21 vs. 8/28, P < 0.05).
Justification There is insufficient evidence to for or against using convalescent plasma. Most of studies have shown no benefit, but the quality of evidence is low. China made the consensus recommendation on convalescent plasma for severe and critical cases. In different contexts, different countries can make their own consensus statements. Plasma components are complex, and there may be risks associated with infusion, such as allergy and the spread of infectious diseases. Therefore, the whole process of recovery, plasma collection, preparation, storage, inspection, and application must conform to quality assurance systems and comply with pharmaceutical production quality management specifications. But there was insufficient data to support or against using convalescent plasma. Some trials involving convalescent plasma for COVID-19 are ongoing.
Question 23: Should lung transplantation be used to treat patients with COVID-19 to improve clinical outcomes?
Recommendation Lung transplantation maybe a therapeutic option for end-stage patients with COVID-19 (Ungraded Consensus-Based Statement).
Implementation consideration Firstly, three critical points should be thoroughly evaluated and confirmed before decision-making regarding lung transplantation candidacy: 1) confirmed irreversibility of refractory respiratory failure despite maximal medical support; 2) confirmed positive-turned-negative virology status by performing consecutive nucleic acid tests with samples derived from multiple sites; and 3) confirmed absence of other organ system dysfunction that could contraindicate lung transplantation.
Secondly, best practices for the protection of the medical team involved are as follows: 1) head covers with positive pressure are necessary for surgeons, nurses, anesthesiologists, and cardiopulmonary physicians; 2) head covers will help surgeons keep their field of view clear without fogging of eye protectors; 3) considering the physical demands and challenges for surgeons in full protective clothing, an intra-procedure rotation plan is necessary to guarantee optimal performance during surgery.
In addition, multiple disciplinary teams (intensive care unit, respiratory, infectious, and radiology departments) are necessary to minimize the possibility of misjudgments whether the lung injury in COVID-19 patients is irreversible.
Evidence summary Two case series reported that five patients received antiviral, hormonal, convalescent plasma, and immune-enhancing supportive treatments and life supporting extracorporeal membrane oxygenation (ECMO), but their condition continued to worsen. After lung transplantation, the vital signs of four patients with end-stage COVID-19 pneumonia were stable, the chest Xray showed the transplant lungs were clear, and the ECMO was removed successfully. However, the right lung of another patient was transplanted uneventfully. During the left lung transplant procedure, ventricular fibrillation developed abruptly and the heart arrested. Cardiac massage was commenced and cardiopulmonary bypass was established with cannulation via the superior, inferior venae cava and ascending aorta. Emergent heart transplant was also performed. The heart was resuscitated to normal rhythm with strength. But bleeding from the chest cavity and anastomosis could not be managed with sutures and coagulation in the following 5 h. The transplanted heart arrested again, and the patient was pronounced dead.
In addition, one case report stated that a COVID-19 patient was treated with high-flow nasal oxygen, methylprednisolone, umifenovir, piperacillin, and tazobactam. And then although repeated nucleic acid tests for 2019-nCoV in sputum and bronchoalveolar lavage fluid were all negative, his condition continued to deteriorate due to pulmonary consolidation complicated by stenotrophomonas maltophilia infection. And then he continued to get ECMO treatment and a bilateral-lung transplantation. Postoperatively, the ECMO was withdrawn and the patient's general condition was more stable. However, ST-segment elevation myocardial infarction after lung transplantation occurred. He received percutaneous coronary intervention. Post percutaneous coronary intervention ECG showed recovery of ST-segment, and cardiac troponin I gradually declined.
Justification In general, the panel did not include case reports or case series as evidence to make recommendations for intervention research question. However, lung transplantation is a very complicated treatment procedure and it is impossible to expect to have a RCT to investigate whether lung transplantation is effective. Based on evidence, five of six survived from dying status, the panel believed that lung transplantation may be a treatment option for dying COVID-19 patients without other treatment options if it is possible. Recommendation ECMO is recommended to treat patients with critical COVID-19, and close monitoring of patient's vital signs is necessary during use. ECMO should be used in the following situations: 1) early stage (such as severe type with a course of less than 7 days) of critical patients with reversible condition; 2) severe hypoxemia: when using optimized PEEP, PaO 2 /FiO 2 < 100 mmHg after using neuromuscular blocker and prone ventilation; 3) excessive compensatory respiratory acidosis (pH < 7.15) when using optimized mechanical ventilation; 4) excessive inspiratory stress (plateau pressure > 30 cmH 2 O) when using lung protective ventilation; 5) using optimized mechanical ventilation setting, the mechanical power is ≥27 J/min; 6) using the optimized mechanical ventilation setting, there is right heart dysfunction due to acute pulmonary heart disease (Grade 1C). Recommendation Patients meeting all the following criteria can be discharged: 1) temperature returned to normal for more than 3 days; 2) respiratory symptoms significantly improved; 3) significant absorption of pulmonary chest lesions on CT imaging; 4) two consecutive negative nucleic acid tests from sputum, nasopharyngeal swabs or other respiratory tract samples (at least 24 h between samples) (Ungraded Consensus-Based Statement).
Implementation and considerations Meanwhile, we need to consider patient's age, combidity, clinical type of COVID-19, and other factors (such as hospital capacity) to decide whether we need to add stool nucleic acid testing and/or serological testing as a part of discharge criteria.
Justification Although there was no direct evidence, the working group members believed that the discharge criteria from expert opinion was reasonable and had achieved good results in China. However, whether it is needed to add stool nucleic acid testing and/or serological testing as a part of discharge criteria is unclear. Different countries may make slightly different discharge criteria based on their context. Question 27: What are the imaging findings in COVID-19 patients whose RT-PCR test is positive for COVID-19 after previously recovering?
Recommendation Most of people have no progressive imaging findings in chest CT of COVID-19 patients whose RT-PCR test shows positive after previously recovering Implementation considerations Chest CT should be performed in recovered patients from COVID-19 whose RT-PCR test showed positive after discharge.
Evidence summary There are seven studies, including 279 patients whose RT-PCR shows positive recovery from COVID-19. All the patients received chest CT imaging, with (29.4-90.2%) cases showing improvement, and (8-32%) cases showing no active progression. The chest CT of one case presented recurrent symptoms with blurred image in the upper lobe of both lungs, more prominent on the left side during the convalescent period, but the severity of image is less than that of late period of hospitalization.
Justification According to the above low-quality evidence, the working group members thought although most patients have no progressive imaging changes was found, confirmation by a larger sample study is needed in the future.showed chest CT images of SARS-CoV-2 reactivation patient from clinical data from Zhongnan Hospital of Wuhan University (also approved by the Committee for Ethical Affairs of this hospital).
Question 28: What is the management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge?
Recommendation After the first discharge, if the RT-PCR test reverts from negative to positive, the patients should be isolated again and may be re-hospitalized based on their clinical characteristics. The effective treatments should be given as early as possible if needed. If the lung image does not have progressive change comparing with that at the first discharge, and patients have three negative RT-PCR tests from sputum and fecal specimens (each≥24 h apart), the patients can be managed according to the requirements of home isolation and follow-up again (Ungraded Consensus-Based Statement).
Implementation considerations A combination of sputum and fecal specimen types (at least one of the three negative RT-PCR tests should coming from a fecal test) should be used to detect the nucleic acid of SARS-CoV-2 for the retested positive patients after discharge, i.e., at least one of the three negative RT-PCR tests should coming from a fecal test.
Evidence summary One cross-sectional study found that viral RNA could also be detected in the feces of 81.8% (54/66) patients with COVID-19 (after discharge 6-11 days) when pharyngeal swabs were negative. Fecal specimens test should be more useful than nasopharyngeal swab.
A cohort study reported that 3% (23/651) patients had positive RT-PCR testing again during the follow-up period. Among the retested positive patients, 12 patients (52%) had moderate, 9 patients had (39%) severe, and 2 patients had (9%) critical conditions during their previous hospitalization. 50% of the patients carried IgG antibodies and 30% of the patients carried IgM antibodies suggested partial immune system recognition of SARS-CoV-2.The detection of IgG and IgM antibodies should be increased on the basis of RT-PCR for retested positive patients. And it also reported that the median duration from hospital discharge to positive retest was 15 days.
A cross-sectional study found that 15.9% (11 / 69) of patients had positive RT-PCR testing again after discharge and the median interval from discharge to positive RT-PCR results again was 14 days, 10 of the 11 patients had mild or moderate infection and only 1 patient had critical infection, which suggest that strict self-isolation protocols and extended follow-up periods might be needed for recovered COVID-19 patients.
Another cross-sectional study from China reported that 14.5% (25/172) of patients had positive RT-PCR testing again after discharge 5-13 days, so discharge criteria should be reevaluated or reset.
A case report from China found that some discharged patients' condition aggravated again after discontinuation of antiviral drugs, which may be one of the reasons for recovered patients with COVID-19 testing positive again. It is suggested that not only consider the patient's viral nucleic acid test results, but also the manifestations on chest computed tomography to determine whether patients can stop taking antiviral drugs.
Justification In order to strengthen epidemic prevention and control, based on the eligible limited evidence and clinical experience, more than 70% of working group members agreed that the number of RT-PCR tests for these patients should be increased from two to three comparing with those at the first hospital discharge. Because all discharged patients followed a strict protocol for self-isolation, which believe that the RNA positivity at follow-up is unlikely to be due to reinfection. Different countries may make different management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge. More high-quality clinical research is needed to confirm this statement. We did not find any trial to verify the management strategies for patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge, so we gave recommendation on "Ungraded Consensus-Based Statement".
Question 29: Is the RT-PCR retesting needed to monitor COVID-19 patient after discharge?
Recommendation Discharged patients may be quarantined for 2 weeks, with follow-up, and PCR tests can be performed at 2 and 4 weeks after discharge (Ungraded Consensus-Based Statement).
Implementation consideration Home quarantine is the primary choice for patients after discharge. If there is a designated centralized isolation area, patients may receive medical observation in this area.
Justification The evidence was same as question of "management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge". The possibility of patients becoming RT-PCR positive again after discharge raises the potential risk of transmission. Thus, surveillance of discharged patients is needed. More than 70% experts reached agreement. Different countries may make different surveillance plan for discharged patients based on their context.
## Guideline implementation tools
We created for chemoprophylaxis and treatments sections, and for diagnosis, and discharge management sections respectively for the implementation purpose.
# Discussion
Our recommendations, based on the best available evidence, can timely provide references to the world-wide clinicians regarding on preventive drug treatments, diagnosis, treatment and discharge management on patients with COVID-19.
We got the recommendation of "Chest CT or x-ray is important alternative tests for RT-PCR test. Suspected COVID-19 patients with typical chest CT or x-ray presentation should be isolated and treated as clinically diagnosed patients". In the worldwide, we can see a nucleic acid test has currently accepted as the gold standard method to confirm diagnosis. In addition, imaging examination and epidemiological history were usually considered as auxiliary diagnosis methods. Although the use of radiological evidence to confirm viral pneumonia may be an important alternative to the diagnosis and monitoring of COVID-19, it also brought some problems. This procedure may include some patients with common pneumonia; hence criteria for clinically diagnosed patients also need to include the nucleic acid results at a later stage to correct the actual number of cases.
Classes of drugs are being evaluated or developed for the management of COVID-19 for months, and more than one thousand trials were conducting in the whole world. Most antiviral drugs undergoing clinical testing in patients with COVID-19 are repurposed antiviral agents originally developed against influenza, HIV, Ebola, or SARS/MERS. Unfortunately, we have no high confidence for any one treatment. Although we gave weak recommendation for using remdesivir, the effect of remdesivir on survival remains unknown.
A human vaccine is currently not available for SARS-CoV-2, but nearly 120 candidates are under development. A randomised, double-blind, placebo controlled, phase 2 trial and a preliminary report of a phase 1/2, single-blind, randomised controlled trial have published recently, and appears to be a promising.
We adhered to the GRADE basic approaches and rules to assess the quality of a body of evidence, and to develop and report recommendations and make some adjustments.
Rigorous search techniques were implemented, so we thought the possibility of unidentified studies leading to publication bias was rare. We formed recommendations based on many small number trials. Generally, publication bias should be suspected when published evidence is limited to a small number of small trials. However, with new research papers emerging continuously, we believed our recommendation should be interpreted with caution and did not downgrade quality of evidence due to publication bias. Downgrading of analysis was difficult for one outcome across all the studies, because of limited studies, different disease types, interventions, doses, medication courses, and the timing of outcome reports involved in the evidence. Traditional GRADE summary tables for each outcome were presented only for pooled effect of outcomes of interest. For diagnosis questions, studies measuring the impact of testing on patient-important or population-important outcomes were not available, the guideline panels only focused on other studies, such as those involving diagnostic test accuracy which were considered a surrogate outcome for patient-important benefits and harm. Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary information files.
Ethics approval and consent to participate The Figs. 1, 2, 3, 4, 5, and 6 from existed clinical data from Zhongnan Hospital of Wuhan University, and also approved by the Committee for Ethical Affairs of this hospital and written informed consent was obtained from each participant ([No. 2020074]). No additional ethical approval is needed.
## Consent for publication
Not applicable.
## Competing interests
No one reported having stock, being a consultant paid by companies or receiving research funding from companies that have an interest in the guideline. Zhen-Shun Cheng reported participating in or hosting a study of Remdesivir for COVID-19. Ya-Dong Gao reported participating in or hosting two studies of Enteric capsule with diammonium glycyrrhizate combined with vitamin C and hydroxychloroquine for COVID-19. Jian Xia reported participating in or hosting two studies of ECOM treatment for critical patients and a prediction model for COVID-19 prognosis. Qi-Wen Yang reported participating in or hosting a study of clinical evaluation of rapid nucleic acid detection kit. Xiao-Chun Zhang reported participating in or hosting a study of COVID-19 technical research and integrated application projects. Yu-Feng Yuan reported participating in or hosting three studies of Clinical course and prognosis, TCM treatment and rapid disinfection of medical items for COVID-
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Antimicrobial treatment guidelines for acute bacterial rhinosinusitis☆☆☆★
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Antimicrobial treatment guidelines for acute bacterial rhinosinusitis☆☆☆★
# Introduction
The Sinus and Allergy Health Partnership, in consultation with representatives of the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and individuals from the fields of infectious disease, pediatric infectious disease, microbiology, clinical pharmacy, and clinical pharmacology, have developed these guidelines as an educational tool for the healthcare provider involved in treating patients with acute bacterial rhinosinustis (ABRS).
There are several problems we attempted to address during the process of writing this document: (1) the diagnosis of bacterial "sinusitis" is made too frequently; patients with viral illnesses of only a few days' duration are inappropriately labeled as having bacterial disease and, therefore, [bib_ref] Appropriate use of antibiotics for URIs in children: part I. Otitis media..., Dowell [/bib_ref] patients are prescribed an antibiotic that is not only ineffective against a viral pathogen but also has the risk of leading to (3) the development and/or increase of resistance of various bacteria, including S pneumoniae. Another problem frequently encountered is that in bacterial infections, antibiotics are frequently used without regard to an understanding of their efficacy against the typical bacterial causes of ABRS. Little logic exists when a patient with ABRS is first prescribed TMP/SMX, then is switched to cefaclor when symptoms do not improve, and subsequently is prescribed azithromycin when again there is still no improvement. No agent in this example provides adequate empirical treatment for S pneumoniae or H influenzae, both major bacterial pathogens in ABRS.
In this paper the reader is taken on a step-by-step approach to ABRS. The terminology, incidence, and definition of ABRS are presented. Various diagnostic modalities are reviewed. Rather than just create a list of antibiotics, numerous factors (eg, microbiology of ABRS, pharmacodynamic/pharmacokinetic principles, features of common oral antibiotics, the resistance mechanisms of bacterial pathogens, and the results of surveillance studies focused on prevalence of resistant pathogens) assisting in the selection of antimicrobial agents are discussed. All this information, in conjunction with a mathematical model for analyzing treatment outcomes, leads to the development of rational treatment guidelines that will assist clinicians in providing optimal treatment for their patients.
Our hope is that these guidelines will be a part of national and international efforts coordinated by the CDC and aimed at educating health care providers and patients about the abuses and overuses of antibiotics. The misuse of antibiotics should not be a replacement for spending time talking with and examining the patient and teaching that patient and/or the patient's family the differences between viral and bacterial infections.
We cannot rely on the pharmaceutical industry to develop new drugs as organisms become resistant; rather, we must decrease unnecessary antimicrobial use as a means to reduce the spread of resistance.
We believe further research is necessary to (1) develop better methods to diagnose ABRS, (2) further explore the clinical application of the antibiotic recommendations presented in this document, and (3) monitor the levels of bacterial resistance-especially those of S pneumoniae and H influenzae.
## Viral respiratory tract infections versus abrs
In the United States, the average child has 3 to 8 and the average adult has 2 to 3 acute viral respiratory illnesses per year. [bib_ref] Acute community-acquired sinusitis, Gwaltney [/bib_ref] [bib_ref] Appropriate use of antibiotics for URIs in children: part I. Otitis media..., Dowell [/bib_ref] Because up to 90% of these patients will have CT scan evidence of paranasal sinus involvement, they are considered to have a self-limiting viral rhinosinusitis (VRS). [bib_ref] Acute community-acquired sinusitis, Gwaltney [/bib_ref] [bib_ref] Computed tomographic study of the common cold, Gwaltney [/bib_ref] Bacterial infections, also referred to as ABRS, complicate roughly 0.5% to 2% of VRS. [bib_ref] Acute community-acquired sinusitis, Gwaltney [/bib_ref] [bib_ref] Occurrence of asymptomatic sinusitis in common cold and other acute ENT-infections, Berg [/bib_ref] It is estimated that more than 1 billion cases of VRS occur annually in the United States. Assuming a 2% bacterial complication rate, 20 million cases of VRS are complicated by ABRS annually. In addition to its public health implications, rhinosinusitis has a considerable economic impact. In 1996, the primary diagnosis of rhi-nosinusitis led to expenditures of approximately $3.39 billion in the United States. [bib_ref] Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other..., Ray [/bib_ref] The National Center for Health Statistics conducts a sample survey of office-based physicians in the United States called the NAMCS. Data from NAMCS for indicate an increase in the number of adult visits to physicians' offices resulting in a diagnosis of acute or chronic rhinosinusitis.According to NAMCS data, sinusitis is the fifth most common diagnosis for which an antibiotic is prescribed. A diagnosis of rhinosinusitis was made for 7%, 9%, and 12% of all antibiotic prescriptions written in , and 1992, respectively.As the total number of antibiotic prescriptions increased throughout the last decade, resistance to antimicrobial agents among bacterial respiratory pathogens emerged as a significant public health issue. Because antibiotic use is causally related to the development and spread of bacterial drug resistance, [bib_ref] Development of β-lactamase-mediated resistance to penicillin in middle-ear isolates of Moraxella catarrhalis..., Nissinen [/bib_ref] [bib_ref] Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children?..., Arason [/bib_ref] [bib_ref] The effect of changes in the consumption of macrolide antibiotics on erythromycin..., Seppala [/bib_ref] [bib_ref] Outpatient use of erythromycin: link to increased erythryromycin resistance in group A..., Seppala [/bib_ref] strategies resulting in prudent and rational antimicrobial use are increasingly important. In rhinosinusitis, two scenarios for antibiotic prescribing are of particular concern. First is the frequent treatment of uncomplicated VRS with antimicrobials. Second is the selection of antimicrobial agents without documented efficacy. The goal of this panel is to develop guidelines for the judicious use of antibiotics in the treatment of ABRS.
## Definition and diagnosis of abrs
In 1997, the American Academy of Otolaryngology-Head and Neck Surgery developed working definitions for sinusitis to clarify communications among providers and researchers. [bib_ref] Adult rhinosinusitis defined, Lanza [/bib_ref] Because sinusitis is usually preceded by rhinitis and rarely occurs without concurrent rhinitis, it was decided that sinusitis be best described as rhinosinusitis. The terms acute, subacute, recurrent acute, and chronic rhinosinusitis were reviewed. This terminology was subsequently adopted by the Agency for Healthcare Research and Quality in the development of their 1999 document on the diagnosis and treatment of ABRS. 7
## Pathophysiologic characteristics of abrs
ABRS is most often preceded by a viral URI. Allergy, trauma, or other environmental factors that lead to inflammation of the nose and paranasal sinuses may also predispose individuals to ABRS. Approximately 50% of common colds are caused by the human rhinovirus. Other viruses that cause colds include coronavirus, influenza A and B viruses, parainfluenza virus, respiratory syncytial virus, adenovirus, and enterovirus. Human rhinovirus and coronavirus do not cause major epithelial damage, but influenza virus and adenovirus do damage the nasal epithelium. [bib_ref] Viruses and bacteria in the etiology of the common cold, Makela [/bib_ref] [bib_ref] Viral-induced rhinitis, Winther [/bib_ref] Most of these infections occur in the early fall to early spring seasons. Human rhinovirus enters the nose and attaches to a rhinovirus receptor on epithelial cells in the posterior nasopharynx. [bib_ref] The major human rhinovirus receptor is ICAM-1, Greve [/bib_ref] Subsequent activation of both inflammatory pathways and the parasympathetic nervous system generates the symptoms and signs of viral rhinitis and viral sinusitis.
In a study of 31 patients by Gwaltney et al, [bib_ref] Computed tomographic study of the common cold, Gwaltney [/bib_ref] 87% of adults with acute onset of URI symptoms demonstrated inflammation within the nose and viscous secretions, sometimes with bubbles, in the sinuses on CT scan. [bib_ref] Computed tomographic study of the common cold, Gwaltney [/bib_ref] After 2 weeks without antibiotic therapy, repeat CT scans in 14 subjects revealed that 79% had either disappearance of or marked improvement in the previously identified abnormalities.
The fever, myalgia, and pharyngitis associated with a viral URI tend to resolve after 5 days. Nasal congestion and cough may persist into the second and third week [fig_ref] Fig 1: Duration of symptoms in rhinovirus URIs [/fig_ref]. [bib_ref] Rhinovirus infections in an industrial population. II. Characteristics of illness and antibody..., Gwaltney [/bib_ref] Fever alone at day 10 is not suggestive of ABRS. Approximately 0.5% to 2% of adult patients with a viral URI have a secondary bacterial infection of the paranasal sinuses develop. The causes of secondary bacterial invasion of the sinuses are unknown, but a combination of factors such as nose blowing [bib_ref] Nose blowing propels nasal fluid into the paranasal sinuses, Gwaltney [/bib_ref] local/systemic immunity, the virulence of the virus, colonization of the nasopharynx with potential bacterial pathogens (eg, S pneumoniae), and various environmental factors may lead to conditions that are conducive for bacterial entry and growth in the sinuses.
Differentiating a viral URI from ABRS is more challenging in children than adults. [bib_ref] Appropriate use of antibiotics for URIs in children: part I. Otitis media..., Dowell [/bib_ref] Because the average child has 3 to 8 viral URIs per year, the potential for inappropriate antibiotic use is high. [bib_ref] Acute respiratory illness in an American community. The Tecumseh study, Monto [/bib_ref] The mean duration of a viral URI ranges between 6.6 days (1-to 2-year-old children in home care) and 8.9 days (children <1 year old in day care). Upper respiratory tract symptoms may, however, last more than 15 days in 6.5% (1-to 3-year-old children in home care) to 13.1% (2-to 3-year-old children in day care) of cases. Children in day care are more likely to have protracted respiratory symptoms. [bib_ref] Upper respiratory tract infections in young children: duration of and frequency of..., Wald [/bib_ref] A variable percentage of children with URI symptoms will be prescribed an antibiotic. [bib_ref] Antibiotics for colds in children: who are the high prescribers?, Mainous [/bib_ref] [bib_ref] Antibiotic prescribing for Canadian preschool children: evidence of overprescribing for viral respiratory..., Wang [/bib_ref]
## Clinical diagnosis
Patients with a common cold usually report some combination of the following symptoms: sneezing, rhinorrhea, nasal congestion, hyposmia/anosmia, facial pressure, postnasal drip, sore throat, cough, ear fullness, fever, and myalgia. Contrary to popular belief, a change in the color or the characteristic of the nasal discharge is not a specific sign of a bacterial infection. [bib_ref] Can nasal bacterial flora be predicted from clinical findings?, Hays [/bib_ref] [bib_ref] Purulent nasal discharge, Wald [/bib_ref] [bib_ref] Acute maxillary sinusitis in children, Wald [/bib_ref] [bib_ref] Effects on the nasal mucosa of upper respiratory viruses (common cold), Winther [/bib_ref] [bib_ref] Study of bacteria in the nasal cavity and nasopharynx during naturally acquired..., Winther [/bib_ref] After a few days of a viral infection, mucopurulent nasal secretions may occur because of an influx of neutrophils. The point at which a viral URI becomes super- infected with pathogenic bacteria can only be determined with repeated sinus aspiration studies. Sinus aspiration studies in adults demonstrate significant bacterial growth in approximately 60% of patients with URI symptoms lasting at least 10 days. [bib_ref] The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis:..., Gwaltney [/bib_ref] The risk that bacterial superinfection has occurred is greater if the illness is no better or worse after 10 days. Because there may be cases that fall out of the "norm" of this typical progression and have specific findings suggesting bacterial infection (fever, facial erythema, swelling, and severe pain), practicing clinicians need to rely on clinical judgment when using these guidelines. In general, however, a diagnosis of ABRS may be made in adults or children with a viral URI that is no better after 10 days or worsens after 5 to 7 days and is accompanied by some or all of the following symptoms: nasal drainage, nasal congestion, facial pressure/pain (especially when unilateral and focused in the region of a particular sinus), postnasal drainage, hyposmia/anosmia, fever, cough, fatigue, maxillary dental pain, and ear pressure/fullness [fig_ref] Table 1: Symptoms associated with bacterial rhinosinusitisA diagnosis of ABRS may be made in... [/fig_ref].
## Diagnostic modalities
Physical examination provides limited information and is not extremely useful in the diagnosis of ABRS. Unlike acute otitis media, in which the tympanic membrane and middle ear space are readily available for direct examination, the paranasal sinuses are hidden deep within the skull. Anterior rhinoscopy (with or without topical decongestant) allows examination of the mucosa of the inferior turbinate, secretions within the anterior nose, and the orientation of the nasal septum. Fiberoptic endoscopy allows visualization of the middle meatus, and direct culture of purulence in this region may correlate with cultures from maxillary sinus aspirates. [bib_ref] Role of middle meatus aspiration culture in the diagnosis of chronic sinusitis, Gold [/bib_ref] [bib_ref] Microbiology of chronic maxillary sinusitis: comparison between specimens obtained by sinus endoscopy..., Brook [/bib_ref] Endoscopy, however, is not necessary in uncomplicated cases of ABRS. Transillumination has a 60% and 90% reproducibility rate for assessing disease within the maxillary sinuses and the frontal sinuses, respectively, but this does not differentiate bacterial from viral infection. [bib_ref] Does this patient have sinusitis? Diagnosing acute sinusitis by history and physical..., Williams [/bib_ref] B-mode ultrasound has replaced A-mode ultrasound for the diagnosis of diseases within the paranasal sinuses. However, because only the maxillary sinus can be adequately assessed, B-mode ultrasound has limited utility. A study correlating CT scan and B-mode ultrasound findings demonstrated a sensitivity for ultrasound of 72.8% for the maxillary sinuses, 23.1% for the frontal sinuses, and 11.3% for the ethmoids. [bib_ref] Value of B-image ultrasound in diagnosis of paranasal sinus diseases in comparison..., Tiedjen [/bib_ref] Compared with clinical evaluation, the sensitivity of B-mode ultrasound was 36% and the specificity was 90%. [bib_ref] Sensitivity and specificity of diagnostic tests in acute maxillary sinusitis determined by..., De Bock [/bib_ref] Because ultrasound is technique-sensitive, there may be marked variations in the reliability of the information provided. [bib_ref] Diagnosing acute maxillary sinusitis in primary care: a comparison of ultrasound, clinical..., Laine [/bib_ref] Ultrasound cannot distinguish between viral and bacterial rhinosinusitis. Plain film radiographs primarily reveal pathologic findings in the maxillary and frontal sinuses, whereas the ethmoids are poorly visualized. Additionally, plain radiographs are imprecise at determining the extent of disease. [bib_ref] Rhinosinusitis: radiologic diagnosis, Zinreich [/bib_ref] A meta-analysis of 6 studies demonstrated that positive plain film radiographs have moderate sensitivity (76%) and specificity (79%) compared with maxillary sinus puncture.A negative radiograph has more diagnostic value than either a negative clinical examination or ultrasound. CT scans clearly demonstrate abnormalities within the sinuses. However, as previously noted, abnormalities are frequently found on CT scans of patients with viral respiratory disease. [bib_ref] Computed tomographic study of the common cold, Gwaltney [/bib_ref] MRI scans, without exposing patients to ionizing radiation, distinctly reveal mucosal thickening and fluid within the paranasal sinuses. In patients with maxillary sinusitis, serial MRI scans demonstrate mucosal thickening persisting for up to 8 weeks. [bib_ref] Clinical course of acute maxillary sinusitis documented by sequential MRI scanning, Leopold [/bib_ref] CT and MRI scans are not indicated in uncomplicated cases of ABRS but are appropriate for cases with complications or those in which a serious problem may be suspected.
Puncture of the maxillary sinus, through the canine fossa or the inferior meatus, provides material that may be cultured to identify bacterial isolates. Technical expertise is required to minimize complications, and it is somewhat uncomfortable for the patient. Maxillary sinus puncture is not routinely used in cases of suspected ABRS. It is usually reserved for the research setting or for patients with unresponsive or complicated infections.
## Microbiology of abrs
Bacteria are broadly classified into groups based on their cell wall composition, morphologic characteristics, and metabolic requirements. The cell wall, an important determinant of inherent susceptibility or resistance for any bacterium to many antimicrobial agents, consists primarily of proteins, lipids, and a peptidoglycan layer. The peptidoglycan layer is composed of oligosaccharide chains cross-linked by short peptides that serve as the major structural component for maintaining cell wall integrity. Although gram-positive and gram-negative bacteria share many common structural elements in their cell walls, the organization and content of these elements vary between these two bacterial classes [fig_ref] Fig 2: Gram-positive and gram-negative bacteria have different configurations of their cell walls [/fig_ref]. The cell wall of gram-positive bacteria consists almost entirely of a thick peptidoglycan layer fused to the outside of the cytoplasmic membrane. Gram-negative bacteria, however, have cell walls composed of a hydrophobic lipopolysaccharide capsule surrounding a lipoprotein-phospholipid membrane that contains small channels called porins. A thin peptidoglycan layer lies between the outer membrane and the inner cytoplasmic membrane. These two biologic layers are separated by the periplasmic space. This space is an important site for degradation of antibiotics by drug inactivating enzymes, such as β-lactamases, in gramnegative bacteria. Penicillin-binding proteins (PBPs), enzymes essential for cell wall synthesis, are located in the cytoplasmic membrane. PBPs are found in gram- negative and gram-positive organisms. Altered PBPs, which have decreased affinity for β-lactams, have been identified in a variety of organisms. The most common bacterial isolates recovered from the maxillary sinuses of patients with ABRS are S pneumoniae, H influenzae, other streptococcal species, and M catarrhalis. A review of sinus aspiration studies that have been performed in adults with ABRS have shown that S pneumoniae is isolated in approximately 20% to 43%, H influenzae in 22% to 35%, and M catarrhalis in 2% to 10% of aspirates [fig_ref] Fig 3: Ranges of prevalence of the major pathogens associated with ABRS in adults [/fig_ref]. [bib_ref] Acute community-acquired sinusitis, Gwaltney [/bib_ref] [bib_ref] The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis:..., Gwaltney [/bib_ref] [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref] [bib_ref] Bacteriology of maxillary sinusitis in relation to character of inflammation and prior..., Berg [/bib_ref] [bib_ref] Microbiology and management of sinusitis, Brook [/bib_ref] In children with ABRS, S pneumoniae is isolated in approximately 35% to 42%, whereas H influenzae and M catarrhalis are each recovered from about 21% to 28% of aspirates. Streptococcus pyogenes and anaerobes account for 3% to 7% [fig_ref] Fig 4: Ranges of prevalence of the major pathogens associated with ABRS in children [/fig_ref]. [bib_ref] The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis:..., Gwaltney [/bib_ref] [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref] [bib_ref] Bacteriology of maxillary sinusitis in relation to character of inflammation and prior..., Berg [/bib_ref] [bib_ref] Treatment of acute maxillary sinusitis in childhood: a comparative study of amoxicillin..., Wald [/bib_ref] Other bacterial isolates found in patients with ABRS include S aureus and anaerobes. [bib_ref] The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis:..., Gwaltney [/bib_ref] [bib_ref] Etiology and antimicrobial treatment of acute sinusitis, Gwaltney [/bib_ref] [bib_ref] Bacteriology of maxillary sinusitis in relation to character of inflammation and prior..., Berg [/bib_ref]
## S pneumoniae
Streptococci are gram-positive, catalase-negative, facultatively anaerobic spherical bacteria that are typically seen in pairs or chains. They are nutritionally fastidious, requiring complex media containing blood or serum for growth, and growth is often enhanced by a carbon dioxide-enriched atmosphere. S pneumoniae belongs to the α-hemolytic group of streptococci and is distinguished from the viridans group by its occurrence in pairs, the requirement for carbon dioxide for primary isolation, and for autolysing in the presence of bile salts (bile solubility) and optochin (inhibition by optochincontaining disks). Pneumococci are usually encapsulated, and the capsular polysaccharides are used for serologic classification. There are 90 antigenically distinct capsu-lar serotypes in 42 distinct serogroups that have been described. Some of the serotypes have common antigens and are grouped together in serogroups, accounting for the designations of 6A and 6B, for example, in serogroup 6.
Sequential colonization of the nasopharynx with pneumococci of different serotypes occurs, starting soon after birth, with each strain persisting for 1 to 12 months. Point prevalence surveys have shown that up to two thirds of children and one third of adults have nasopharyngeal colonization with pneumococci, with prevalence being highest in winter and during respiratory viral infections. [bib_ref] Relationship between nasopharyngeal colonization and the development of otitis media in children...., Faden [/bib_ref] More than 90% of children demonstrate colonization by 3 years of age; the frequent serotypes/serogroups colonizing infants are Pneumococci have also been shown to have a high frequency of genetic recombination, and strains carried in the nasopharynx may frequently change serotype. [bib_ref] Population biology of Streptococcus pneumoniae isolated from oropharyngeal carriage and invasive disease, Muller-Graf [/bib_ref] The incidence of disease varies with serotype, and infection caused by serotype 14 and serogroups [bib_ref] Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children?..., Arason [/bib_ref] [bib_ref] Acute respiratory illness in an American community. The Tecumseh study, Monto [/bib_ref] [bib_ref] Upper respiratory tract infections in young children: duration of and frequency of..., Wald [/bib_ref] , and 23 is highest in children, whereas that caused by serotypes 3 and 8 is highest in adults. Serotypes 1, 5, and 7 and serogroup 4 tend to cause disease at similar frequency in all age groups. Furthermore, it has been found that only 12 serogroups account for approximately 80% of infections. [bib_ref] Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex, and geography in..., Scott [/bib_ref] Seven serotypes, 14, 6B, 19F, 18C, 23F, 4, and 9V (in order of decreasing frequency) accounted for 78% of isolates from blood, cerebrospinal fluid, and middle ear sources of children in the United States. [bib_ref] Epidemiology of pneumococcal serotypes and conjugate vaccine formulations, Butler [/bib_ref] These are present in the newly available conjugated pneumococcal vaccine.
Antimicrobial resistance is seen mainly in serotypes 6A, 6B, , and 23F. These serotypes are also
## Otolaryngology-head and neck surgery
## H influenzae
This organism belongs to the genus Haemophilus, which consists of small, pleomorphic, and facultatively anaerobic gram-negative bacilli. Most species have complex nutritional requirements, and growth is enhanced by a carbon dioxide-enriched atmosphere. H influenzae is characterized by its requirement for both hemin (X factor) and NAD (V factor). Strains of H influenzae may be either encapsulated or unencapsulated; encapsulated strains include 6 serotypes (serotypes a to f). H influenzae type b was the leading cause of bacteremia and meningitis in children before the introduction of effective vaccines for this serotype. However, nontypeable strains typically cause URIs such as otitis media, sinusitis, and acute exacerbations of chronic bronchitis; accordingly, the occurrence of these infections has not been affected by the use of type b vaccines. Strains of nontypeable H influenzae sequentially colonize the nasopharynx; this process starts in infancy. By 2 years of age 44% of children demonstrate colonization, with each strain being carried for 1 to 7 months (mean 2.2 months). [bib_ref] Epidemiology of nasopharyngeal colonization with nontypeable Haemophilus influenzae in the first 2..., Faden [/bib_ref] Production of H influenzae-specific IgA results in eradication of carriage of a strain, which is followed by acquisition of a new strain with different surface proteins.
## M catarrhalis
This species consists of aerobic, oxidase-positive, gram-negative diplococci. It has much less fastidious growth requirements than either streptococci or Haemophilus species and will grow on simple media without blood or serum.
As is the case with S pneumoniae and H influenzae, M catarrhalis colonizes the nasopharynx in early childhood; 78% of children demonstrate colonization by 2 years of age. [bib_ref] Epidemiology of Moraxella catarrhalis in children during the first 2 years of..., Faden [/bib_ref] Each child is sequentially colonized with different strains of M catarrhalis. Otitis-prone children are more frequently colonized than normal children.
## Nasopharyngeal flora
Starting soon after birth, the nasopharynx is colonized with flora such as viridans streptococci, Corynebacterium species, Neisseria species, and anaerobes. Colonization with "respiratory pathogens" occurs intermittently as discussed, and by 12 months of age 70% of children are colonized by at least 1 of the 3 major respiratory pathogens: S pneumoniae, H influenzae, and M catarrhalis. Colonization by these pathogens increases considerably during periods of viral URI and often results in these organisms causing bacterial otitis media and sinusitis. In addition, administration of antimicrobials increases carriage of antimicrobial-resistant strains of these bacterial pathogens. [bib_ref] Dynamics of pneumococcal nasopharyngeal colonization during the first days of antibiotic treatment..., Dagan [/bib_ref] Adults also have colonization of the nasopharynx, but their duration of carriage is shorter than in children. [bib_ref] Duration of nasopharyngeal carriage of penicillin-resistant Streptococcus pneumoniae: experiences from the South..., Ekdahl [/bib_ref]
## Assessment of antimicrobial activity
Numerous methods may be used to assess the in vitro activity of an antibiotic. Tests such as the minimal inhibitory concentration (MIC), minimal bactericidal Otolaryngology-Head and Neck Surgery S10 SINUS AND ALLERGY HEALTH PARTNERSHIP July 2000 concentration (MBC) or minimum lethal concentration, and time-kill testing are valid methods for the assessment of antimicrobial activity. It is, however, important to understand the usefulness and limitations of each of these tests. Antimicrobial activity is commonly evaluated by determining the MIC of a particular antibiotic against a specific bacterial strain [fig_ref] Fig 5: MIC is the lowest concentration of the antimicrobial that results in the... [/fig_ref]. Therefore, if an MIC is reported as 2 µg/mL, the true inhibitory concentration is somewhere between >1 µg/mL and 2 µg/mL. Two other terms used are MIC [bib_ref] Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae, Appelbaum [/bib_ref] , the MIC that inhibits 50% of the isolates tested, and MIC 90 , the MIC that inhibits 90% of the isolates tested. It is extremely important to remember that the MIC is an in vitro characteristic of the antimicrobial and is determined under strictly adhered to conditions. Because the environmental conditions at the site of infection rarely correspond to in vitro susceptibility test conditions, effects of elements such as oxygen tension, pH, and protein binding on the activity of the antimicrobial of interest need to be considered. For example, low pH can have a significantly detrimental effect on the activity of the macrolides. Therefore, even if an organism appears susceptible in vitro, clinical failure may occur if in vivo conditions detract from the activity of the drug. Similarly, some host factors may actually serve to improve the in vivo activity of an antimicrobial. Macrophages, opsonic factors, and complement may all act synergistically with an antibiotic and thus provide enhanced antibacterial activity over that which would be predicted in vitro. Additionally, many bacterial infections resolve spontaneously without the use of antimicrobial agents.
The MIC defines the amount of an antimicrobial necessary to inhibit the growth of a microbe. In contrast, the MBC provides information regarding the concentration of drug required to kill the organism. The MBC, like the MIC, is an in vitro test that is subject to similar limitations in relation to clinical effectiveness. The MBC is calculated by determining changes in inocula of bacteria incubated in the presence of varying drug concentrations over time and is defined as the lowest drug concentration that results in a 99.9% reduction in viable count at 24 hours compared with the initial inoculum. MBC values generally range from 0 to 2 doubling dilutions higher than MIC values. Because MICs are better standardized, less costly, and less labor intensive, they are used more often than are MBCs. However, if the MBC is much higher than the MIC (unless the drug is not known to be bacteriostatic), the organism is said to display tolerance to the antimicrobial.
## Bacterial resistance in abrs mechanisms of bacterial resistance
There are 3 primary mechanisms by which antimicrobial resistance is expressed: (1) production of antibioticinactivating enzymes, (2) alteration of the antimicrobial target site, and (3) alteration of the bacterial influx/ efflux processes. Bacteria may exhibit some or all of these different mechanisms. amide bond of the β-lactam ring, resulting in inactivation, have been isolated from numerous gram-positive and gram-negative bacteria. β-Lactamase production can be either constitutive (not requiring antibiotic exposure) or inducible (production is stimulated by the presence of an antimicrobial).
In an effort to overcome the effects of β-lactamase-mediated resistance, new antibiotics that are resistant to β-lactamase hydrolysis as well as β-lactamase inhibitors have been developed. Clavulanic acid is a broad-spectrum irreversible inhibitor of β-lactamases of staphylococci and many gram-negative bacteria. Because the clavulanic acid is destroyed in the process of β-lactamase inhibition, it is often described as a "suicide inhibitor." Combinations such as amoxicillin/clavulanic acid are useful for the treatment of many βlactamase-producing bacteria including S aureus, H influenzae, and M catarrhalis. Other β-lactamase inhibitors include tazobactam and sulbactam. It is important to note that β-lactamase inhibitors only serve to increase the amount of the active β-lactam compound that reaches the target site and is available to exert its activity against otherwise susceptible bacteria. Therefore, if the bacteria are not inherently susceptible to the β-lactam in the absence of β-lactamase, addition of a β-lactamase inhibitor will not make the organism susceptible to the drug.
Alteration in target site. The target or binding site for an antimicrobial is the component of the bacterium to which the antimicrobial must attach to produce its desired effect. If a change occurs in the configuration of the binding site, the affinity of the antimicrobial for the target site may be significantly decreased. As a result, the action of the drug against the bacterium may be significantly lessened or eliminated. Targets with reduced affinity for antimicrobial binding have been described for βlactams, macrolides, and quinolones.
For S pneumoniae, resistance to β-lactams develops as a stepwise alteration of PBPs that leads to a decrease in the binding affinities of the β-lactams. [bib_ref] Epidemiology and in vitro susceptibility of drug-resistant Streptococcus pneumoniae, Appelbaum [/bib_ref] Various degrees of resistance may develop because numerous changes can occur to alter PBP affinity for the β-lactams. [bib_ref] Antibiotic resistant pneumococci, Jacobs [/bib_ref] PBP 2b alterations are responsible for most of the resistance in S pneumoniae.
Fluoroquinolone resistance can occur as a result of alterations in binding sites. Target site alterations generally occur in a 2-step fashion. With S pneumoniae, for instance, an initial alteration in the parC gene that encodes for topoisomerase IV results in low-level quinolone resistance. A second mutation at the gyrA gene encoding for the Gyr A subunit of DNA gyrase results in the expression of high-level quinolone resistance. Although cross-resistance commonly occurs among the fluoroquinolones, the newest agents often remain active against strains that have become resistant to older agents. The different fluoroquinolones likely target and interact with different regions of the DNA gyrase and topoisomerase molecules because a variety of mutations in the genes encoding the 2 enzymes can confer fluoroquinolone resistance.
Resistance to TMP/sulfonamide combinations is also primarily a result of alterations in the target binding sites (eg, dihydropteroate synthase, dihydrofolate reductase).
## Alteration in bacterial influx/efflux processes.
Before an antimicrobial can exert its desired biologic effect, it must first penetrate several protective barriers of the microbe. These barriers, which include the inner membrane, cell wall, and outer membrane (gram-negative bacteria), help the cell to regulate flow of substances. Lipophilic substances are capable of passive diffusion across these membranes; however, passage of hydrophilic materials may be facilitated by water-filled porin channels. Porins are one mechanism by which antimicrobials may traverse the hydrophobic barriers. Antimicrobials may also enter the cell through proteinmediated transport. If a change occurs in either the number or configuration of porin channels or transport proteins, the ability of an antimicrobial to reach its active site may be greatly reduced. Another structural change that can significantly reduce the concentration of antibiotic at the target site is the activation of antimicrobial efflux pumps. This is an important mechanism of resistance regulated by the activation of energy-dependent proteins that actively pump antimicrobials out of the cell.
Mechanisms of macrolide resistance. Macrolide resistance results from destruction by drug-modifying enzymes, alteration in ribosomal binding sites, and decreased cellular permeability. There are two important genes responsible for macrolide resistance: erm (a ribosomal methylase) and mef (a macrolide-specific efflux mechanism). Among isolates of S pneumoniae, resistance results most frequently from target site modification (methylation) and altered efflux pumps (mef). [bib_ref] Variation in erythromycin and clindamycin susceptibilities of Streptococcus pneumoniae in four test..., Fasola [/bib_ref] [bib_ref] Detection of erythromycin-resistant determinants by PCR, Sutcliffe [/bib_ref] The efflux mechanism confers a more moderate degree of resistance compared with the high level of resistance seen in strains possessing the methylase mechanism. The efflux mechanism is generally more common in the United States and relatively uncommon in most other parts of the world. Ribosomal methylase mediated but not efflux macrolide resistance confers cross-resistance to clindamycin. Macrolide use is therefore the most Otolaryngology-Head and Neck Surgery S12 SINUS AND ALLERGY HEALTH PARTNERSHIP July 2000
likely cause of the measurable increase in S pneumoniae resistance to macrolides and to clindamycin.
## Prevalence of resistance in isolates of s pneumoniae
Isolates of S pneumoniae with penicillin MICs of ≤0.06 µg/mL are defined as susceptible. Intermediate strains have penicillin MICs of 0.12 to 1.0 µg/mL, whereas resistant isolates of S pneumoniae have penicillin MICs of ≥2 µg/mL. These two groups are often referred to as "penicillin nonsusceptible" [fig_ref] Table 2: Interpretative breakpoints for penicillin againist S pneumoniae *Nonsusceptible includes intermediate and resistant... [/fig_ref]. DRSP is a term used to describe isolates of S pneumoniae with penicillin MICs of >0.06 µg/mL and/or resistance to other classes of antibiotics. Multidrug-resistant S pneumoniae is defined as an organism resistant to 3 or more classes of antibiotics.
The increasing prevalence of isolates of S pneumoniae that are penicillin nonsusceptible is a problem in the United States . [bib_ref] Trends in antimicrobial susceptibility of bacterial pathogens of the respiratory tract, Doern [/bib_ref] [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] In the late 1980s and early 1990s penicillin nonsusceptible S pneumoniae became a major concern. 54 One recent source of resistance data for isolates of S pneumoniae comes from the US component of the 1998 Alexander Project, a surveillance study that collected respiratory tract isolates from community-based physicians throughout the United States. The US component of the 1998 Alexander Project demonstrated that 16.1% and 28.6% of the S pneumoniae isolates were penicillin-intermediate and penicillin-resistant, respectively. [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] The prevalence of penicillin resistance was significantly higher in middle ear and sinus isolates than in strains recovered from other sites. A 1998 CDC surveillance study of invasive (ie, blood or cerebrospinal fluid) S pneumoniae isolates from hospitals and clinical laboratories demonstrated that 10.5% and 13.9% of the isolates were penicillin-intermediate and penicillin-resistant, respectively.The disparity in the prevalence of penicillin nonsusceptible S pneumoniae isolates in these studies may be related to the isolates from the US component of the 1998 Alexander Project being more likely to originate from patients not responding to treatment. The true prevalence of penicillin-nonsusceptible S pneumoniae probably lies somewhere in between that reported in the 2 studies.
The
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Only 2.7% of the isolates of S pneumoniae were resistant to ofloxacin. [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] DRSP isolates are most prevalent in children younger than 2 years of age, especially those with prior antibiotic exposure. In otitis media, DRSP has been associated with bacteriologic treatment failure for several oral cephalosporins and macrolides.
## Prevalence of resistance in isolates of h influenzae and m catarrhalis
β-Lactamase production is the primary mechanism of resistance for isolates of H influenzae and M catarrhalis. [bib_ref] Trends in the antimicrobial susceptibility of bacterial respiratory tract pathogens: findings of..., Felmingham [/bib_ref] The US prevalence of β-lactamase producing isolates of H influenzae has increased over the past 15 years and is currently stable at approximately 40% [fig_ref] Fig 8: Prevalence of β-lactamase production by H influenzae in the United States from... [/fig_ref]. [bib_ref] Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus..., Jorgensen [/bib_ref] [bib_ref] Prevalence of antimicrobial resistance among respiratory tract isolates of Streptococcus pneumoniae in..., Doern [/bib_ref] [bib_ref] Trends in antimicrobial susceptibility of bacterial pathogens in the respiratory tract, Doern [/bib_ref] [bib_ref] Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States..., Doern [/bib_ref] [bib_ref] In vitro activities of 12 orally administered antimicrobial agents against four species..., Barry [/bib_ref] The US component of the 1998 Alexander Project reported a 36.8% prevalence of β-lactamase production in isolates of H influenzae. [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] Sinus specimens from adults aged 31 to 50 years tend to have a higher prevalence of β-lactamase-producing isolates of H influenzae.Currently available macrolides (including azithromycin and clarithromycin) have intrinsically poor "baseline" activity against isolates of H influenzae. In otitis media, "double tap" eradication studies showed these agents had an H influenzae eradication rate comparable to placebo. [bib_ref] Bacteriologic efficacies of oral azithromycin and oral cefaclor in treatment of acute..., Dagan [/bib_ref] In the US component of the 1998 Alexander Project, 24% of isolates of H influenzae were TMP/SMXresistant and none were fluoroquinolone-resistant. [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] The β-lactams amoxicillin/clavulanate, cefixime, and cefpo-doxime proxetil are very effective against β-lactamase-producing H influenzae.
The 1998 outpatient US prevalence of βlactamase-producing isolates of M catarrhalis was 98%. More than 90% of isolates of M catarrhalis were resistant to TMP/SMX. All the isolate of M Catarrhalis were susceptible to amoxicillin/clavulanate, cefixime, fluoroquinolones, and macrolides/azalides. 56
## Antimicrobial use and bacterial resistance
The extensive use of antibiotics may be associated with the development and spread of resistant microorganisms. [bib_ref] Development of β-lactamase-mediated resistance to penicillin in middle-ear isolates of Moraxella catarrhalis..., Nissinen [/bib_ref] [bib_ref] Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children?..., Arason [/bib_ref] [bib_ref] The effect of changes in the consumption of macrolide antibiotics on erythromycin..., Seppala [/bib_ref] [bib_ref] Outpatient use of erythromycin: link to increased erythryromycin resistance in group A..., Seppala [/bib_ref] Nasopharyngeal carriage of resistant isolates of S pneumoniae is related to recent antimicrobial use as well as living in an area with a high volume of antibiotic use. [bib_ref] Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children?..., Arason [/bib_ref] The prevalence of β-lactamase-producing isolates of M catarrhalis was found to grow with increasing consumption of cephalosporins. [bib_ref] Development of β-lactamase-mediated resistance to penicillin in middle-ear isolates of Moraxella catarrhalis..., Nissinen [/bib_ref] In Finland, consumption of erythromycin was related to an increase in the prevalence of erythromycin-resistant group A streptococci. [bib_ref] Outpatient use of erythromycin: link to increased erythryromycin resistance in group A..., Seppala [/bib_ref] However, a steady and statistically significant decline in macrolide resistant group A streptococci occurred after reducing the use of macrolide antibiotics for 2 years. [bib_ref] The effect of changes in the consumption of macrolide antibiotics on erythromycin..., Seppala [/bib_ref] These data reinforce the rationale for judicious antibiotic use.
## Antimicrobial selection in abrs antimicrobial classes
Antimicrobial classes include β-lactams, fluoroquinolones, macrolides/azalides, lincosamides, tetracyclines, and sulfonamides/trimethoprim. Cross-resistance between penicillin and other drug classes in S pneumonlae. As resistance of S pneumoniae to penicillin rises, resistance to other antibiotics also increases.
Otolaryngology-Head and Neck Surgery S14 SINUS AND ALLERGY HEALTH PARTNERSHIP July 2000
β-Lactams. The β-lactam class of antimicrobials includes a broad range of compounds with significantly different spectra of activity. These agents all share a common structural component: the β-lactam ring. The β-lactams exert their antibacterial action through inhibition of cell wall synthesis. This action is accomplished through the binding of the antimicrobial to the various PBPs in the cell wall. There are 6 different PBPs in penicillin-susceptible S pneumoniae: 1a, 1b, 2b, 2x, 2z, and 3.
Orally available agents include the penicillins (with and without β-lactamase inhibitor compounds) and the cephalosporins. Cephalosporins have been modified to broaden the spectrum of antimicrobial activity, enhance pharmacokinetic properties, and circumvent the problem of drug degradation by β-lactamases.
Amoxicillin (Amoxil). A less potent but better absorbed derivative of ampicillin, amoxicillin is relatively safe and well tolerated. Activity is limited by its destruction by the β-lactamases produced by some strains of H influenzae, M catarrhalis, Staphylococcus, and gram-negative oral anaerobic species. Given its intrinsic activity and excellent bioavailability, amoxicillin is generally considered the most active of all the oral β-lactams against streptococci, including pneumococci. Resistance to penicillin in isolates of S pneumoniae is relative and may be overcome in most cases by using higher doses of amoxicillin. Although the typical adult amoxicillin dose is 1.5 to 1.75 g/day and the typical pediatric amoxicillin dose is 40 to 45 mg/kg per day, 2 to 3 times higher daily doses may be necessary to eradicate isolates of S pneumoniae. Even the high doses may not be sufficient to treat the most highly penicillinresistant S pneumoniae strains. High-dose amoxicillin has not been approved by the FDA or systematically evaluated, and its safety profile is not yet well defined.
The intrinsic activity of amoxicillin against β-lactamase-negative strains of H influenzae is fair to good. Amoxicillin is 20 to 50 times less potent than third-generation cephalosporins (eg, cefixime, cefpodoxime proxetil), and some failures may be expected in infections caused by β-lactamase-negative strains of H influenzae treated with standard doses of amoxicillin. High-dose amoxicillin may alleviate this problem. However, amoxicillin is ineffective against β-lactamaseproducing strains.
Amoxicillin/clavulanate (Augmentin). Because resistance to β-lactam agents among isolates of S pneumoniae does not involve β-lactamase production, the addition of clavulanate to amoxicillin does not increase its activity against DRSP. Clavulanate does, however, enhance amoxicillin's activity against β-lactamase-producing strains of H influenzae, M catarrhalis, staphylococci (except methicillin-resistant strains), and oral anaerobes by irreversibly binding to β-lactamase and restoring the activity of amoxicillin. The addition of clavulanate does not appear to be a driving force toward the development of resistance. When given as a 3 times a day regimen, this broad-spectrum β-lactam has been associated with a high incidence of gastrointestinal side
## Otolaryngology-head and neck surgery
Volume 123 Number 1 Part 2 SINUS AND ALLERGY HEALTH PARTNERSHIP S15 effects compared with most of its alternatives. This problem has significantly decreased with twice a day dosing. The clavulanate dose, however, should not exceed approximately 10 mg/kg per day or diarrhea becomes a problem. Cefuroxime axetil (Ceftin). Parenteral cefuroxime sodium has a long-established history in the treatment of moderate to severe lower respiratory infections caused by H influenzae and S pneumoniae. An oral formulation, cefuroxime axetil was introduced in the 1980s. It has demonstrated a good potency, efficacy, and side-effect profile. It has limited activity against S pneumoniae with high levels of penicillin resistance but maintains activity against penicillinintermediate strains. Cefuroxime axetil is effective against most strains of H influenzae.
Cefpodoxime proxetil (Vantin). A structural analog of the parenteral agent ceftriaxone, cefpodoxime proxetil has much of the same activity against respiratory pathogens. It has potent activity against H influenzae strains, activity comparable to cefuroxime axetil and cefprozil against penicillin-susceptible S pneumoniae isolates, and reasonable activity against penicillin-intermediate S pneumoniae.
Cefprozil (Cefzil). Among the best-tasting and tolerated broad-spectrum oral β-lactams, cefprozil has activity against pneumococcus that is comparable to cefuroxime axetil and cefpodoxime proxetil. However, it has markedly less activity against H influenzae. Cefixime (Suprax). As the prototype of the oral thirdgeneration oral cephalosporins, cefixime has potent activity against H influenzae but provides weak grampositive coverage including S pneumoniae. Cefixime has no activity against staphylococci, may occasionally fail against even penicillin-susceptible pneumococci, and has no clinically significant activity against DRSP.
Cefaclor (Ceclor). Cefaclor has poor activity against H influenzae, fair activity against penicillin-susceptible pneumococci, and no activity against DRSP. Therefore cefaclor has poor overall efficacy against bacterial respiratory tract pathogens.
Loracarbef (Lorabid). Loracarbef is comparable to cefaclor in its activity against pathogens in respiratory tract infections. Topoisomerase II is also known as DNA gyrase and is involved in the decoiling of DNA during replication. Topoisomerase IV is involved in separation of DNA strands. Fluoroquinolones exert their bactericidal activity by binding to DNA gyrase and topoisomerase IV. This impedes the formation of supercoiled DNA, inhibits the relaxation of supercoiled DNA, and promotes doublestrand DNA breakage.
In general, DNA gyrase appears to be the target molecule in gram-negative bacteria, and topoisomerase IV appears to be the target in gram-positive pathogens.
The newer fluoroquinolones (gatifloxacin, levofloxacin, and moxifloxacin) have remarkable potency against H influenzae and M catarrhalis and, unlike ciprofloxacin, strong potency against S pneumoniae. [bib_ref] New antibiotics in pulmonary critical care medicine; focus on advanced generation quinolones..., Ambrose [/bib_ref] Although the gastrointestinal absorption of these agents is inhibited by the coadministration of foods or supplements with certain multivalent cations (magnesium, aluminum, iron, calcium), they generally lack the phototoxicity seen in some other quinolones. The major concerns surrounding the fluoroquinolones have to do with the selection of class resistance in organisms such as gramnegative enterics (especially Pseudomonas aeruginosa) staphylococci, and pneumococci. Toxicity, known or unrecognized, is also an issue, particularly with newly approved agents. The fluoroquinolones are currently not approved for use in children.
## Macrolides/azalides: erythromycin, clarithromycin
(Biaxin), and azithromycin (Zithromax). The macrolides include agents such as erythromycin and clarithromycin. Azithromycin, an azalide, is structurally similar to the macrolides. These agents have activity against gram-positive and some gram-negative bacteria. These antimicrobials inhibit RNA-dependent protein synthesis by reversibly binding to the 50S subunit of the bacterial ribosome. Although they are generally considered to be bacteriostatic, some studies have demonstrated bactericidal activity in the presence of high macrolide concentrations.
Macrolides exhibit better antibacterial activity in an environment with a neutral to basic pH. This physiochemical characteristic is caused by the fact that at a low pH macrolides become positively charged and do not readily pass through biologic membranes. This effect is most pronounced for azithromycin because it carries a double positive charge at a low pH.
All the macrolides have good activity against macrolide-susceptible pneumococci. However, the increasing rate of macrolide resistance to S pneumoniae is associated with a significant likelihood of clinical failure. [bib_ref] Bacteriologic efficacies of oral azithromycin and oral cefaclor in treatment of acute..., Dagan [/bib_ref] Although clarithromycin and azithromycin have slightly greater activity against H influenzae than erythromycin, most of the available eradication and efficacy studies suggest an activity that is similar to or marginally higher than that of placebo. Although controversy has been created about the activity of metabolites (14-OH clarithromycin), the intracellular concentrations of the newer agents, and the effects of pH on MIC results, none of these issues affects the foregoing conclusions about These antibiotics are bacteriostatic and inhibit bacterial growth through inhibition of RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunit. A derivative of tetracycline, doxycycline has adequate activity against penicillin-susceptible pneumococci. Like other oral non-β-lactams, the likelihood of resistance to doxycycline rises in pneumococcal strains exhibiting any degree of penicillin resistance. Doxycycline also has activity against M catarrhalis but its activity against H influenzae is limited by its pharmacokinetics. Clinicians should be aware of the possibility of photosensitivity and infrequent esophageal caustic burns. Like the other tetracyclines, usage in children younger than 8 years is contraindicated because of the possibility of tooth enamel discoloration.
## Sulfonamides and tmp:
Trimethoprim-sulfamethoxazole (Bactrim, Septra). Sulfonamides disrupt bacterial folic acid synthesis by inhibiting dihydropteroate synthase; this results in their bacteriostatic activity. TMP is a pyrimidine analog that inhibits dihydrofolate reductase. Because sulfonamides and trimethoprim block folic acid synthesis at different sites, they potentiate each other's antimicrobial activity, producing synergistic bac-teriostatic activity. High rates of resistance to these drugs is now present in pneumococci and H influenzae. M catarrhalis is intrinsically resistant to sulfamethoxazole. In addition, these agents are more likely to cause skin rash, erythema multiforme, and toxic epidermal necrolysis, which can be potentially fatal.
New antibiotics. New classes of antibiotics such as ketolides, oxazolidinones, and glycylcyclines, as well as antibiotics in clinical trials (at the time of this writing), are not reviewed in this document.
## Antimicrobial efficacy in abrs
A recent meta-analysis including 27 randomized clinical trials of antibiotic treatment prescribed for ABRS evaluated the efficacy of (1) antibiotics versus placebo (n = 6), (2) amoxicillin versus other antibiotics (n = 13), and (3) folate inhibitors versus other antibiotics (n = 8).Even though 69% of patients receiving placebo for ABRS had symptomatic improvement or cure, antibiotics significantly reduced treatment failures by approximately one half. There were no statistically significant or clinically meaningful differences in cure rates between amoxicillin or folate inhibitors and other antibiotics. The antibiotic versus placebo trials evaluated the following antibiotics: lincomycin, penicillin V, cyclacillin, amoxicillin, amoxicillin/clavulanate, and doxycycline. The amoxicillin and folate inhibitors versus other antibiotic trials included the following antibiotics: amoxicillin/clavulanate, azithromycin, clarithromycin, cefaclor, cefixime, cefpodoxime proxetil, cefuroxime axetil, minocycline, cephalexin, tetracycline, pivampicillin, and roxithromycin. The results of the meta-analysis apply only to uncomplicated and community-acquired cases of ABRS. Because these individual trials were performed before the development of resistance currently found in S pneumoniae, H influenzae, and M catarrhalis, results from this metaanalysis may not be applicable to the current treatment of ABRS. [bib_ref] Are amoxycillin and folate inhibitors as effective as other antibiotics for acute..., De Ferranti [/bib_ref] The methods used in this paper for evaluating antimicrobial therapy for ABRS do, however, take into account the current high levels of antibiotic-resistant organisms.
## Pharmacokinetic/pharmacodynamic principles
MICs and MBCs are commonly used to describe the in vitro potency of antimicrobial agents. These measurements, however, do not take into consideration the pharmacokinetic properties of antimicrobial agents; therefore their ability to predict therapeutic efficacy is limited.
The pharmacokinetics (absorption, distribution, metabolism, and excretion) of many antimicrobials have been well established. However, the discipline of pharmacodynamics has only recently emerged. Pharmacodynamics describes the relation between drug concentration and pharmacologic effect. For an antibiotic, it describes the relation that exists between the drug concentrations to which the bacteria are exposed at various sites of infection and bacterial killing. The evolution of this science has augmented the body of knowledge about how antimicrobials best treat infections. Because pharmacokinetic and pharmacodynamic principles form the scientific basis for the rational use of antimicrobial agents, this portion of the guidelines will provide a review.
Pharmacodynamically, in vivo bacterial killing may be described as a function of the duration of an antimicrobial's drug concentration over time relative to the MIC of that agent against a particular pathogen. The product of these pharmacokinetic parameters (drug concentration and time of drug exposure) over the dosing interval is expressed as the area under the concentra- β-Lactams, macrolides, and clindamycin show little concentration-dependent bactericidal activity. Once the antimicrobial concentration exceeds a critical value (2 to 4 times the MIC of that drug against a particular organism), killing proceeds. Increasing the drug concentration further does not increase the rate or extent of bacterial Otolaryngology-Head and Neck Surgery S18 SINUS AND ALLERGY HEALTH PARTNERSHIP July 2000
death. These antibiotics exhibit time-dependent or concentration-independent killing. Hence the best predictor of clinical outcome is the duration of time the concentration of the drug in serum and/or at the site of infection is above its MIC (T > MIC) against the bacteria. For βlactams and extracellular pathogens, the free-drug concentration in serum is generally proportional to that in the interstitial fluid bathing the organism. Therefore the proportion of the dosing interval that the free-drug concentration in serum exceeds the antimicrobials MIC against a pathogen also reflects this parameter at most sites of infection. The amount of time that the concentration of a timedependent antibiotic should remain above the MIC (T > MIC) against a given bacteria may vary with the pathogen and the immunocompetence of the host. Data from in vitro pharmacokinetic simulations, animal models, and human clinical studies suggest that the T > MIC should be >40% to 50% of the dosing interval in immunocompetent hosts for time-dependent antibiotics [fig_ref] Fig 9: Fig 9 [/fig_ref]. [bib_ref] Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model, Vogelman [/bib_ref] [bib_ref] Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men, Craig [/bib_ref] The relationship between the T > MIC and clinical efficacy has been evaluated in patients with acute otitis media caused by S pneumoniae and H influenzae.
Bacteriologic cure rates of 80% to 85% were observed when the T > MIC for β-lactams and macrolides were >40% to 50% of the dosing interval. [bib_ref] Pharmacokinetics and pharmacodynamics of antibiotics in otitis media, Craig [/bib_ref] [bib_ref] Antimicrobial resistance issues of the future, Craig [/bib_ref] Moreover, in hospitalized patients with community-acquired pneumonia, no differences in clinical outcome were observed between patients receiving cefuroxime sodium as a 1500 mg per day continuous infusion (T > MIC = 100%) compared with 750 mg intermittently 3 times daily (estimated T > MIC of 50% to 60%). [bib_ref] Continuous vs intermittent infusion of cefuroxime for the treatment of community-acquired pneumonia, Ambrose [/bib_ref] Thus a serum concentration present for 40% to 50% of the dosing interval may be used to determine the susceptibility limit or "breakpoint" of an organism for a given dosing regimen. Additionally, the proportion of bacteria with MICs at or below these susceptibility limits or breakpoints may be determined. summarizes the susceptibility of S pneumoniae, H influenzae, and M catarrhalis to various antimicrobials at PK/PD breakpoints. β-lactams. Two large in vitro susceptibility and pharmacodynamic studies have been conducted in the United States. In the first study, 1476 isolates of S pneumoniae were evaluated.Antimicrobials tested included amoxicillin, amoxicillin/clavulanate, cefuroxime axetil, cefprozil, cefaclor, cefixime, and loracarbef. For most of the oral β-lactams evaluated against peni- . 1998 susceptibility of respiratory tract isolates to antimicrobial agents at PK/PD breakpoints [bib_ref] Streptoccus pneumoniae in the United States: in vitro susceptibility and pharmacodynamic analysis, Mason [/bib_ref] For penicillin-susceptible isolates of S pneumoniae, the serum concentrations maintained for at least 40% of the dosing interval exceeded the geometric mean MICs of the 6 cephalosporins evaluated. Serum concentrations of cefuroxime axetil and cefprozil were above their mean MICs for 100% of the dosing interval, whereas the corresponding values were 94% for cefpodoxime proxetil, 69% for cefixime, 43% for loracarbef, and 40% for cefaclor. Only cefuroxime axetil (64%), cefpodoxime proxetil (63%), and cefprozil (56%) exceeded their geometric mean MICs for >40% of the dosing interval against penicillin-intermediate isolates of S pneumoniae. None of these cephalosporins achieved serum concentrations that exceeded their geometric mean MICs for >40% of the dosing interval in penicillin-resistant isolates of S pneumoniae. Had MIC 90 s been used in place of geometric mean MICs, it would not have changed the rank order of the agents. Rather, the percentage of adequate T > MIC would decrease. Based on these two pharmacodynamic studies, the βlactams may be indexed as follows against isolates of S pneumoniae: amoxicillin = amoxicillin/clavulanate > cefuroxime axetil = cefpodoxime proxetil = cefprozil > cefixime = loracarbef = cefaclor.
## Percentage of isolates susceptible at pk/pd/nccls breakpoints
A similar pharmacodynamic analysis of 1676 isolates of H influenzae was conducted. [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] The susceptibility of oral β-lactams based on their pharmacodynamic breakpoints were as follows: cefixime (100%), amoxicillin/clavulanate (97.5%), cefuroxime axetil (78.1%), amoxicillin (56.5%), cefprozil (14.5%), loracarbef (9.4%), and cefaclor (1.7%).
Macrolides/azalides. Macrolides (eg, erythromycin and clarithromycin) and azalides (eg, azithromycin) exhibit concentration-independent killing. As with βlactams, the duration of time that the drug concentration exceeds the MIC of the infecting pathogen at the site of infection is the primary determinant of efficacy for the macrolides. Because these agents have a prolonged postantibiotic effect (PAE) against gram-positive cocci and H influenzae, [bib_ref] Postantibiotic effects and postantibiotic sub-MIC effects of roxithromycin, clarithromycin, and azithromycin on..., Odenholt-Tornqvist [/bib_ref] the optimal duration of time above the MIC remains controversial. It has been postulated that the PAE allows these drugs to yield maximal effi- Pharmacodynamic concept: time above the MIC. Schematic illustration of the serum pharmacokinetic profile of 2 time-dependent oral drug regimens over one 8-hour dosing interval. Drug A is present at 2 µg/mL for >50% of the dosing interval. Drug B is present at 2 µg/mL for approximately 35% of the dosing interval, but at 1 µg/mL for >50% of the dosing interval. Therefore infections caused by pathogens for which the MICs of both drugs are 2 µ/mL are more likely to be cured by drug A rather than drug B. Drug B would, however, be effective against strains in which the MIC is 1 µg/mL or less because drug B is present at 1 µg/mL for >50% of the dosing interval. Drugs A and B can be two different time-dependent drugs or two different dosing regimens of the same agent.
Otolaryngology-Head and Neck Surgery S20 SINUS AND ALLERGY HEALTH PARTNERSHIP July 2000 cacy in murine thigh infections when concentrations exceed the MIC for significantly less than 50% of the dosing interval (ie, 35%). Because of its extended PAE and long serum half-life, the proper pharmacodynamic correlate for azithromycin may be the AUC/MIC ratio rather than T > MIC. Concern has been raised regarding azithromycin's propensity to select for bacteria that are macrolide-resistant. [bib_ref] Breakthrough sepsis in macrolide resistant pneumococcal infection, Jackson [/bib_ref] The impact of community-based azithromycin use on the carriage and resistance of S pneumoniae has been prospectively studied. [bib_ref] A prospective study of the impact of community-based arithromycin treatment of trachoma..., Leach [/bib_ref] Single-dose azithromycin (20 mg/kg) was given to children with trachoma (a chronic disease caused by Chlamydia trachomatis) and to their household contacts who were children. Carriage rates of azithromycin-resistant S pneumoniae immediately before treatment and 2 to 3 weeks, 2 months, and 6 months after treatment were 1.9%, 54.5%, 34.5% and 5.9%, respectively. The selective pressure of azithromycin may have allowed the growth and transmission of preexisting azithromycin-resistant strains.
One possible explanation for this observation relates to azithromycin's long serum half-life and the long duration of subinhibitory concentrations of the drug. [bib_ref] In influence of antibiotics on the normal flora, Guggenbichler [/bib_ref] If the serum AUC for two antimicrobials, one with a short and the other with a long serum half-life, are compared with MIC values superimposed, a period or "window" for potential Darwinian selection can be plotted [fig_ref] Fig 1: Duration of symptoms in rhinovirus URIs [/fig_ref]. For the antimicrobial with a short half-life, the duration of time between the drug concentration falling below the MIC and its total elimination from the body is relatively short compared with that of the antimicrobial with the longer half-life. For an antimicrobial with a 68-hour half-life (eg, azithromycin), total elimination from the body does not occur for 5 to 7 half-lives, or 14 to 20 days. This period of subinhibitory concentrations of drug may be the pharmacodynamic explanation for the aforementioned observations. This concept is controversial and requires validation in future studies.
Antimicrobials exhibiting concentration-dependent killing. Unlike the concentration-independent antimicrobial agents, fluoroquinolones kill most rapidly when their concentrations are appreciably above the MIC of the targeted microorganism. [bib_ref] Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men, Craig [/bib_ref] [bib_ref] Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration..., Moore [/bib_ref] [bib_ref] Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials, Preston [/bib_ref] This type of killing is referred to as concentration-dependent or time-independent killing [fig_ref] Fig 1: Duration of symptoms in rhinovirus URIs [/fig_ref]. It has been shown that fluoroquinolones eradicate organisms best at levels 10 to 12 times above the microbe's MIC. [bib_ref] Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials, Preston [/bib_ref] [bib_ref] Pharmacodynamics of a fluouroquinolone antimicrobial agent in a neutropenic rat model of..., Drusano [/bib_ref] [bib_ref] Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical..., Powell [/bib_ref] Higher drug concentrations do not improve the rate or extent of bacterial killing. If the optimal peak to MIC ratio is obtained, most bacteria die rapidly, and consequently the period of time over which the bacteria are exposed to the drug is minimal.
Although peak to MIC ratios of greater than 10 to 12:1 correlate with optimal bactericidal activity, [bib_ref] Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials, Preston [/bib_ref] the AUC/MIC ratio is a better parameter for determining efficacy of fluoroquinolones for moderately susceptible bacteria, such as S pneumoniae. In fact, in most fluoroquinolone dose fractionation studies, the AUC/MIC ratio has a better correlation with efficacy than peak to MIC ratio. Data obtained from several sources, including animal models of sepsis, in vitro pharmacodynamic experiments, and clinical outcome studies, indicate that the magnitude of the AUC/MIC ratio can be used to predict response. Forrest et al 82 demonstrated that an AUC/MIC ratio of ≥125 was associated with the highest bacterial eradication rates in the treatment of infections caused by gram-negative enteric pathogens. However, for gram-positive bacteria, it appears that effective AUC/MIC ratios can be appreciably lower. For instance, against S pneumoniae an in vitro model of infection demonstrated that for levofloxacin and ciprofloxacin an AUC/MIC ratio of approximately 30 was associated with a 4-log reduction in bacterial titers; whereas ratios less than 30 were associated with significantly reduced rates of bacterial killing and in some instances bacterial regrowth. [bib_ref] Pharmacodynamic comparisons of levofloxacin, ciprofloxacin, and ampicillin against Streptococcus pneumoniae in an..., Lacy [/bib_ref] Similarly, Lister and Sanders 84 reported that for levofloxacin and ciprofloxacin an AUC to MIC ratio of 32 to 44 was associated with maximal eradication of S pneumoniae in an in vitro model of infection. These observations are supported by data from nonneutropenic animal models of infection in which survival was associated with an AUC/MIC ratio of 25 to 30 against the pneumococcus. 85
## Otolaryngology-head and neck surgery
## Adequacy of therapeutic regimens
There are relatively few factors that affect the adequacy of a therapeutic regimen. Two of the most important factors are the drug exposure seen in a patient and how susceptible the offending pathogen is to the antiinfective agent selected for therapy. Unfortunately, the major limitation of the type of pharmacodynamic analysis described above is that variability in pharmacokinetic and microbiologic data are not accounted for. Both of these factors are highly variable. The variability in susceptibility is tracked by differences in MIC. Consequently, large collections of target organisms give the clinician a reasonable idea of the distribution of susceptibility to the drug among the pathogen(s) they care about.
Often clinicians fail to realize that patients taking the same dose of a drug (particularly by the oral route, but by any route of administration) may have very different drug exposures. For instance, Preston et al 79 studied 272 patients with infections receiving levofloxacin. Although the median plasma clearance was approximately 9 L/h, some patients had a clearance as low as 2 L/h, whereas others were as high as 17 L/h. For a standard 500-mg dose, some patients would have an AUC as low as 29 mg/hr per liter, whereas others would have an AUC of 250 mg/hr per liter.
These differing drug exposures would be therapeutically adequate for differing MICs and differing organisms. For instance, for pneumococcus, in which the target AUC/MIC ratio is approximately 30, essentially all patients would have adequate coverage, with a 500-mg dose producing the target AUC/MIC for MICs as high as 1.0 g/mL. For P aeruginosa, in which the pharmacodynamic target is 100 to 125, a substantial fraction of patients would not hit the target if the MIC was 1.0 g/mL or greater. For some patients, this target AUC/ MIC ratio could only be achieved if the organism had an MIC of 0.25 g/mL or less. For patients with a low plasma clearance, relatively high AUCs would result and patients would have adequate coverage for a organism with a higher MIC. "Monte Carlo" simulation is a way to take the variability seen in patients and microbiologic data into account when choosing a dose and schedule of an antibiotic. In Monte Carlo simulation, prior knowledge is used about the handling of a drug in a population of patients. This can be done by using the mean values for the pharmacokinetic parameters and also providing the covariance matrix for the parameters. The covariance matrix provides information about the variability of the pharmacokinetic parameters in the population and how they covary with one another. A Monte Carlo simulation program randomly samples from the population of patients described by the mean parameters and the covariance matrix. The program can be directed to perform the sampling a large number of times (eg, 1000 to 10,000 times). In this way, a population of simulated patients can be created. By using a large number of simulated patients, an accurate estimate can be developed of how often a patient whose plasma clearance is 2 L/h (AUC = 250 for a 500-mg dose of levofloxacin) will be encountered and how often a subject with a plasma clearance of 17 L/h (AUC approximately 30 for a 500-mg dose) will be encountered. At each value of the MIC, it is possible to determine how frequently the therapeutic target for the simulated population of patients is attained. The FDA advisory committee on anti-infective drug products found this method, as presented by Drusano, to be a reasonable approach in October 1998. A pharmacodynamic analysis conducted by some members of this panel [bib_ref] Effect of pharmacokinetic and microbiological variability on the pharmacodynamics of gatifloxacin and..., Ambrose [/bib_ref] on H influenzae isolates, used the Monte Carlo method described by Ambrose and Grasela. [bib_ref] Effect of pharmacokinetic and microbiological variability on the pharmacodynamics of gatifloxacin and..., Ambrose [/bib_ref] Data used for this analysis included human pharmacokinetic data obtained from FDA licensing trials and susceptibility data from 901 isolates collected in the United States during 1999. From this analysis and that of Jacobs et al,oral β-lactams may be indexed as follows: cefixime = cefpodoxime proxetil = amoxicillin/clavulanate (high dose) > cefuroxime axetil > amoxicillin > cefprozil = loracarbef > cefaclor.
## Defining antimicrobial susceptibility breakpoints
As previously discussed, pharmacokinetic/pharma-codynamic (PK/PD) parameters can define susceptibility breakpoints for oral antibiotics for the β-lactams and macrolides; serum concentrations that are maintained for at least 40% to 50% of the dosing interval can be determined and used as PK/PD breakpoints. For the fluoroquinolones and azithromycin, the PK/PD breakpoints can be based on the AUC/MIC ratio exceeding 25 to 30. compares the susceptibility of isolates of S pneumoniae, H influenzae, and M catarrhalis to various antibiotics according to their PK/PD breakpoints. [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] The panel used PK/PD breakpoints in preference to the National Committee for Clinical Laboratory Standards 87 or FDA breakpoints to allow unbiased comparisons of sinusitis pathogens using one breakpoint for each agent. Current NCCLS breakpoints for the same agents vary considerably by pathogen. For example, the susceptible cefprozil breakpoint is ≤8 µg/ml for Haemophilus but is [fig_ref] Table 6: Recommended antibiotic therapy for adults with ABRS [/fig_ref] (continued). Footnotes. [bib_ref] Acute community-acquired sinusitis, Gwaltney [/bib_ref] The terms mild and moderate are designed to aid the clinician in an antibiotic choice. Differences in severity of disease do not imply presence or absence of antimicrobial resistance. Rather, this terminology indicates the relative degree of acceptance of possible failure of therapy. The determination of the severity of disease rests on the clinician's evaluation of the patient's history and clinical presentation. Severe, life-threatening infection, with or without complications, is not addressed in these guidelines. [bib_ref] Appropriate use of antibiotics for URIs in children: part I. Otitis media..., Dowell [/bib_ref] Prior antibiotic therapy within the past 4 to 6 weeks is a risk factor for infection with resistant organisms. Antibiotic choices need to be based on this risk factor. [bib_ref] Computed tomographic study of the common cold, Gwaltney [/bib_ref] Bacterial efficacy (microbiologic adequacy) is the mean and range of 3 sets of calculations from the Poole therapeutic outcome model using 3 susceptibility data bases: the US component of the 1998 Alexander Project, 1998 Sentry surveillance, and the 1998 CDC Active Bacterial Core Surveillance Report. These values do not guarantee clinical success or failure. [bib_ref] Occurrence of asymptomatic sinusitis in common cold and other acute ENT-infections, Berg [/bib_ref] These values, which reflect the potential for therapeutic failure of initial therapy, are based on the US component of the Alexander Project 1998 surveillance study. Use of local surveillance data can provide valuable additional information on the prevalence of resistance applicable to a region. [bib_ref] Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other..., Ray [/bib_ref] When a change in antibiotic therapy is made, the clinician needs to take into account the limitations in coverage of the initial antibiotic. Amoxicillin lacks complete H influenzae coverage; cefuroxime and cefpodoxime do not cover penicillin-resistant S pneumoniae. Erythromycin, doxycycline, and TMP/SMX have limited coverage for both H influenzae and S pneumoniae. Amoxicillin/clavulanate, gatifloxacin, levofloxacin, and moxifloxacin currently have the best coverage for both H influenzae and S pneumoniae.Reevaluation is necessary because the antibiotics recommended at day 0 (initial therapy) are effective against S pneumoniae and H influenzae. Additional history, physical examination, cultures, and/or CT scan may be indicated and the possibility of other less common pathogens considered.The total daily dose of amoxicillin and the amoxicillin component of amoxicillin/clavulanate can vary from 1.5 to 3.5 g/day. Lower daily doses (1.5 to 2 g/day) are more appropriate in mild disease in patients with no prior antibiotic use. Higher daily doses (3 to 3.5 g/day) may be advantageous in areas with a high prevalence of DRSP and in patients with moderate disease or who have had recent prior antibiotic use. There is a greater potential for treatment failure or resistant pathogens in these patient groups. These higher doses are currently not approved by the FDA in the United States and formal safety studies have not been published. [bib_ref] Development of β-lactamase-mediated resistance to penicillin in middle-ear isolates of Moraxella catarrhalis..., Nissinen [/bib_ref] Although cefpodoxime and cefixime have excellent activity against H influenzae, they are not active against penicillin-resistant S pneumoniae. [bib_ref] Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children?..., Arason [/bib_ref] Clindamycin provides excellent coverage for S pneumoniae but has no activity against H influenzae. [bib_ref] The effect of changes in the consumption of macrolide antibiotics on erythromycin..., Seppala [/bib_ref] These antibiotics are not recommended unless the patient is allergic to β-lactam. Their effectiveness against the major pathogens of ABRS is limited, and bacterial failure of 20% to 25% is possible. Life-threatening toxic epidermal necrolysis has been associated with the use of TMP/SMX. [bib_ref] Outpatient use of erythromycin: link to increased erythryromycin resistance in group A..., Seppala [/bib_ref] Based on in vitro spectrum of activity, combination therapy with amoxicillin (3.5 g/day) or clindamycin for gram-positive coverage plus cefixime for gram-negative coverage is suggested/recommended. There is no clinical evidence at this time, however, of the safety or efficacy of these combinations. [bib_ref] Adult rhinosinusitis defined, Lanza [/bib_ref] β-Lactams should be considered initially. A fluoroquinolone is recommended for patients who have allergies or intolerance to β-lactams or who have recently not responded to other regimens of therapy.
## Antimicrobial treatment guidelines
These recommendations are based on the Poole Therapeutic Outcome Model described below. [fig_ref] Table 6: Recommended antibiotic therapy for adults with ABRS [/fig_ref] summarize the panel's antimicrobial treatment guidelines for adults and children, respectively. Multiple factors played a role in the antimicrobial selection process. Because serious intracranial and extrasinus complications associated with ABRS usually arise as a result of S pneumoniae infection, it is important for initial therapy to adequately cover S pneumoniae.
Gram-negative coverage for H influenzae (and M catarrhalis in children) cannot be ignored, however. A rational approach to the treatment of ABRS should consider the aforementioned concerns along with the logical application of microbiology and PK/PD principles. In the selection of an antibiotic for ABRS, the clinician should consider the severity of the disease, the rate of progression of the disease, recent antibiotic therapies, and varying rates of resistance within the United States and other countries that may use these guidelines.
The panel's guidelines for adults and children with ABRS characterize several different groups of patients. These patient types include (1) those with mild or moderate disease, (2) those with and without antibiotic therapy during the previous month, and (3) those without a clinical response at ≥72 hours of initiation of therapy.
The terms mild and moderate disease reflect the degree of discomfort of the patient as evidenced by the symptom complex and the time course of the disease. The healthy patient with 10 days of persistent anterior and posterior rhinorrhea, and fatigue (mild disease) is different from the patient with 10 days of nasal congestion who over the past 3 days has developed a low-grade elevation of temperature and increasing unilateral maxillary or frontal tenderness that worsens with bending over (moderate disease). Patients, however, may not always be neatly categorized into degrees of disease. An evaluation of the severity of the disease requires clinical judgment gained only by the clinician familiar with the patient. The differences in severity of disease do not imply the presence or absence of antimicrobial resistance. Rather, this terminology indicates the relative degree of acceptance of possible failure of therapy. Severe, life-threatening infec- [bib_ref] Acute community-acquired sinusitis, Gwaltney [/bib_ref] The terms mild and moderate are designed to aid the clinician in an antibiotic choice. Differences in severity of disease do not imply presence or absence of antimicrobial resistance. Rather, this terminology indicates the relative degree of acceptance of possible failure of therapy. The determination of the severity of disease rests on the clinician's evaluation of the patient's history and clinical presentation. Severe, life-threatening infection, with or without complications, is not addressed in these guidelines. [bib_ref] Appropriate use of antibiotics for URIs in children: part I. Otitis media..., Dowell [/bib_ref] Prior antibiotic therapy within the past 4 to 6 weeks is a risk factor for infection with resistant organisms. Antibiotic choices need to be based on this risk factor. [bib_ref] Computed tomographic study of the common cold, Gwaltney [/bib_ref] Bacterial efficacy (microbiologic adequacy) is the mean and range of 3 sets of calculations from the Poole therapeutic outcome model (see text), using 3 susceptibility databases: the US component of the 1998 Alexander Project, 1998 Sentry surveillance, and the 1998 CDC Active Bacterial Core Surveillance Report. These values do not guarantee clinical success or failure. [bib_ref] Occurrence of asymptomatic sinusitis in common cold and other acute ENT-infections, Berg [/bib_ref] These values reflect the potential for therapeutic failure of initial therapy are based on the US component of the Alexander Project 1998 surveillance study. Use of local surveillance data can provide valuable additional information on the prevalence of resistance applicable to a region. [bib_ref] Healthcare expenditures for sinusitis in 1996: contributions of asthma, rhinitis, and other..., Ray [/bib_ref] When a change in antibiotic therapy is made, the clinician needs to take into account the limitations in coverage of the initial antibiotic. Amoxicillin lacks complete H influenzae and M catarrhalis coverage; cefuroxime and cefpodoxime do not cover penicillin-resistant S pneumoniae. Erythromycin and TMP/SMX have limited coverage for both H influenzae and S pneumoniae. Amoxicillin/clavulanate currently has the best coverage for S pneumoniae, H influenzae, and M catarrhalis.Reevaluation is necessary because the antibiotics recommended at day 0 are effective against S pneumoniae, H influenzae, and M catarrhalis. Additional history, physical examination, cultures, and/or CT scan may be indicated and the possibility of other less common pathogens considered. The dose of amoxicillin can range from 45 mg to 90 mg/kg per day. If lower doses of amoxicillin are used initially, treatment failure may be due to DRSP or β-lactamase-positive H influenzae or M catarrhalis. The higher dose schedule gives better DRSP coverage. The amoxicillin component of amoxicillin/clavulanate also ranges from 45 mg to 90 mg/kg per day. The higher daily dose (80 to 90 mg/kg per day) may be advantageous in areas with a high prevalence of DRSP and for patients with moderate disease or who have had recent prior antibiotic use. There is a greater potential for treatment failure or resistant pathogens in these patient groups. These higher doses are currently not approved by the FDA in the United States. [bib_ref] Development of β-lactamase-mediated resistance to penicillin in middle-ear isolates of Moraxella catarrhalis..., Nissinen [/bib_ref] Although cefpodoxime proxetil, cefuroxime axetil, and cefixime have higher activity against H influenzae and M catarrhalis than amoxicillin, they are not active against penicillin-resistant S pneumoniae. [bib_ref] Do antimicrobials increase the carriage rate of penicillin resistant pneumococci in children?..., Arason [/bib_ref] Excluding β-lactams, clindamycin is the most active oral agent currently available with activity against 89% to 95% of S pneumoniae. It has no activity, however, against H influenzae or M catarrhalis. [bib_ref] The effect of changes in the consumption of macrolide antibiotics on erythromycin..., Seppala [/bib_ref] Based on in vitro spectrum of activity, combination therapy (amoxicillin [80 to 90 mg/kg per day] or clindamycin) for grampositive coverage plus cefixime, cefpodoxime proxetil, or TMP/SMX for gram-negative coverage is suggested/recommended. There is no clinical evidence at this time, however, of the safety or efficacy of these combinations. [bib_ref] Outpatient use of erythromycin: link to increased erythryromycin resistance in group A..., Seppala [/bib_ref] These antibiotics are not recommended unless the patient is β-lactam allergic. Their effectiveness against the major pathogens of ABRS is limited, and bacterial failure of 20% to 25% is possible. In addition, TMP/SMX is associated with increases in the risk of life threatening toxic epidermal necrolysis. The clinician should differentiate an immediate hypersensitivity reaction from other less dangerous side effects. Children with immediate hypersensitivity reactions to β-lactams may need desensitization, sinus cultures, or other ancillary procedures and studies. Children with other types of reactions and side effects may tolerate one specific β-lactam but not another. tion with or without complications is not addressed in these guidelines. Prior antibiotic use is a major risk factor associated with the development of infection from antimicrobialresistant strains. Other risk factors include age less than 5 years and attendance in day care centers. Risk factors for invasive infection include prior β-lactam use, residence in nursing homes or recent hospitalization, hematologic malignancy or serious comorbid illness, and immunosuppressive underlying disease. Prior use of TMP/SMX has also been identified as a risk factor for carriage of penicillin-nonsusceptible S pneumoniae. [bib_ref] Antimicrobial Resistance in Streptococcus pneumoniae: implications for treatment in the new century, Lynch [/bib_ref] [bib_ref] Acute otitis media: management and surveillance in an era of pneumococcal resistance:..., Dowell [/bib_ref] [bib_ref] Risk factors for carriage of drug-resistant Streptococcus pneumoniae among children in, Arnold [/bib_ref] [bib_ref] Influence of increased macrolide consumption on macrolide resistance of common respiratory pathogens, Cizman [/bib_ref] [bib_ref] Carriage of penicillin-resistant pneumococci in a military population in Washington, DC: risk..., Fairchok [/bib_ref] [bib_ref] Childhood bacterial meningitis in Southwestern Greece: a population-based study, Syrogiannopoulos [/bib_ref] Because recent antimicrobial exposure increases the risk of carriage and infection from resistant organisms, antimicrobial therapy should be based on the patient's history of recent antibiotic use. The panel's guidelines, therefore, stratify patients according to antibiotic exposure in the previous 4 to 6 weeks.
Lack of response to therapy at ≥72 hours is an arbitrary time established to define treatment failures. Clinicians should monitor the patient's response to antibiotic therapy. This may include instructing the patient to call the office or clinic if there is persistence or worsening of the symptoms.
The current recommendations for the duration of antimicrobial treatment for ABRS is 10 to 14 days. This is based on the results of published studies of clinical trials in which pretreatment and posttreatment sinus aspirates were performed. [bib_ref] The microbial etiology and antimicrobial therapy of adults with acute communityacquired sinusitis:..., Gwaltney [/bib_ref] The use of longer or shorter courses of antimicrobial treatment should be based on the results of sinus aspiration studies.
Allergies to antibiotics (ie, β-lactams) or age limitations for certain antimicrobials (eg, fluoroquinolones) may force the use of less than optimal antimicrobials. The clinician must be aware of the potential for treatment failure in these situations.
The panel used the Poole Therapeutic Outcome Model as one tool in developing its antimicrobial guidelines. Although the most recent and best data were used for this model, the panel realizes that resistance rates may change over time and may vary from community to community. The panel will therefore revise the guidelines as resistance rates change and new antibiotics are introduced. In addition, the Poole Therapeutic Outcome Model developed by Michael Poole, University of Texas Medical School at Houston, is available at the Sinus and Allergy web site (http://www.allergysinus.org). Clinicians may input their own local resistance rates and obtain their own optimal
## Otolaryngology-head and neck surgery
Volume 123 Number 1 Part 2 SINUS AND ALLERGY HEALTH PARTNERSHIP S27 treatment recommendations. Local resistance data should be based on PK/PD breakpoints, not NCCLS breakpoints, as discussed in this supplement.
## The poole therapeutic outcome model: a data-driven model for prediction of therapeutic outcome
In 1992, Marchant et al 94 correlated the in vivo potency of various antimicrobial agents with clinical outcomes based on double tap otitis media studies. In addition, PK/PD susceptibility breakpoints for given dosing regimens have been shown to correlate with bacteriologic cure rates. [bib_ref] Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men, Craig [/bib_ref] [bib_ref] Pharmacokinetics and pharmacodynamics of antibiotics in otitis media, Craig [/bib_ref] With the appropriate data, Marchant et al 94 predicted the clinical response rate to a given dosing regimen of an antimicrobial agent. The parameters used to adapt this model to ABRS included (1) the proportion of patients with a clinical diagnosis of ABRS who have a positive sinus aspirate (typically 60% of patients in primary care practices); (2) the clinical resolution of disease in the culture-negative patient group (typically 40% of patients, with complete resolution of disease occurring in 88% of this group [or 35% of the total patient group]) and disease failing to resolve occurring in the remaining 5% of the total patient group; (3) the distribution of pathogens found in the culture-positive group; (4) the spontaneous resolution rate of each pathogen; and (5) the in vitro susceptibility of the major sinusitis pathogens to antimicrobial agents at PK/PD breakpoints.
Based on published studies of maxillary sinus punctures performed in patients with ABRS, the pathogen distribution used in adults was 42% for S pneumoniae, 35% for H influenzae, 5% for M catarrhalis, and 18% for other pathogens. The pathogen distribution in children used was 42% for S pneumoniae, 20% for H influenzae, and 20% for M catarrhalis. Because S pneumoniae is the more pathogenic bacterial organism, the model incorporates a higher prevalence of S pneumoniae in children to ensure appropriate antimicrobial coverage. For each of the major pathogens, the spontaneous resolution rate was estimated from published data in which placebo was used in otitis media. The values used in this model were 30% for S pneumoniae, 60% for H influenzae, 80% for M catarrhalis, and 50% for other pathogens. Based on these values, spontaneous resolution is predicted to occur in 46.6% of adults with ABRS (28% of the total patient group). Therefore spontaneous resolution will occur in 63% of the untreated adult group (28% with infection plus 35% without infection).
Of the 37% adult patients whose symptoms do not resolve if untreated, 5% are uninfected and will not respond because of non-microbiologically related factors, whereas 32% will not respond because of untreated bacterial infection. However, if a drug with 100% bacteriologic efficacy were to be used, the disease will theoretically resolve in all of the adult patients in the infected group and in 95% of all adult patients. Thus the theoretical disease resolution rates in the adults in this model, depending on efficacy of treatment, can vary from 46.6% (the rate from spontaneous resolution) to 100% (for patients treated with an antimicrobial with 100% bacterial efficacy). For the total adult group, these limits vary from 63% (untreated) to 95% (using agent with 100% efficacy). On the other hand, spontaneous resolution will occur in 49.6% of untreated children in the bacterially infected group and 64.8% of the untreated total pediatric patient group. Importantly, the individual values of the various parameters are estimates. Interested investigators could change any value and use the model to calculate the resulting effect on bacteriologic and clinical outcome. The next step was to calculate the resolution of disease based on current susceptibility data for each organism at PK/PD breakpoints. Agents with poor activity against all pathogens will result in resolution rates similar to the spontaneous resolution seen in the untreated group, whereas agents active against all pathogens will result in higher resolution rates. Resolution rates for the bacterially infected group and the total patient group (using the mean susceptibility data from the US component of the 1998 Alexander Project, the 1998 SENTRY Surveillance Report, and the 1998 CDC Active Bacterial Core Surveillance Report) are shown in Marchant plots [fig_ref] Fig 1: Duration of symptoms in rhinovirus URIs [/fig_ref]. [bib_ref] Susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis to oral agents:..., Jacobs [/bib_ref] These datasets were used because complete MIC distributions were available and the proportion of isolates inhibited at PK/PD breakpoints could be determined. The outcomes of these calculations are shown as Marchant plots showing predicted bacteriologic outcomes in the bacterial infection group and the total patient group. The Marchant plot is only a relative rank order for the data used. Other surveillance data may therefore alter this relative rank order. These resolution rates are based on in vitro microbiologic efficacy and do not guarantee clinical outcome. However, in the absence of microbiologic outcome data from clinical studies for most agents, this model was used as the best method available for predicting clinical outcome.
## Antimicrobial choices
According to the Marchant plot, antibiotics were placed into the following relative rank order of predicted efficacy in adult patients with ABRS: >90% (gatifloxacin, levofloxacin, moxifloxacin, and amoxicillin/ clavulanate), 80% to 90% (high-dose amoxicillin, cefpodoxime proxetil, cefixime [based on H influenzae and M catarrhalis coverage only], cefuroxime axetil, TMP/SMX, and doxycycline), 70% to 80% (clindamycin [based on gram-positive coverage only], cefprozil, azithromycin, clarithromycin, and erythromycin], and 50% to 60% (cefaclor and loracarbef). The predicted spontaneous resolution rate in untreated adults with ABRS is 46.6%.
According to the Marchant plot, antibiotics were placed into the following relative rank order of predicted efficacy in children with bacterial infection: >90% (amoxicillin/clavulanate and high-dose amoxicillin); 80% to 90% (cefpodoxime proxetil, cefixime [based on H influenzae and M catarrhalis coverage only], cefuroxime axetil, clindamycin [based on gram-positive coverage only], azithromycin, clarithromycin, erythromycin, and TMP/SMX), 70% to 80% (cefprozil), and 60% to 70% (cefaclor and loracarbef). The predicted spontaneous resolution rate in untreated children with ABRS is 49.6%.
The recommendations made in the treatment guidelines take into account 3 major factors: (1) severity of disease, (2) use of antibiotics in the preceding 4 to 6 weeks, and (3) the relative rank order of each agent on the Marchant plots. In addition, recommendations for patients who are not improving or are worsening at ≥72 hours of treatment are provided based on spectrum of activity of initial therapy against the major sinusitis pathogens. The estimated likelihood of a particular pathogen being encountered in treatment failures with each type of initial therapy was used in lieu of obtaining a culture to guide "switch" therapy at 72 hours. Because the data used to predict percentage of organisms likely to produce failure is from the US component of the 1998 Alexander Project, which reflects mostly patients that have not responded to empiric initial antibiotic therapy, our model is a better guide of "switch" therapy.
Recommendations for adult patients. Recommendations for initial therapy for adult patients with mild disease and who have not received antibiotics in the previous 4 to 6 weeks include the following choices [fig_ref] Table 4: Antimicrobial agents stratified by pharmacodynamic profile against S pneumoniae and H influenzaeCheckmark,... [/fig_ref] : amoxicillin/clavulanate, amoxicillin (1.5 to 3.5 g/day), cefpodoxime proxetil, or cefuroxime axetil. Cefprozil may have up to a 25% bacterial failure rate. Although TMP/SMX, doxycycline, azithromycin, clarithromycin, or erythromycin may be considered for patients with β-lactam allergies, bacteriologic failure rates of 20% to 25% are possible. Also, potentially fatal toxic epidermal necrolysis has been associated with the use of TMP/SMX. Recommendations for initial therapy for adults with mild disease who have received antibiotics in the previous 4 to 6 weeks or adults with moderate disease who have not received antibiotics in the previous 4 to 6 weeks include the following choices: amoxicillin/clavulanate, amoxicillin (3 to 3.5 g/day), cefpodoxime proxetil, or cefuroxime axetil. Gatifloxacin, levofloxacin, and moxifloxacin are indicated for patients who are allergic or intolerant to β-lactam.
Recommendations for initial therapy for adults with moderate disease who have received antibiotics in the previous 4 to 6 weeks include gatifloxacin, levofloxacin, moxifloxacin, amoxicillin/clavulanate, or combination therapy (amoxicillin or clindamycin for gram-positive coverage, cefpodoxime proxetil or cefixime for gramnegative coverage).
Recommendations for "switch" therapy for patients without improvement or worsening at ≥72 hours varies depending on the likely organism to be producing clinical failure. Patients who have received effective antibiotic therapy and continue to be symptomatic need further evaluation. A CT scan, fiberoptic endoscopy, or sinus aspiration for culture may be necessary.
When amoxicillin/clavulanate is prescribed in areas with a high incidence of DRSP or as "switch" therapy, a total of 3 to 3.5 g/day of the amoxicillin component should be considered (although this is currently not approved in the United States).
Recommendations for pediatric patients. Recommendations for initial therapy for children with mild disease who have not received antibiotics in the previous 4 to 6 weeks include the following : amoxicillin/clavulanate, amoxicillin (45 to 90 mg/kg per day), cefpodoxime proxetil, or cefuroxime axetil. Azithromycin, clarithromycin, erythromycin, or TMP/SMX are recommended if the patient has a history of immediate type I hypersensitivity reaction to β-lactams. These antibiotics have limited effectiveness against the major pathogens of ABRS, and bacterial failure of 20% to 25% is possible. The use of TMP/SMX is associated with a large increase in the risk of life-threatening toxic epidermal necrolysis. [bib_ref] Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis, Roujeau [/bib_ref] The clinician should differentiate an immediate hypersensitivity reaction from other less dangerous side effects. Children with immediate hypersensitivity reactions to βlactams may need desensitization, sinus cultures, or other ancillary procedures and studies. Children with other types of reactions and side effects may tolerate one specific βlactam but not another.
Recommendations for children with mild disease who have received antibiotics in the previous 4 to 6 weeks or children with moderate disease who have not received antibi-otics in the previous 4 to 6 weeks: amoxicillin/clavulanate, amoxicillin (80-90 mg/kg per day), cefpodoxime proxetil, or cefuroxime axetil. Azithromycin, clarithromycin, erythromycin, or TMP/SMX are recommended if the patient is allergic to β-lactam. Clindamycin is appropriate if S pneumoniae is identified as a pathogen.
Moderate disease, on the other hand, in children receiving antibiotics in the previous 4 to 6 weeks should be treated with the following alternatives: amoxicillin/ clavulanate or combination therapy (amoxicillin or clindamycin for gram-positive coverage plus cefpodoxime proxetil or cefixime for gram-negative coverage).
"Switch" therapy for patients without improvement or worsening at ≥72 hours varies depending on the likely organism to be producing clinical failure. Patients who have received effective antibiotic therapy and continue to be symptomatic need further evaluation. A CT scan, fiberoptic endoscopy, or sinus aspiration with culture may be necessary.
When amoxicillin/clavulanate is prescribed in areas with a high incidence of DRSP or as "switch" therapy, a total of 80 to 90 mg/kg per day of the amoxicillin component should be considered (although this is currently not approved in the United States).
# Conclusions
These guidelines have been developed to provide evidence-based recommendations for the diagnosis and optimal treatment of ABRS based on the limited information available for this disease. This approach is based on a mathematic model using pathogen distribution and spontaneous resolution data and pharmacodynamically derived susceptibility values of the major ABRS pathogens, from which bacteriologic outcome can be predicted. The panel hopes that these guidelines will provide a rational approach to the need for antimicrobial therapy in bacterial rhinosinusitis, reduction in the use of antibiotics for nonbacterial infections, and the appropriate use of antibiotics when bacterial disease is likely.
[fig] Fig 1: Duration of symptoms in rhinovirus URIs. There are 3 patterns of symptoms and resolution: (1) fever and myalgia, (2) sneezing and sore throat, and (3) cough and rhinorrhea, which are common and persistent in a significant proportion of patients. Persistence of these last 2 symptoms is entirely consistent with an uncomplicated rhinovirus infection. [/fig]
[fig] Fig 2: Gram-positive and gram-negative bacteria have different configurations of their cell walls. PBPs play an important role in cell wall synthesis. [/fig]
[fig] Fig 3: Ranges of prevalence of the major pathogens associated with ABRS in adults. [/fig]
[fig] Fig 4: Ranges of prevalence of the major pathogens associated with ABRS in children. [/fig]
[fig] Fig 5: MIC is the lowest concentration of the antimicrobial that results in the inhibition of growth of a microorganism. MICs are generally performed by placing a known inoculum of bacteria into media containing a range of doubling concentrations of the antimicrobial (eg, 0.5 µg/mL, 1 µg/mL, 2 µg/mL, 4 µg/mL). The MIC in this figure is 4 µg/mL. [/fig]
[fig] 56 Fig 6: US component of the 1998 Alexander Project reported a prevalence of macrolide-, clindamycin-, TMP/SMX-, and doxycycline-resistant S pneumoniae isolates of 32.5%, 10.8%, 43.2%, and 21.7%, respectively. Macrolide, clindamycin, TMP/SMX, and doxycycline resistance were most prevalent in penicillin-intermediate and penicillin-resistant S pneumoniae isolates(Figure 7). Prevalence of intermediate and resistant S pneumoniae to penicillin has been increasing over the past decade in the United States. Percentages ranged from 25% to 50% depending on the surveillance study used in 1997 to 1998. [/fig]
[fig] Fig 7: Fig 7. Cross-resistance between penicillin and other drug classes in S pneumonlae. As resistance of S pneumoniae to penicillin rises, resistance to other antibiotics also increases. [/fig]
[fig] Fig 8: Prevalence of β-lactamase production by H influenzae in the United States from 1986 to 1998. [/fig]
[fig] Fig 9: Fig 9. Pharmacodynamic concept: time above the MIC. Schematic illustration of the serum pharmacokinetic profile of 2 time-dependent oral drug regimens over one 8-hour dosing interval. Drug A is present at 2 µg/mL for >50% of the dosing interval. Drug B is present at 2 µg/mL for approximately 35% of the dosing interval, but at 1 µg/mL for >50% of the dosing interval. Therefore infections caused by pathogens for which the MICs of both drugs are 2 µ/mL are more likely to be cured by drug A rather than drug B. Drug B would, however, be effective against strains in which the MIC is 1 µg/mL or less because drug B is present at 1 µg/mL for >50% of the dosing interval. Drugs A and B can be two different time-dependent drugs or two different dosing regimens of the same agent. [/fig]
[table] Table 1: Symptoms associated with bacterial rhinosinusitisA diagnosis of ABRS may be made in adults or children with a viral URI that is no better after 10 days or worsens after 5 to 7 days and is accompanied by some or all of these symptoms. Modified from Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg 1997;117:S1-7. [/table]
[table] Table 2: Interpretative breakpoints for penicillin againist S pneumoniae *Nonsusceptible includes intermediate and resistant categories. [/table]
[table] Table 3: Antimicrobial agents classified by pattern of bactericidal activity [/table]
[table] Table 4: Antimicrobial agents stratified by pharmacodynamic profile against S pneumoniae and H influenzaeCheckmark, Adequate pharmacodynamic profile using conventional dosing in patients with normal renal and hepatic function; ±, borderline pharmacodynamic profile using conventional dosing in patients with normal renal and hepatic function. *For β-lactams and macrolides: T > MIC >40% of the dosing interval; for quinolones: 24-h AUC/MIC ratio >100-125 for H influenzae and >30-50 for S pneumoniae. † High-dose amoxicillin. [/table]
[table] Table 6: Recommended antibiotic therapy for adults with ABRS. [/table]
[table] Table 7: Recommended antibiotic therapy for children with ABRS. [/table]
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The purpose of these treatment guidelines is to provide recommendations for the diagnosis and optimal treatment of acute bacterial rhinosinusitis (ABRS). The desired outcomes are (1) education for the clinician and patient (or patient’s family) about the differences between viral and bacterial rhinosinusitis; (2) reduction in the use of antibiotics for nonbacterial nasal/sinus infections; and (3) the use of appropriate antibiotics when bacterial disease is likely.
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Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices
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Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices
# Introduction
Hepatitis B virus (HBV) is transmitted through percutaneous (i.e., puncture through the skin) or mucosal (i.e., direct contact with mucous membranes) exposure to infectious blood or body fluids. HBV is highly infectious, can be transmitted in the absence of visible blood [bib_ref] PHS guidelines for management of occupational exposure to HBV, HCV and HIV:..., Preboth [/bib_ref] , and remains viable on environmental surfaces for at least seven days [bib_ref] Survival of hepatitis B virus after drying and storage for one week, Bond [/bib_ref]. Persons with chronic infection (e.g., those with persistent hepatitis B surface antigen in the serum for at least 6 months following acute infection) serve as the main reservoir for HBV transmission.
This report summarizes and consolidates previously published recommendations from the Advisory Committee on Immunization Practices (ACIP) and CDC. It also
## New or updated recommendations
The following recommendations are new or updated: - universal hepatitis B (HepB) vaccination within 24 hours of birth for medically stable infants weighing ≥2,000 grams; - testing HBsAg-positive pregnant women for hepatitis B virus deoxyribonucleic acid (HBV DNA); - postvaccination serologic testing for infants whose mother's HBsAg status remains unknown indefinitely (e.g., when a parent or person with lawful custody surrenders an infant confidentially shortly after birth); - single-dose revaccination for infants born to HBsAgpositive women not responding to the initial vaccine series;
- vaccination for persons with chronic liver disease (including, but not limited to, those with hepatitis C virus infection, cirrhosis, fatty liver disease, alcoholic liver disease, autoimmune hepatitis, and an alanine aminotransferase or aspartate aminotransferase [AST] level greater than twice the upper limit of normal); and - removal of permissive language for delaying the birth dose until after hospital discharge. This report also briefly summarizes American Association for the Study of Liver Diseases (AASLD) guidelines for maternal antiviral therapy to reduce perinatal HBV transmission, published previously [bib_ref] AASLD guidelines for treatment of chronic hepatitis B, Terrault [/bib_ref]. Recommendations from the Infectious Diseases Society of America (IDSA) regarding vaccination of the immunocompromised host are published separately [bib_ref] Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination..., Rubin [/bib_ref].
# Methods
ACIP's Hepatitis Work Group comprises professionals from academic medicine (pediatrics, family medicine, internal medicine, infectious disease, occupational health, and preventive medicine specialists), federal and state public health agencies, and medical societies.* The Work Group reviewed epidemiology and literature, directed an economic analysis, and deliberated upon recommendations. The Work Group considered existing published ACIP and CDC vaccine recommendations in summarizing recommendations contained herein for the prevention of HBV infection.
This report updates and supplants ACIP recommendations for HepB vaccination of children and adults published previously [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref]. This report incorporates ACIP and CDC recommendations published previously [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref] [bib_ref] Update: shortened interval for postvaccination serologic testing of infants born to hepatitis..., Schillie [/bib_ref].
Guidelines from AASLD inform the use of antiviral therapy among pregnant women with elevated HBV DNA for the purpose of preventing perinatal HBV transmission. Surveillance data were obtained from the National Notifiable Diseases Surveillance System (NNDSS) (https://wwwn.cdc. gov/nndss/). Data informing clarifications to the recommendations were summarized on the basis of findings from literature searches that were completed on . Two search terms were used to ascertain data regarding maximum number of doses for dialysis patients and minimum intervals for dialysis dosing: "Hepatitis b vacc* dialysis boost*" and "Dialysis hepatitis b vacc* schedule." Epidemiologic and vaccine coverage data were reviewed, as well as publicly available data on the number of infant abandonments and safely surrendered infants. The literature searches included clinical trials and comparative * A list of the members appears on page 30. To assess vaccine safety, the Work Group searched two postlicensure surveillance systems for adverse events from 2005 through 2015: the Vaccine Adverse Events Reporting System (VAERS) (https://vaers.hhs.gov) and the Vaccine Safety Datalink (VSD) (https://www.cdc.gov/vaccinesafety/ ensuringsafety/monitoring/vsd). VAERS is a national passive surveillance system, and VSD conducts population-based vaccine safety studies. VAERS can generate vaccine safety hypotheses but cannot assess causality and is subject to several limitations, including reporting biases and inconsistent data quality [bib_ref] Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS), Shimabukuro [/bib_ref] [bib_ref] Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)-United States, Zhou [/bib_ref]. VSD can be used to assess hypotheses that arise from reviews of medical literature, reports to VAERS, changes in immunization schedules, or the introduction of new vaccines [bib_ref] The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety, Mcneil [/bib_ref].
## Box 1. abbreviations used in this report
During February-September 2016, the Work Group held five teleconference meetings. Work Group and ACIP members also reviewed and commented on a draft of the statement prior to the ACIP's October 2016 meeting. A summary of Work Group discussions was presented to ACIP on At that time, ACIP members voted to approve a draft HepB vaccine recommendations statement, including recommending universal HepB vaccination within 24 hours of birth for medically stable infants weighing ≥2,000 grams. In January 2017, the Work Group held a teleconference meeting to review results of an economic analysis of single-dose revaccination for infants born to HBsAg-positive women. Results from that analysis were presented to ACIP on February 22, 2017. Recommendations were not evaluated using GRADE, but expert opinion was used to shape the recommendations. At that time, ACIP members voted to approve language for singledose revaccination for infants (regardless of birth weight) born to HBsAg-positive women. Modifications were made to the ACIP statement during the subsequent review process at CDC to update and clarify wording in the report.
# Hbv background epidemiology
In 2015, a total of 3,370 cases of acute HBV infection were reported to CDC. The actual number of acute cases is believed to be 6.5 times the number of reported cases in any year. It is estimated that 21,900 new cases of HBV occurred in 2015 after under-ascertainment and under-reporting were considered. The rate of reported acute HBV infections declined 88.5% since recommendations for HepB vaccination were first issued, from 9.6 cases per 100,000 population in 1982 to 1.1 cases per 100,000 population in 2015, although the rate of acute HBV infections remained fairly stable during 2010-2015 (4) [fig_ref] FIGURE 1: Incidence of hepatitis B virus infection -National Notifiable Diseases Surveillance System, United... [/fig_ref]. The 2015 incidence is greatest for persons aged 30-39 years (2.6 per 100,000 population). In 2015, persons aged ≤19 years had the lowest incidence (0.02 cases per 100,000 population), likely a result of routine infant vaccination. Although the incidence of acute HBV infection is greater for males than for females, the gap has narrowed; in 2015, the rate for males was approximately 1.6 times higher than that for females (1.3 cases and 0.8 cases per 100,000 population, respectively) (4). During 2009-2013, the combined incidence of acute HBV infection in three states (Kentucky, Tennessee, and West Virginia) increased 114% and was associated with increasing injection-drug use.
On the basis of national health survey data, it is estimated that approximately 850,000 persons are living with HBV infection (prevalence) in the United States [bib_ref] Prevalence of chronic hepatitis B virus (HBV) infection in U.S. households: National..., Roberts [/bib_ref] [bib_ref] The prevalence of hepatitis B virus infection in the United States in..., Wasley [/bib_ref]. Studies based on data from countries of persons migrating to the United States and census data indicate that the total prevalence of chronic hepatitis B might be as high as 2.2 million persons [bib_ref] Prevalence of chronic hepatitis B among foreign-born persons living in the United..., Kowdley [/bib_ref] , suggesting that the national health survey-based estimate might be conservative. Foreign-born persons account for approximately 95% of newly reported chronic infections in the United States [bib_ref] The increasing burden of imported chronic hepatitis B-United States, Mitchell [/bib_ref] ; the prevalence of chronic HBV infection is approximately 3.5% among foreign-born persons [bib_ref] Prevalence of chronic hepatitis B among foreign-born persons living in the United..., Kowdley [/bib_ref] , and the majority of chronic HBV infections in the United States are among Asians/Pacific Islanders.
## Strategy to eliminate hbv
In 1991, the United States adopted a strategy for universal HepB vaccination of infants. A comprehensive strategy to eliminate HBV transmission evolved over the ensuing three decades and encompasses 1) routine testing of all pregnant women for HBsAg and prophylaxis for infants born to HBsAgpositive mothers, 2) universal vaccination of infants beginning at birth, 3) routine vaccination of previously unvaccinated children and adolescents, and 4) vaccination of adults at risk for HBV infection [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref] [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref] [bib_ref] Update: shortened interval for postvaccination serologic testing of infants born to hepatitis..., Schillie [/bib_ref]. Preventing perinatal transmission relies upon testing all pregnant women for HBsAg and administering timely prophylaxis (HepB vaccine and hepatitis B immune globulin to infants born to infected mothers. Universal HepB vaccination of all infants beginning at birth provides a critical safeguard and prevents infection among infants born to HBsAg-positive mothers not identified prenatally (e.g., in situations where the mother was not tested or when testing, interpretation, or transcription errors occurred). Vaccination of children and adolescents not previously vaccinated and vaccination of adults at risk for HBV infection (e.g., by sexual or percutaneous exposure and international travelers to certain countries) is recommended to prevent HBV transmission outside of the perinatal setting (Box 2).
HBV prevention strategies have been implemented successfully in the United States, but challenges remain. Approximately 88% of commercially insured women and 84% of Medicaid-enrolled women are tested for HBsAg during pregnancy [bib_ref] Hepatitis B surface antigen testing among pregnant women, Kolasa [/bib_ref]. In one study of a large health system in northern California, 93% of HBsAg-positive pregnant women were tested for HBV DNA [bib_ref] Prevention of vertical transmission of hepatitis B: an observational study, Kubo [/bib_ref]. Most (94.9%) infants born to infected women receive recommended prophylaxis within 12 hours of birth [bib_ref] Outcomes of infants born to women infected with hepatitis B, Schillie [/bib_ref]. Universal HepB vaccine birth dose coverage, defined as 1 dose of vaccine administered [bib_ref] CDC. Surveillance of vaccination coverage among adult populations-United States, Williams [/bib_ref]. New strategies for further reducing HBV transmission in this report include testing HBsAg-positive pregnant women for HBV DNA to identify infants at greatest risk for infection and guide the use of maternal antiviral therapy [bib_ref] Cost-effectiveness of testing hepatitis B-positive pregnant women for hepatitis B e antigen..., Fan [/bib_ref]. Published evidence indicates that maternal antiviral therapy during pregnancy further reduces perinatal HBV transmission; hence, AASLD suggests antiviral therapy when maternal HBV DNA is >200,000 IU/mL [bib_ref] An algorithm for risk assessment and intervention of mother to child transmission..., Pan [/bib_ref] [bib_ref] Telbivudine prevents vertical transmission from HBeAg-positive women with chronic hepatitis B, Pan [/bib_ref].
## Virus description and transmission
HBV is a 40-42-nm enveloped virus classified in the Hepadnaviridae family. HBV contains a circular, partially double-stranded DNA genome that is 3.2 kb in length. After a susceptible person is exposed, the virus enters the liver via the bloodstream. The liver is the primary site of HBV replication [bib_ref] Immunopathogenesis of hepatitis B virus infection, Chang [/bib_ref] [bib_ref] Chronic hepatitis B: Virology, natural history, current management and a glimpse at..., Gish [/bib_ref] [bib_ref] Serologic diagnosis of acute and chronic viral hepatitis, Hoofnagle [/bib_ref] [bib_ref] Viral hepatitis, type B. Studies on natural history and prevention re-examined, Krugman [/bib_ref].
HBV has been classified by two separate systems: serologic subtype and genotype. Nine serologic subtypes initially were described based on the heterogeneity of HBsAg: adrq+, adrq-, ayr, ayw1, ayw2, ayw3, ayw4, adw2, and adw4 [bib_ref] Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected..., Magnius [/bib_ref]. Ten HBV genotypes, designated A-J, have been described. HBV serotypes and genotypes vary geographically. Infection or immunization with one genotype generally confers immunity to all genotypes [bib_ref] Genotypes and genetic variability of hepatitis B virus, Kramvis [/bib_ref] [bib_ref] The clinical implications of hepatitis B virus genotypes and HBeAg in pediatrics, Kramvis [/bib_ref].
HBV is highly infectious, can be transmitted in the absence of visible blood, and remains infectious on environmental surfaces for at least 7 days (2,3). All HBsAg-positive persons are infectious, but those with elevated HBV DNA or those with hepatitis B e antigen (HBeAg), a protein from the hepatitis B virus that circulates in the blood and is a marker of infectivity, are most infectious. Persons with occult HBV infection (i.e., those who test negative for HBsAg but have detectable HBV DNA) also might transmit infection [bib_ref] Occult hepatitis B virus infection, Allain [/bib_ref].
HBV is transmitted through percutaneous, mucosal, or nonintact skin exposure to infectious blood or body fluids. HBV is concentrated most highly in blood, and percutaneous exposure is an efficient mode of transmission. Semen and vaginal secretions are infectious, and HBV also can be detected in saliva, tears, and bile. Cerebrospinal fluid, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, and amniotic fluid are also considered potentially infectious. Urine, feces, vomitus, nasopharyngeal washings, sputum, and sweat are not efficient vehicles of transmission unless they contain blood because they contain low quantities of infectious HBV. HBsAg found in breast milk is also unlikely to lead to transmission, and hence HBV infection is not a contraindication to breastfeeding [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref].
Among adults, HBV is transmitted primarily by percutaneous exposure to blood (e.g., by injection-drug use) and sexual contact. HBV is transmitted efficiently by sexual contact both among heterosexuals and among men who have sex with men (MSM). Risk factors for sexual transmission among heterosexuals include having unprotected sex with an infected partner, having unprotected sex with more than one partner, and a history of another sexually transmitted infection (STI). Risk factors associated with sexual transmission among MSM include having multiple sex partners, history of another STI, and anal intercourse. Transmission can occur from interpersonal contact (e.g., sharing a toothbrush or razor, contact with exudates from dermatologic lesions, or contact with HBsAg-contaminated surfaces) and in settings such as schools, child care centers, and facilities for developmentally disabled persons. Transmission of HBV from transfusion of blood or blood products is rare because of donor screening and viral inactivation procedures. Other possible sources of infection include contaminated medical or dental instruments, unsafe injections, needle-stick injuries, organ transplantation, and dialysis [bib_ref] Hepatitis B virus infection, Trépo [/bib_ref] [fig_ref] TABLE 3: Hepatitis B vaccine schedules for infants, by infant birthweight and maternal HBsAg... [/fig_ref] for prophylaxis recommendations for infants born to women with unknown HBsAg status. § Within 24 hours of birth for medically stable infants weighing ≥2,000 grams. ¶ Refer to [fig_ref] TABLE 3: Hepatitis B vaccine schedules for infants, by infant birthweight and maternal HBsAg... [/fig_ref] for birth dose recommendations for infants weighing <2,000 grams.
## Clinical features and natural history
Clinical manifestations of HBV infection range from asymptomatic infection to fulminant hepatitis. The average incubation period is 60 days (range: 40-90 days) from exposure to onset of abnormal serum ALT levels and 90 days (range: 60-150 days) from exposure to onset of jaundice [bib_ref] Serologic diagnosis of acute and chronic viral hepatitis, Hoofnagle [/bib_ref] [bib_ref] Viral hepatitis, type B. Studies on natural history and prevention re-examined, Krugman [/bib_ref]. Infants, children aged <5 years, and immunosuppressed adults with newly acquired HBV infection typically are asymptomatic, whereas symptomatic illness is noted in 30%-50% of older children, adolescents, and adults [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref] [bib_ref] Acute hepatitis B virus infection: relation of age to the clinical expression..., Mcmahon [/bib_ref]. When present, signs and symptoms include nausea, vomiting, abdominal pain, fever, dark urine, changes in stool color, hepatomegaly, splenomegaly, and jaundice. Malaise and anorexia might precede jaundice by 1-2 weeks. Fulminant HBV infection is uncommon (<1%) but often results in death or liver failure necessitating liver transplantation. Extrahepatic manifestations of disease (e.g., skin rash, arthralgias, and arthritis) also might occur [bib_ref] Immunopathogenesis of the extrahepatic manifestations of hepatitis B virus infection, Dienstag [/bib_ref]. The fatality rate among persons with reported cases of acute HBV infection is <1.5%, with the highest rates in adults aged ≥55 years. Because a substantial number of infections are asymptomatic and therefore are not reported, the overall fatality rate among all persons with HBV infection is likely lower [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref].
Chronic infection occurs among 80%-90% of persons infected during infancy, 30% of persons infected before age 6 years, and <1%-12% of persons infected as an older child or adult [bib_ref] Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune..., Beasley [/bib_ref] [bib_ref] The influence of age on the development of the hepatitis B carrier..., Edmunds [/bib_ref] [bib_ref] Risks of chronicity following acute hepatitis B virus infection: a review, Hyams [/bib_ref]. Approximately 95% of primary infections in immunocompetent adults are self-limited, with elimination of the virus from blood and generally immunity to reinfection. Chronic infection develops more frequently in immunosuppressed persons (e.g., hemodialysis patients and persons with human immunodeficiency virus infection) [bib_ref] Risks of chronicity following acute hepatitis B virus infection: a review, Hyams [/bib_ref] [bib_ref] Outcome of hepatitis B virus infection in homosexual men and its relation..., Hadler [/bib_ref] and persons with diabetes [bib_ref] Risks of chronicity following acute hepatitis B virus infection: a review, Hyams [/bib_ref]. Chronic HBV infection can result in cirrhosis of the liver, liver cancer, liver failure, and death. Approximately 25% of persons who become chronically infected during childhood and 15% of those who become chronically infected after childhood will die prematurely from cirrhosis or liver cancer [bib_ref] Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707..., Beasley [/bib_ref] [bib_ref] A mathematical model to estimate global hepatitis B disease burden and vaccination..., Goldstein [/bib_ref] [bib_ref] Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigenpositive Alaska..., Mcmahon [/bib_ref].
There are four phases of chronic HBV infection: immune tolerant, immune active, immune inactive, and reactivation. Chronically infected persons do not necessarily pass through these phases in a linear fashion. Persons in the immune tolerant phase have no or minimal hepatic inflammation or fibrosis; most chronically infected children will remain in the immune tolerant phase until late childhood or adolescence. The immune active phase is characterized by an active immune response resulting in hepatic inflammation, with or without fibrosis. Persons who remain in the immune active phase for prolonged periods of time are at high risk for developing cirrhosis and hepatocellular carcinoma. Persons in the immune inactive phase have improvement of hepatic inflammation and fibrosis. Risk for progression to hepatocellular carcinoma is lower among persons in the immune inactive phase compared with the active phase. Persons in the reactivation phase have active liver inflammation with or without fibrosis [bib_ref] Antiviral therapy in management of chronic hepatitis B viral infection in children:..., Jonas [/bib_ref] [bib_ref] Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic..., Lok [/bib_ref] [bib_ref] Chronic hepatitis B virus infection, Mcmahon [/bib_ref]. HBV reactivation might occur with immunosuppressive therapy or treatment for HCV [bib_ref] Hepatitis due to reactivation of hepatitis B virus in endemic areas among..., Wang [/bib_ref].
No specific treatment exists for acute HBV infection; supportive care is the mainstay of therapy. Guidelines for management of chronic HBV infection in children and adults, including disease monitoring and antiviral therapy, are available [bib_ref] AASLD guidelines for treatment of chronic hepatitis B, Terrault [/bib_ref]. Antiviral therapy generally should be initiated in patients with chronic HBV infection who are likely to respond to treatment and who are at high risk for liver-related morbidity [bib_ref] AASLD guidelines for treatment of chronic hepatitis B, Terrault [/bib_ref]. Maternal antiviral therapy to reduce perinatal transmission is suggested for HBsAg-positive pregnant women whose HBV DNA level is >200,000 IU/mL [bib_ref] AASLD guidelines for treatment of chronic hepatitis B, Terrault [/bib_ref].
In areas in which HBV is highly endemic, HBV frequently is transmitted perinatally from HBV-infected pregnant women to their newborns. The majority of cases of perinatal HBV transmission occur during delivery, with rare instances of in utero transmission [bib_ref] Prevention of perinatal hepatitis B virus transmission, Nelson [/bib_ref]. HBV transmission might occur in germ cell lines, as the virus has been detected in sperm, oocytes, and embryos. Available data do not support the need for a cesarean delivery among HBV-infected pregnant women with low HBV DNA [bib_ref] Prevention of perinatal hepatitis B virus transmission, Nelson [/bib_ref]. Prior to the widespread availability of postexposure prophylaxis, the proportion of infants born to HBsAg-positive women acquiring HBV infection was approximately 30% for those born to HBeAg-negative mothers and 85% for those born to HBeAg-positive mothers. With postexposure prophylaxis, comprised of HepB vaccine and HBIG at birth, followed by completion of the HepB vaccine series, 0.7%-1.1% of infants develop infection [bib_ref] Prevention of vertical transmission of hepatitis B: an observational study, Kubo [/bib_ref] [bib_ref] Outcomes of infants born to women infected with hepatitis B, Schillie [/bib_ref] [bib_ref] Seroprotection after recombinant hepatitis B vaccination among newborn infants: a review, Schillie [/bib_ref] ; infants born to mothers with high viral loads are at greatest risk for infection despite receipt of HepB vaccine and HBIG [bib_ref] Outcomes of infants born to women infected with hepatitis B, Schillie [/bib_ref]. Unvaccinated infants and children are also at risk for horizontal transmission from infected household and other contacts.
## Interpretation of serologic markers
Serologic markers for HBV infection include HBsAg, antibody to HBsAg (anti-HBs), immunoglobulin class M (IgM) antibodies to hepatitis B core antigen (IgM anti-HBc), and immunoglobulin class G (IgG) anti-HBc (IgG anti-HBc) [bib_ref] Hepatitis B virus infection, Trépo [/bib_ref] [bib_ref] Atypical serological profiles in hepatitis B virus infection, Pondé [/bib_ref] [bib_ref] The underlying mechanisms for the 'anti-HBc alone' serological profile, Pondé [/bib_ref]. At least one serologic marker is present during the different phases of infection. HBV DNA is a measure of viral load and reflects viral replication (49) [fig_ref] BOX 2 [/fig_ref]. Hepatitis B e antigen (HBeAg) can be detected in persons with acute or chronic HBV infection; the presence of HBeAg correlates with viral replication and high infectivity; antibody to HBeAg (anti-HBe) correlates with the loss of replicating virus, although reversion to HBeAg positivity can occur [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref].
A confirmed positive HBsAg result indicates current HBV infection, either acute or chronic. All HBsAg-positive persons are infectious. If HBsAg persists for >6 months, spontaneous clearance is unlikely, and the infection is deemed chronic. HBV DNA can be detected prior to the detection of HBsAg in an infected person. Occult infection occurs when HBsAg is undetectable despite the presence of HBV DNA [bib_ref] The underlying mechanisms for the 'anti-HBc alone' serological profile, Pondé [/bib_ref] [bib_ref] Hepatitis B virus infection among children born in the United States to..., Franks [/bib_ref] [bib_ref] Are current screening protocols for chronic hepatitis B virus infection adequate?, Mortensen [/bib_ref]. Transient HBsAg positivity can occur up to 18 days following vaccination (up to 52 days among hemodialysis patients) and is clinically insignificant [bib_ref] Persistence of hepatitis B surface antigen in blood in a chronic haemodialysis..., Calisti [/bib_ref].
In acute HBV infection, anti-HBc (initially both IgM and IgG) appears 1-2 weeks after the appearance of HBsAg (49) [fig_ref] FIGURE 2: Acute [/fig_ref]. IgM anti-HBc often becomes undetectable within 6 months, and IgG anti-HBc predominates and remains detectable for a lengthy period of time, often life-long [bib_ref] Atypical serological profiles in hepatitis B virus infection, Pondé [/bib_ref] [bib_ref] The underlying mechanisms for the 'anti-HBc alone' serological profile, Pondé [/bib_ref]. The presence of IgM anti-HBc is indicative of acute infection, while IgG anti-HBc indicates past infection [bib_ref] Atypical serological profiles in hepatitis B virus infection, Pondé [/bib_ref] [bib_ref] The underlying mechanisms for the 'anti-HBc alone' serological profile, Pondé [/bib_ref]. In persons who recover from HBV infection, HBsAg is eliminated from the blood and anti-HBs develops, typically within 3-4 months. The presence of anti-HBs is generally indicative of immunity to HBV infection [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref]. Anti-HBs also can be detected for 4-6 months following HBIG administration [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref]. Persons who recover from natural HBV infection are typically positive for both anti-HBs and anti-HBc, whereas persons who respond to HepB vaccine are positive only for anti-HBs. Approximately 0.5%-2% of persons with chronic infection spontaneously clear HBsAg yearly; anti-HBs will develop in the majority of these persons [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref].
In certain persons, anti-HBc is the only serologic marker detected. Isolated anti-HBc-positivity can be detected following HBV infection in persons who have recovered but whose anti-HBs levels have waned; in populations with a high prevalence of HBV infection, isolated anti-HBc likely indicates previous infection with loss of anti-HBs. Some chronically infected persons with isolated anti-HBc-positivity have circulating HBsAg that is not detectable by a laboratory assay. HBV DNA has been detected in <10% of persons with isolated anti-HBc [bib_ref] Serological pattern "anti-HBc alone": report on a workshop, Grob [/bib_ref] [bib_ref] Hepatitis B virus DNA in persons with isolated antibody to hepatitis B..., Silva [/bib_ref] , although the presence of detectable HBV DNA might fluctuate [bib_ref] Occult hepatitis B infection in blood donors from South East Asia: molecular..., Candotti [/bib_ref]. These persons are unlikely to transmit infection except under circumstances in which they are the source of a large exposure, such as a blood transfusion [bib_ref] Liver and Heart North Italy Transplant Program Study Groups. Risk of transmission..., De Feo [/bib_ref]. Persons who are HBsAg-negative and anti-HBc-positive can experience reactivation of infection during chemotherapy or immunosuppressive therapy, with reappearance of HBsAg [bib_ref] Hepatitis B virus infection, Trépo [/bib_ref]. Infection with a mutant HBV strain can result in positive laboratory tests for HBsAg, total anti-HBc, anti-HBs, and HBV DNA, with a negative IgM anti-HBc.
Perinatal HBV infection in a child aged ≤24 months is typically asymptomatic although fulminant hepatitis can occur; a positive HBsAg test, positive HBeAg test, or detectable HBV DNA may be considered laboratory evidence of perinatal HBV in an infant born to an HBV-infected mother if timing criteria are met. Infants who are born to HBsAg-positive mothers and who do not become infected might have detectable anti-HBc for up to 24 months after birth from passively acquired maternal antibody [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref].
## Adults at risk for hbv infection
In 2015, CDC received 3,370 surveillance case-reports of acute HBV infection. Of 2,207 case-reports with risk information, 1,151 (52.2%) indicated no risk for HBV during the 6 weeks to 6 months prior to illness onset, and the remainder indicated at least one risk factor. Injection-drug use and multiple sex partners were the most common reported sources of HBV transmission (4).
Injection-drug use. Injection-drug use was reported by 30.3% of 1,657 new reported HBV cases that included information about injection-drug use (4). Since 2009, there has been an increase in acute HBV infection among non-Hispanic whites aged 30-39 years residing in nonurban areas reporting injection-drug use as a risk factor. Chronic HBV infection has been identified in 3.5%-20.0% (midpoint estimate 11.8%) of persons who inject drugs (PWID) in a variety of settings (75) and 22.6% of PWID have evidence of past infection [bib_ref] Global epidemiology of hepatitis B and hepatitis C in people who inject..., Nelson [/bib_ref]. The proportion of HBV cases reporting injection-drug use in three states (Kentucky, Tennessee, and West Virginia) increased significantly, from 53% during 2006-2009 to 75% during 2010-2013 (p<0.001, chi-square).
Sexual (heterosexual and MSM) exposure. Among persons with case-reports of HBV infection with information about sexual exposure, 26.4% reported having two or more sexual partners, 3.3% reported sexual contact with an HBV-infected person, and 11.8% of males reported having had sex with another male (4). As many as 10%-40% of adults seeking treatment in STI clinics have evidence of current or past HBV infection. Among adults with acute HBV infection, 39% were screened or sought care for an STI prior to becoming infected with HBV.
Household contacts. An estimated 45% of persons living in households with others with chronic HBV infection have serologic evidence of past HBV infection, and 16% have evidence of current infection (CDC, unpublished data, 2017). Prior to universal infant vaccination, the risk for infection was greatest among unvaccinated children living with a person with chronic HBV infection in a household or in an extended family setting [bib_ref] Hepatitis B virus infection among children born in the United States to..., Franks [/bib_ref] [bib_ref] Horizontal transmission of hepatitis B virus infection to United States-born children of..., Hurie [/bib_ref] [bib_ref] Prevalence of hepatitis B infection among residents of an institution for the..., Chaudhary [/bib_ref].
Developmentally disabled persons in long-term-care facilities. Developmentally disabled persons in residential and nonresidential facilities historically have had a chronic HBV infection prevalence as high as 20%. The prevalence of infection has declined substantially since the implementation of routine HepB vaccination in these settings [bib_ref] Nonhospital health care-associated hepatitis B and C virus transmission: United States, Thompson [/bib_ref] [bib_ref] Hepatitis B vaccination of susceptible elderly residents of long term care facilities..., Williams [/bib_ref] [bib_ref] Prevalence of hepatitis virus infections in an institution for persons with developmental..., Woodruff [/bib_ref] [bib_ref] Prevalence of HIV, hepatitis B, and hepatitis C in people with severe..., Rosenberg [/bib_ref].
Correctional facilities. The prevalence of chronic HBV infection has been higher among prison inmates (1.0%-3.7%) than among the general population [bib_ref] Recommendations for identification and public health management of persons with chronic hepatitis..., Weinbaum [/bib_ref] [bib_ref] Prevention and control of infections with hepatitis viruses in correctional settings, Weinbaum [/bib_ref] , reflecting an overrepresentation of persons entering correctional facilities with risks for HBV infection (e.g., injection-drug use and histories of multiple sex partners).
Persons at risk for occupational exposure to HBV. Before HepB vaccination was widely implemented, HBV infection was recognized as a common occupational risk among HCP [bib_ref] Occupational exposure to hepatitis B virus in hospital personnel: infection or immunization?, Dienstag [/bib_ref] [bib_ref] Occupational risk of hepatitis B infection in hospital workers, Hadler [/bib_ref]. Routine HepB vaccination of HCP and the use of standard precautions have resulted in a 98% decline in HBV infections from 1983 through 2010 among HCP (10). The Occupational Safety and Health Administration mandates that employers offer HepB vaccination to all employees who have occupational risk and that postexposure prophylaxis be available following an exposure [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref].
Hemodialysis patients. Since the initiation of HepB vaccination and additional infection control precautions for hepatitis B in dialysis centers, the incidence of HBV infection among hemodialysis patients has declined approximately 95% [bib_ref] Impact of infection control strategies on the incidence of dialysis-associated hepatitis in..., Alter [/bib_ref]. Since 1995, the annual incidence has been stable and HBsAg seroprevalence has remained at 1% [bib_ref] National surveillance of dialysis-associated diseases in the United States, Finelli [/bib_ref]. Receipt of dialysis was reported in <1% of acute HBV surveillance cases with information reported to CDC (4).
Persons with HCV infection. The number of reported HCV cases in four Appalachian states (Kentucky, Tennessee, Virginia, and West Virginia) increased 364% during 2006-2012 among persons aged ≤30 years, with injection-drug use as the most common reported risk factor. The increase in HCV infections occurred concomitantly with an increase in HBV infections among young adults in rural communities in Appalachian states.
Persons with chronic liver disease. Persons with chronic liver disease (e.g., cirrhosis, fatty liver disease, alcoholic liver disease, and autoimmune hepatitis) are not at increased risk for HBV infection unless they have percutaneous or mucosal exposure to blood or body fluids. However, concurrent chronic HBV infection might increase the risk for progressive chronic liver disease in these persons [bib_ref] Hepatitis A and hepatitis B vaccination of patients with chronic liver disease, Bell [/bib_ref]. Travelers to countries where HBV is endemic. Shortterm travelers to countries in which HBV infection is of high or intermediate endemicity (Box 3) typically are at risk for infection only through exposure to blood in medical or disasterrelief activities, receipt of medical care that involves parenteral exposures, sexual activity, or drug use. Monthly incidence of 25-420 per 100,000 travelers has been reported among longterm travelers to countries where the disease is endemic [bib_ref] Hepatitis B and C infection in international travelers, Johnson [/bib_ref].
Persons with HIV. Approximately 10% of HIV-positive persons are coinfected with HBV [bib_ref] Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection..., Kellerman [/bib_ref] [bib_ref] Infectious Disease Clinical Research Program HIV Working Group. Epidemiology of Hepatitis B..., Chun [/bib_ref] [bib_ref] High incidence of hepatitis B infection and evolution of chronic hepatitis B..., Homann [/bib_ref] [bib_ref] Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural history, and..., Thio [/bib_ref]. Chronic HBV infection has been identified in 6%-14% of HIV-positive persons, including in 9%-17% of MSM and in 7%-10% of PWID [bib_ref] Epidemiology of viral hepatitis and HIV co-infection, Alter [/bib_ref]. Coinfected persons have increased rates of cirrhosis and liver-related mortality [bib_ref] Multicenter AIDS Cohort Study. HIV-1, hepatitis B virus, and risk of liver-related..., Thio [/bib_ref].
Persons with diabetes. Compared with adults without diabetes, adults with diabetes have a 60% higher prevalence of past or present HBV infection and twice the odds of acquiring acute HBV. Repeated outbreaks of HBV infection associated with assisted blood glucose monitoring underscore the continued risk for this population [bib_ref] Increased risk of acute hepatitis B among adults with diagnosed diabetes mellitus, Reilly [/bib_ref] [bib_ref] Prevalence of hepatitis B virus infection among persons with diagnosed diabetes mellitus..., Schillie [/bib_ref] [bib_ref] Nosocomial transmission of hepatitis B virus associated with the use of a..., Polish [/bib_ref]. Data also suggest the possibility of a higher case-fatality proportion among persons with diabetes acutely infected with HBV compared with those without diabetes (9).
## Prophylaxis against hbv infection
## Hepatitis b vaccines and hepatitis b immune globulins
HepB vaccination is the mainstay of HBV prevention efforts; HBIG is generally used as an adjunct to HepB vaccine in infants born to HBsAg-positive mothers and in certain other postexposure prophylaxis situations. The first HepB vaccines consisted of plasma-derived HBsAg. Recombinant HepB vaccines containing yeast-derived HBsAg purified by biochemical and biophysical separation techniques replaced the plasma-derived vaccines in the United States by the late 1980s [bib_ref] Seroprotection after recombinant hepatitis B vaccination among newborn infants: a review, Schillie [/bib_ref] [bib_ref] Production and immunological analysis of recombinant hepatitis B vaccine, Emini [/bib_ref] [bib_ref] Development and production aspects of a recombinant yeast-derived hepatitis B vaccine, Stephenne [/bib_ref]. HepB vaccines recommended for use in the United States are formulated to contain 10-40 µg of HBsAg protein/mL and do not contain thimerosal as a preservative. HBIG can augment protection until a response to vaccination is attained. For those who do not respond to HepB vaccination, HBIG administered alone is the primary means of protection after an HBV exposure. HBIG provides passively acquired anti-HBs and temporary protection (i.e., 3-6 months). Passively acquired anti-HBs can be detected for 4-6 months after administration of HBIG [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref].
HepB vaccines are available as a single-antigen formulation and in combination with other vaccines. The two singleantigen vaccines recommended for use in the United States, Engerix-B (GlaxoSmithKline Biologicals, Rixensart, Belgium) and Recombivax HB (Merck & Co., Inc., Whitehouse Station, New Jersey), are used for the vaccination of persons starting at birth. Of the two combination vaccines, Pediarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is used for the vaccination of persons aged 6 weeks-6 years and contains recombinant HBsAg, diphtheria and tetanus toxoids and acellular pertussis adsorbed, and inactivated poliovirus and Twinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is used for the vaccination of persons aged ≥18 years and contains recombinant HBsAg and inactivated hepatitis A virus [fig_ref] BOX 2 [/fig_ref]. Comvax (Merck & Co., Inc., Whitehouse Station, New Jersey), which was used previously for the vaccination of persons aged 6 weeks-15 months and contained recombinant HBsAg and Haemophilus b conjugate vaccine, has not been available for purchase directly from Merck since January 1, 2015. Discontinuation of Comvax was not related to any product safety or manufacturing issues. Aluminum salts generally are used as adjuvants to enhance the immune response of vaccinated persons. Two HBIG products are licensed for use in the United States: HepaGam B (Cangene Corporation, Winnipeg, Canada) and Nabi-HB (Biotest Pharmaceuticals Corporation, Boca Raton, Florida). HBIG is prepared from the plasma of donors with high concentrations of anti-HBs. Source plasma tests negative for evidence of HIV, HBV, and HCV. Investigational nucleic acid testing for hepatitis A virus and parvovirus B19 also is performed on pooled samples of source plasma. The manufacturing process contains two steps to inactivate viruses in the final product: the solvent and detergent step inactivates enveloped viruses, and the virus filtration step removes viruses based on their size. HBIG products licensed for use in the United States contain no preservative and are intended for single use only.
## Vaccine-induced seroprotection
The presence of anti-HBs typically indicates immunity against HBV infection. Immunocompetent children and adults who have vaccine-induced anti-HBs levels of ≥10 mIU/mL 1-2 months after having received a complete HepB vaccine series are considered seroprotected and deemed vaccine responders [bib_ref] What level of hepatitis B antibody is protective?, Jack [/bib_ref]. Vaccine-induced seroprotection is considered a surrogate of clinical protection. Anti-HBs levels wane over time following vaccination related in part to the age at vaccination. Approximately 16% of persons vaccinated at age <1 year have antibody levels of ≥10 mIU/mL 18 years following vaccination, compared with 74% for those vaccinated at age ≥1 year (10). However, persons initially responding to the full 3-dose HepB vaccine series and who are later found to have anti-HBs <10 mIU/mL remain protected. Most persons (88%) who receive a challenge dose of HepB vaccine 30 years after HepB vaccination as children or adults develop an antibody response of ≥10 mIU/mL indicating persistent immunity to HBV infection [bib_ref] Antibody levels and protection after hepatitis B vaccine: results of a 30-year..., Bruce [/bib_ref]. Data from this and other studies suggests protection against acute symptomatic and chronic HBV infection persists for 30 years or more among immunocompetent persons who originally responded to HepB vaccine [bib_ref] Antibody levels and protection after hepatitis B vaccine: results of a 30-year..., Bruce [/bib_ref] [bib_ref] Hepatitis B and the need for a booster dose, Leuridan [/bib_ref] [bib_ref] A longitudinal hepatitis B vaccine cohort demonstrates long-lasting hepatitis B virus (HBV)..., Simons [/bib_ref].
The 3-dose HepB vaccine series produces a protective antibody response (anti-HBs ≥10 mIU/mL) in approximately 95% of healthy infants overall (response is lower for infants with lower birth weights) (64) and >90% of healthy adults aged <40 years [bib_ref] Summary of safety and efficacy data on a yeast-derived hepatitis B vaccine, André [/bib_ref] [bib_ref] Immune response of hepatitis B vaccine among persons with diabetes: a systematic..., Schillie [/bib_ref]. Among healthy infants, 25% and 63% achieve anti-HBs levels ≥10 mIU/mL after the first and second dose, respectively. Among healthy adults aged <40 years, 30%-55% and 75% achieve anti-HBs levels ≥10 mIU/mL after the first and second dose, respectively [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref] [bib_ref] Seroprotection after recombinant hepatitis B vaccination among newborn infants: a review, Schillie [/bib_ref]. Vaccine response is decreased among infants weighing <2000 grams and older adults. Other factors (e.g., smoking, obesity, aging, chronic medical conditions, drug use, diabetes, male sex, genetic factors, and immune suppression) contribute to a decreased response to vaccine [bib_ref] Immunogenicity of hepatitis B Vaccines. Implications for persons at occupational risk of..., Averhoff [/bib_ref] [bib_ref] Effect of anatomic injection site, age and smoking on the immune response..., Shaw [/bib_ref] [bib_ref] Factors associated with hepatitis B vaccine series completion in a randomized trial..., Bowman [/bib_ref] [bib_ref] Vaccination against hepatitis B in children and adolescent patients on dialysis, Drachman [/bib_ref]. Although immunogenicity is lower among immunocompromised persons, those who achieve and maintain seroprotective antibody levels before exposure to HBV have a high level of protection [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref].
Birth dose. A birth dose of HepB vaccine serves as postexposure prophylaxis to prevent perinatal HBV infection among infants born to HBV-infected mothers. Although infants requiring postexposure prophylaxis should be identified by maternal HBsAg testing, administration of a birth dose to all infants (even without HBIG) serves as a safeguard to prevent perinatal transmission among infants born to HBsAgpositive mothers not identified prenatally because of lack of maternal HBsAg testing or failures in reporting test results. HepB vaccine or HBIG given alone are 75% and 71% effective in preventing perinatal HBV transmission, respectively; their combined efficacy is 94% [bib_ref] Outcomes of infants born to women infected with hepatitis B, Schillie [/bib_ref] [bib_ref] Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune..., Beasley [/bib_ref] [bib_ref] Effect of hepatitis B immunisation in newborn infants of mothers positive for..., Lee [/bib_ref]. The birth dose also provides protection to infants at risk from household exposure after the perinatal period [bib_ref] Outcomes of infants born to women infected with hepatitis B, Schillie [/bib_ref] [bib_ref] Seroprotection after recombinant hepatitis B vaccination among newborn infants: a review, Schillie [/bib_ref].
Vaccination produces seroprotection in 98% of healthy term infants. Vaccine response is lower among infants with birth weights <2000 grams [bib_ref] Seroprotection after recombinant hepatitis B vaccination among newborn infants: a review, Schillie [/bib_ref]. A study among low birth weight infants demonstrated that more infants achieved seroprotective anti-HBs levels when vaccine was initiated at 1 month of age versus within the first 3 days of life (96% vs. 68%, p<0.02) [bib_ref] Immunogenicity of hepatitis B vaccine in healthy very low birth weight infants, Patel [/bib_ref]. Vaccine response among infants does not vary appreciably by maternal HBsAg status or HBIG administration [bib_ref] Seroprotection after recombinant hepatitis B vaccination among newborn infants: a review, Schillie [/bib_ref].
Adolescents. Approximately 95% of adolescents achieve seroprotection following HepB vaccination with a complete series [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref]. The adult (10 µg) dose of Recombivax HB administered using a 2-dose compressed schedule at 0 and 4 months or 0 and 6 months for persons aged 11-15 years produces seroprotection proportions nearly equivalent to those obtained with the standard regimen of 5 µg administered on a 3-dose schedule at 0, 1, and 6 months (99.2% vs. 98.3%) [bib_ref] A two-dose hepatitis B vaccine regimen: proof of priming and memory responses..., Marsano [/bib_ref] [bib_ref] A randomized trial of alternative two-and three-dose hepatitis B vaccination regimens in..., Cassidy [/bib_ref]. Data on long-term antibody persistence or protection among adolescents for 2-dose schedules are lacking.
Adults. Vaccination with a complete series results in seroprotection in >90% of healthy adults aged <40 years. Response decreases with age, and seroprotection is achieved in 75% of persons aged 60 years (8).
Diabetes. A review of studies assessing HepB vaccine response among persons with diabetes mellitus demonstrated seroprotection in 93.9% for children with diabetes mellitus compared with 100% for children without diabetes mellitus [bib_ref] Immune response of hepatitis B vaccine among persons with diabetes: a systematic..., Schillie [/bib_ref] [bib_ref] Hepatitis B virus vaccine in chronic kidney disease: improved immunogenicity by adjuvants?..., Fabrizi [/bib_ref].
Among adults, 88.2% of those with diabetes mellitus, compared with 93.6% of those without diabetes mellitus, achieved seroprotection [bib_ref] Immune response of hepatitis B vaccine among persons with diabetes: a systematic..., Schillie [/bib_ref]. Among hemodialysis/chronic kidney disease patients, the median proportion protected was 60.1% for those with diabetes mellitus, compared with 75.1% for those without diabetes mellitus [bib_ref] Immune response of hepatitis B vaccine among persons with diabetes: a systematic..., Schillie [/bib_ref].
Immunocompromising conditions. The humoral response to HepB vaccine is reduced in children and adults who are immunocompromised (e.g., hematopoietic stem cell transplant recipients, patients undergoing chemotherapy, and HIV-infected persons) [bib_ref] Impaired response to hepatitis B vaccine in children receiving anticancer chemotherapy, Hovi [/bib_ref] [bib_ref] Impaired response to hepatitis B vaccine in HIV infected children, Zuin [/bib_ref]. Modified dosing regimens, including a doubling of the standard antigen dose or administration of additional doses, might increase response rates. However, data on response to these alternative vaccination schedules are limited [bib_ref] Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination..., Rubin [/bib_ref].
## Vaccine safety
In prelicensure trials, adverse events following HepB vaccination were most commonly injection site reactions and mild systemic reactions. Commonly reported mild adverse events from postmarketing data include pain (3%-29%), erythema (3%), swelling (3%), fever (1%-6%), and headache (3%). The estimated incidence of anaphylaxis among HepB vaccine recipients is 1.1 per million vaccine doses [bib_ref] Vaccine Safety Datalink Team. Risk of anaphylaxis after vaccination of children and..., Bohlke [/bib_ref]. In 2011, the Institute of Medicine concluded that the evidence convincingly supports a causal relationship between HepB vaccine and anaphylaxis in yeast-sensitive persons, and that the evidence is inadequate to accept or reject a causal relation between HepB vaccine and several neurologic, chronic, and autoimmune diseases.
During early postlicensure surveillance, several adverse events following HepB vaccination have been described in the scientific literature, including Guillain-Barré Syndrome (GBS), chronic fatigue syndrome, optic neuritis, multiple sclerosis, and diabetes mellitus; however, multiple studies have demonstrated no association between receipt of HepB vaccine and these conditions [bib_ref] Viral Hepatitis Prevention Board. Hepatitis B vaccine and central nervous system demyelinating..., Halsey [/bib_ref] [bib_ref] Hepatitis B vaccine and risk of multiple sclerosis, Destefano [/bib_ref]. In addition, no evidence of a causal association between rheumatoid arthritis (130), Bell's palsy [bib_ref] Immunization and Bell's palsy in children: a case-centered analysis, Rowhani-Rahbar [/bib_ref] , autoimmune thyroid disease [bib_ref] Hepatitis B vaccine and risk of autoimmune thyroid disease: a Vaccine Safety..., Yu [/bib_ref] , hemolytic anemia in children (133), anaphylaxis [bib_ref] Risk of anaphylaxis after vaccination in children and adults, Mcneil [/bib_ref] , optic neuritis (135), Guillain-Barré Syndrome (136), sudden-onset sensorineural hearing loss (137), or other chronic illnesses and receipt of HepB vaccine has been demonstrated through analysis of VSD data.
During 2005-2015, a total of 20,231 reports of adverse events following HepB vaccination among all ages were submitted to VAERS. The majority of primary U.S. reports (15,787 of 20,231, 78%) were following HepB vaccine administered with other vaccines on the same visit. Among these, the percentage classified as serious (i.e., if one or more of the following is reported: death, life-threatening illness, hospitalization or prolongation of existing hospitalization, or permanent disability) † was 16.7%, including 402 deaths, of which 388 were among infants aged 6 weeks-23 months [bib_ref] Safety of currently licensed hepatitis B surface antigen vaccines in the United..., Haber [/bib_ref]. The most frequently reported adverse events for vaccines given in combination were fever (23%), injection site erythema (11%), and vomiting (10%) [bib_ref] Safety of currently licensed hepatitis B surface antigen vaccines in the United..., Haber [/bib_ref]. Among the 4,444 single-antigen HepB reports, 6.5% were classified as serious, including 43 deaths, of which 27 were among infants aged ≤4 weeks. The most frequently reported adverse events for single-antigen HepB vaccine were nausea/dizziness (8%) and fever/headache (7%).
## Vaccination schedules
Vaccine schedules are determined on the basis of immunogenicity data, and, for infants and children, the need to integrate HepB vaccine into a harmonized immunization schedule [fig_ref] TABLE 3: Hepatitis B vaccine schedules for infants, by infant birthweight and maternal HBsAg... [/fig_ref]. Primary vaccination generally consists of three intramuscular doses administered on a 0-, 1-, and 6-month schedule [fig_ref] TABLE 4: Hepatitis B vaccine schedules for children, adolescents, and adults [/fig_ref]. Recombivax HB may be administered in a 2-dose schedule at 0 and 4-6 months for Abbreviations: HBIG = hepatitis B immune globulin; HBsAg = hepatitis B surface antigen. * Mothers should have blood drawn and tested for HBsAg as soon as possible after admission for delivery; if the mother is found to be HBsAg positive, the infant should receive HBIG as soon as possible but no later than age 7 days. † Pediarix should not be administered before age 6 weeks. § HBIG should be administered at a separate anatomical site from vaccine. ¶ The final dose in the vaccine series should not be administered before age 24 weeks (164 days).
persons aged 11-15 years using the adult formulation. Pediarix is administered at ages 2, 4, and 6 months; it is not used for the birth dose. Twinrix may be administered before travel or any other potential exposure on an accelerated schedule at 0, 7, and 21-30 days, followed by a dose at 12 months. HepB vaccination of adult hemodialysis patients consists of high-dose (40 µg) Recombivax HB administered on a 0-, 1-, and 6-month schedule or high-dose (40 µg) Engerix-B administered on a 0-, 1-, 2-, and 6-month schedule.
Alternative vaccination schedules (e.g., 0, 1, and 4 months or 0, 2, and 4 months) have been demonstrated to elicit dosespecific and final rates of seroprotection similar to those obtained on a 0-, 1-, and 6-month schedule. Increasing the interval between the first 2 doses has little effect on immunogenicity or the final antibody concentration [bib_ref] Effect of timing of hepatitis B vaccine doses on response to vaccine..., Hadler [/bib_ref] [bib_ref] Hepatitis B vaccine administered to children and adolescents at yearly intervals, Halsey [/bib_ref] [bib_ref] Booster vaccination with recombinant hepatitis B vaccine four years after priming with..., Wiström [/bib_ref]. The third dose confers the maximum level of seroprotection and provides long-term protection [bib_ref] Vaccination against hepatitis B: comparison of three different vaccination schedules, Jilg [/bib_ref]. Longer intervals between the last 2 doses (e.g., 11 months) result in higher final antibody levels (142) but might increase the risk for acquisition of HBV infection among persons who have a delayed response to vaccination. Higher geometric mean titers are associated with longer persistence of measurable anti-HBs.
## Response to revaccination
A challenge dose of HepB vaccine may be used to determine the presence of vaccine-induced immunologic memory through generation of an anamnestic response. The term "booster dose" has been used to refer to a dose of HepB vaccine administered after a primary vaccination series to provide rapid protective immunity against significant infection (i.e., infection resulting in serologic test results positive for HBV and/or clinically significant disease). Among persons who were vaccinated prior to age 1 year and found to have anti-HBs levels <10 mIU/mL 6-18 years later, a single challenge dose of HepB vaccine resulted in anti-HBs levels ≥10 mIU/mL in 60%-97% of those tested. Similar results were found among persons initially vaccinated at age ≥1 year [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref]. Immunocompetent persons with a response ≥10 mIU/mL following a challenge dose are considered protected, regardless of subsequent declines in anti-HBs [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref] [bib_ref] Hepatitis B and the need for a booster dose, Leuridan [/bib_ref].
One study found that of infants born to HBsAg-positive women who were not infected at birth and who did not respond to a primary vaccine series, all developed seroprotective levels of anti-HBs after receipt of 3 additional doses [bib_ref] Immunogenicity of recombinant yeast-derived hepatitis B vaccine in nonresponders to perinatal immunization, Tan [/bib_ref]. No data exist that suggest that children who have no detectable antibody after 6 doses of vaccine benefit from additional doses.
## Maternal antiviral therapy for preventing perinatal hbv transmission
Antiviral therapy (i.e., lamivudine, telbivudine, and tenofovir) has been studied as an intervention to reduce perinatal HBV transmission among pregnant women with high HBV DNA levels (e.g., average HBV DNA levels of 7.6 log10 IU/mL) [bib_ref] Antiviral therapy in chronic hepatitis B viral infection during pregnancy: A systematic..., Brown [/bib_ref]. Maternal antiviral therapy started at 28-32 weeks' gestation, as an adjunct to HepB vaccine and HBIG administered to the infant shortly after delivery, has been associated with significantly reduced rates of perinatal HBV transmission [bib_ref] AASLD guidelines for treatment of chronic hepatitis B, Terrault [/bib_ref]. The use of lamivudine and telbivudine is limited by viral resistance and mutations. Tenofovir is not associated with resistance and is the preferred agent [bib_ref] AASLD guidelines for treatment of chronic hepatitis B, Terrault [/bib_ref]. Available data support the safety of tenofovir during pregnancy, although its use might be associated with reduced bone mineral content in infants with in utero exposure [bib_ref] Telbivudine prevents vertical transmission from HBeAg-positive women with chronic hepatitis B, Pan [/bib_ref] [bib_ref] Prevention of perinatal hepatitis B virus transmission, Nelson [/bib_ref] [bib_ref] Antiviral therapy in chronic hepatitis B viral infection during pregnancy: A systematic..., Brown [/bib_ref] [bib_ref] Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebocontrolled,..., Jourdain [/bib_ref] [bib_ref] Efficacy and safety of telbivudine treatment: an open-label, prospective study in pregnant..., Han [/bib_ref]. AASLD suggests antiviral therapy to reduce perinatal HBV transmission when maternal HBV DNA is >200,000 IU/mL. Maternal therapy is generally discontinued at birth to 3 months postpartum (5).
## Cost-effectiveness considerations
HBV prevention strategies targeting perinatal transmission are considered very cost-effective (i.e., an incremental cost-effectiveness ratio <$25,000). The current strategy of administering HepB vaccine and HBIG within 12 hours of birth for infants born to HBsAg-positive mothers and universal infant vaccination prior to hospital discharge has an incremental cost-effectiveness ratio of $6,957 per quality-adjusted life year (QALY) saved when compared with a strategy of universal infant HepB vaccination prior to hospital discharge alone [bib_ref] Cost-effectiveness of active-passive prophylaxis and antiviral prophylaxis during pregnancy to prevent perinatal..., Fan [/bib_ref]. CDC's U.S. Perinatal Hepatitis B Prevention Program (https://www.cdc.gov/hepatitis/partners/perihepbcoord. htm), which provides case management services to infants born to HBsAg-positive women, also has been demonstrated to decrease infections, increase QALYs saved, and be a costeffective use of resources [bib_ref] Cost-effectiveness analysis of the national Perinatal Hepatitis B Prevention Program, Barbosa [/bib_ref]. A strategy of testing HBsAgpositive pregnant women for HBV DNA, followed by maternal antiviral prophylaxis for women with high HBV DNA, would
## Schedule* (interval represents time in months from first dose)
Children (1-10 yrs) 0, 1, and 6 mos 0, 1, 2, and 12 mos Adolescents 0, 1, and 6 mos 0, 12, and 24 mos 0 and 4-6 mos † 0, 1, 2, and 12 mos 0, 7 days, 21-30 days, 12 mos § Adults (≥20 yrs) 0, 1, and 6 mos 0, 1, 2, and 12 mos 0, 1, 2, and 6 mos ¶ 0, 7 days, 21-30 days, 12 mos § * Refer to package inserts for further information. For all ages, when the HepB vaccine schedule is interrupted, the vaccine series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be separated by an interval of at least 8 weeks. If only the third dose has been delayed, it should be administered as soon as possible. The final dose of vaccine must be administered at least 8 weeks after the second dose and should follow the first dose by at least 16 weeks; the minimum interval between the first and second doses is 4 weeks. Inadequate doses of hepatitis B vaccine or doses received after a shorter-than-recommended dosing interval should be readministered, using the correct dosage or schedule. Vaccine doses administered ≤4 days before the minimum interval or age are considered valid. Because of the unique accelerated schedule for Twinrix, the 4-day guideline does not apply to the first three doses of this vaccine when administered on a 0-day, 7-day, 21-30-day, and 12-month schedule (new recommendation). † A 2-dose schedule of Recombivax adult formulation (10 µg) is licensed for adolescents aged 11-15 years. When scheduled to receive the second dose, adolescents aged >15 years should be switched to a 3-dose series, with doses 2 and 3 consisting of the pediatric formulation administered on an appropriate schedule. § Twinrix is approved for use in persons aged ≥18 years and is available on an accelerated schedule with doses administered at 0, 7, 21-30 days, and 12 months. ¶ A 4-dose schedule of Engerix administered in two 1 mL doses (40 µg) on a 0-, 1-, 2-, and 6-month schedule is recommended for adult hemodialysis patients.
cost an additional $3 million but would save 2,080 QALYs and prevent 324 chronic HBV infections, and therefore would be considered cost-effective, with an incremental cost-effectiveness ratio of $1,583 per QALY saved [bib_ref] Cost-effectiveness of testing hepatitis B-positive pregnant women for hepatitis B e antigen..., Fan [/bib_ref]. Cost-effectiveness also has been assessed for HBV prevention strategies outside of the perinatal setting. Vaccinating adults aged 20-59 years with diabetes mellitus costs $75,094 per QALY saved; cost-effectiveness ratios increase with age at vaccination [bib_ref] Cost-effectiveness of hepatitis B vaccination in adults with diagnosed diabetes, Hoerger [/bib_ref]. Among previously vaccinated current HCP (including those in training), pre-exposure anti-HBs testing followed by revaccination and retesting (if necessary, based on anti-HBs levels), compared with no intervention, was not considered cost-effective with an incremental cost per QALY saved of $3-$4 million at year one and approximately $800,000 over 10 years [bib_ref] Costeffectiveness of ensuring hepatitis B protection for previously vaccinated healthcare personnel, Hoerger [/bib_ref].
## Recommendations
This section contains guidance for the prevention of HBV infection, including ACIP recommendations for HepB vaccination of infants, children, adolescents, and adults (Box 4) and CDC and ACIP recommendations for HBV prophylaxis following occupational and nonoccupational exposures, respectively.
## Prevention of perinatal hbv transmission identification and management of hbv-infected pregnant women
- All pregnant women should be tested for HBsAg during an early prenatal visit (e.g., first trimester) in each pregnancy, even if they have been vaccinated or tested previously. Testing those pregnant women known to be chronically infected with HBV provides documentation of the positive HBsAg test result obtained during pregnancy and helps to ensure that their infants will be identified for timely prophylaxis.
-All HBsAg-positive pregnant women should be tested for HBV DNA to guide the use of maternal antiviral therapy during pregnancy for the prevention of perinatal HBV transmission (new recommendation). -AASLD suggests maternal antiviral therapy when the maternal HBV DNA is >200,000 IU/mL (new recommendation). -All HBsAg-positive pregnant women should be referred to their jurisdiction's Perinatal Hepatitis B Prevention Program (PHBPP) for case management to ensure that their infants receive timely prophylaxis and follow-up. A copy of the original laboratory report indicating the pregnant woman's HBsAg-positive status should be provided to the hospital or birthing facility where the delivery is planned and to the HCP who will care for the newborn infant. -All HBsAg-positive pregnant women should receive information concerning HBV that discusses the potential use of antiviral therapy, the importance of prophylaxis for their infant (HepB vaccine and HBIG within 12 hours of birth), completion of the vaccine series, and postvaccination serologic testing. - Women not tested prenatally, those with clinical hepatitis, and those whose behaviors place them at high risk for HBV infection (e.g., recent or current injection-drug use, having had more than one sex partner in the previous 6 months or an HBsAg-positive sex partner, having been evaluated or treated for a STI) should be tested at the time of admission to the hospital or birthing facility for delivery.
## Management of infants born to women who are hbsag-positive
- All infants born to HBsAg-positive women should receive HepB vaccine and HBIG within 12 hours of birth, administered at different injection sites (e.g., separate limbs). Only single-antigen HepB vaccine should be used for the birth dose [fig_ref] TABLE 3: Hepatitis B vaccine schedules for infants, by infant birthweight and maternal HBsAg... [/fig_ref]. - Infants born to women for whom HBsAg testing results during pregnancy are not available but other evidence suggestive of maternal HBV infection exists (e.g., presence of HBV DNA, HBeAg-positive, or mother known to be chronically infected with HBV) should be managed as if born to an HBsAg-positive mother (new recommendation). - The HepB vaccine series should be completed according to the recommended schedule for infants born to HBsAgpositive mothers. The final dose in the series should not be administered before age 24 weeks (164 days). Although not indicated in the manufacturers' package labeling, Pediarix may be used for infants aged ≥6 weeks born to HBsAg-positive mothers to complete the vaccine series after receipt of a birth dose of single-antigen HepB vaccine and HBIG. - For infants weighing <2,000 grams, the birth dose (i.e., the initial HepB vaccine dose) should not be counted as part of the vaccine series because of the potentially reduced immunogenicity of HepB vaccine in these infants; 3 additional doses of vaccine (for a total of 4 doses) should be administered beginning when the infant reaches age 1 month. The final dose in the series should not be administered before age 24 weeks (164 days). - Postvaccination serologic testing for anti-HBs and HBsAg should be performed after completion of the vaccine series at age 9-12 months (generally at the next well-child visit following completion of the HepB vaccine series). Postvaccination serologic testing should be performed for infants born to HBsAg-positive mothers and infants whose mother's HBsAg status remains unknown (i.e., those infants who are safely surrendered shortly after birth) (new recommendation). Anti-HBs testing should be performed using a method that allows detection of the protective concentration of anti-HBs (≥10 mIU/mL). Testing should not be performed before age nine months to avoid detection of passive anti-HBs from HBIG administered at birth and to maximize the likelihood of detecting late HBV infection. Anti-HBc testing of infants is not recommended because passively acquired maternal anti-HBc might be detected in infants born to HBsAg-positive mothers up to age 24 months.
-HBsAg-negative infants with anti-HBs levels ≥10 mIU/ mL are protected and need no further medical management. -HBsAg-negative infants with anti-HBs <10 mIU/mL should be revaccinated with a single dose of HepB vaccine and receive postvaccination serologic testing 1-2 months later (new recommendation). Infants whose anti-HBs remains <10 mIU/mL following single dose revaccination should receive two additional doses of HepB vaccine to complete the second series followed by postvaccination serologic testing 1-2 months after the final dose. -Based on clinical circumstances or family preference, HBsAg-negative infants with anti-HBs <10 mIU/mL may instead be revaccinated with a second, complete 3-dose series, followed by postvaccination serologic testing performed 1-2 months after the final dose of vaccine. -Available data do not suggest a benefit from administering additional HepB vaccine doses to infants who have not attained anti-HBs ≥10 mIU/mL following receipt of two complete HepB vaccine series. -HBsAg-positive infants should be referred for appropriate follow-up. - Infants who are born to HBsAg-positive mothers and receive postexposure prophylaxis may be breastfed beginning immediately after birth. - For infants transferred to a different facility after birth (e.g., hospital with higher level of neonatal care), staff at the transferring and receiving facilities should communicate regarding the infant's HepB vaccination and HBIG receipt status to ensure prophylaxis is administered in a timely manner (new recommendation).
## Management of infants born to women with unknown hbsag status
- Infants born to women for whom HBsAg testing results during pregnancy are not available but other evidence suggestive of maternal HBV infection exists (e.g., presence of HBV DNA, HBeAg-positive, or mother known to be chronically infected with HBV) should be managed as if born to an HBsAg-positive mother (new recommendation [fig_ref] TABLE 3: Hepatitis B vaccine schedules for infants, by infant birthweight and maternal HBsAg... [/fig_ref].
-If the mother is determined to be HBsAg-positive, the infant should receive HBIG as soon as possible but no later than age seven days, and the vaccine series should be completed according to the recommended schedule for infants born to HBsAg-positive mothers. The final dose in the series should not be administered before age 24 weeks (164 days). If the mother is determined to be HBsAg-negative, the vaccine series should be completed according to the recommended schedule for infants born to HBsAg-negative mothers. The final dose in the series should not be administered before age 24 weeks (164 days). - Because of the potentially decreased immunogenicity of vaccine in infants weighing <2,000 grams, these infants should receive both single-antigen HepB vaccine and HBIG, administered at different injection sites (e.g., separate limbs), if the mother's HBsAg status cannot be determined within 12 hours of birth. The birth dose of vaccine should not be counted as part of the 3 doses required to complete the vaccine series; 3 additional doses of vaccine (for a total of 4 doses) should be administered according to a recommended schedule on the basis of the mother's HBsAg test result. The final dose in the series should not be administered before age 24 weeks (164 days).
-If it is not possible to determine the mother's HBsAg status (e.g., when a parent or person with lawful custody safely surrenders an infant confidentially shortly after birth), the vaccine series should be completed according to a recommended schedule for infants born to HBsAgpositive mothers (new recommendation). The final dose in the series should not be administered before age 24 weeks (164 days). These infants should receive postvaccination serologic testing at age 9-12 months, and revaccination if necessary (new recommendation). - Anti-HBs testing should be performed using a method that allows detection of the protective concentration of anti-HBs (≥10 mIU/mL). Testing should not be performed before age nine months to avoid detection of passive anti-HBs from HBIG administered at birth and to maximize the likelihood of detecting late HBV infection. Anti-HBc testing of infants is not recommended because passively acquired maternal anti-HBc might be detected in infants born to HBsAg-positive mothers up to age 24 months.
-HBsAg-negative infants with anti-HBs levels ≥10 mIU/mL are protected and need no further medical management.
-HBsAg-negative infants with anti-HBs <10 mIU/mL should be revaccinated with a single dose of HepB vaccine and receive postvaccination serologic testing 1-2 months later (new recommendation). Infants whose anti-HBs remains <10 mIU/mL following single dose revaccination should receive two additional doses of HepB vaccine to complete the second series, followed by postvaccination serologic testing 1-2 months after the final dose. -Based on clinical circumstances or family preference, HBsAg-negative infants with anti-HBs <10 mIU/mL may instead be revaccinated with a second, complete 3-dose series, followed by postvaccination serologic testing performed 1-2 months after the final dose of vaccine. -Available data do not suggest a benefit from administering additional HepB vaccine doses to infants who have not attained anti-HBs ≥10 mIU/mL following receipt of two complete HepB vaccine series. -HBsAg-positive infants should be referred for appropriate follow-up. - Infants born to mothers with unknown HBsAg status may be breastfed beginning immediately after birth. - For infants transferred to a different facility after birth (e.g., a hospital with a higher level of neonatal care), staff at the transferring and receiving facilities should communicate regarding the infant's HepB vaccination and HBIG receipt status to ensure prophylaxis is administered in a timely manner (new recommendation).
## Persons recommended for hepb vaccination universal vaccination of infants
- All infants should receive the HepB vaccine series as part of the recommended childhood immunization schedule, beginning at birth as a safety net (Box 4;
## Vaccination of children and adolescents
- HepB vaccination is recommended for all unvaccinated children and adolescents aged <19 years (Box 4). - Children and adolescents who have not previously received HepB vaccine should be vaccinated routinely at any age (i.e., children and adolescents are recommended for catch-up vaccination) [fig_ref] TABLE 4: Hepatitis B vaccine schedules for children, adolescents, and adults [/fig_ref].
## Vaccination of adults
- HepB vaccination is recommended for all unvaccinated adults at risk for HBV infection and for all adults requesting protection from HBV infection. Acknowledgement of a specific risk factor should not be a requirement for vaccination (Box 4). - Adults recommended to receive HepB vaccine:
-Persons at risk for infection by sexual exposure (e.g., sex partners of HBsAg-positive persons, sexually active persons who are not in a mutually monogamous relationship [e.g., persons with more than one sex partner during the previous 6 months], persons seeking evaluation or treatment for a sexually transmitted infection, and MSM). -Persons with a history of current or recent injectiondrug use are at increased risk for HBV infection. An increased incidence of HBV incidence among young adults in rural U.S. communities has been associated with an increase in injection-drug use. -Other persons at risk for infection by percutaneous or mucosal exposure to blood (household contacts of HBsAg-positive persons; residents and staff of facilities for developmentally disabled persons; health care and public safety personnel with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids; hemodialysis patients and predialysis, peritoneal dialysis, and home dialysis patients; persons with diabetes mellitus aged <60 years and persons with diabetes mellitus aged ≥60 years at the discretion of the treating clinician
## Vaccination of pregnant women
- Pregnant women who are identified as being at risk for HBV infection during pregnancy (e.g., having more than one sex partner during the previous 6 months, been evaluated or treated for an STI, recent or current injectiondrug use, or having had an HBsAg-positive sex partner) should be vaccinated. - Pregnant women at risk for HBV infection during pregnancy should be counseled concerning other methods to prevent HBV infection.
## Implementation strategies delivery hospital policies and procedures
- All delivery hospitals and birthing facilities should implement policies and procedures to ensure identification of infants born to HBsAg-positive mothers and infants born to mothers with unknown HBsAg status, initiation of prophylaxis for these infants, and routine birth dose for medically stable infants weighing ≥2,000 grams within 24 hours of birth. Such policies and procedures should include standing orders and electronic medical record reminders or prompts.
## Case-management programs to prevent perinatal hbv infection
- States and localities should establish case-management programs, including appropriate policies, procedures, laws, and regulations to ensure that all pregnant women are tested for HBsAg during each pregnancy, and that those who are HBsAg-positive are tested for HBV DNA to guide maternal antiviral therapy. Infants born to HBsAg-positive women and women with unknown HBsAg status also should receive case management.
## Settings providing services to adults
- In settings in which a high proportion of persons have risk factors for HBV infection (e.g., health care settings targeting services to injection-drug users, correctional facilities, institutions and nonresidential day care facilities for developmentally disabled persons), all adults should be assumed to be at risk for HBV infection and should be offered HepB vaccination if they have not previously completed vaccination. - HCP should implement standing orders to administer HepB vaccine as part of routine services to adults who have not completed the vaccine series and make HepB vaccination a standard component of evaluation and treatment for STIs and HIV/AIDS. - When feasible, HepB vaccination should be offered in outreach and other settings in which services are provided to persons at risk for HBV infection (e.g., needle-exchange programs, HIV testing sites, HIV prevention programs, and homeless shelters). - In medical settings, HCP should implement standing orders to identify adults recommended for HepB vaccination and administer vaccination as part of routine services.
## Postexposure prophylaxis
This section provides recommendations for management of persons who are exposed to HBV through a distinct, identifiable exposure to blood or body fluids that contain blood, in occupational and nonoccupational settings.
- Wounds and skin sites that have been in contact with blood or body fluids should be washed with soap and water; mucous membranes should be flushed with water. Using antiseptics (e.g., 2%-4% chlorhexidine) for wound care or expressing fluid by squeezing the wound further have not been shown to reduce the risk for HBV transmission; however, the use of antiseptics is not contraindicated. The application of caustic agents (e.g., bleach) or the injection of antiseptics or disinfectants into the wound is not recommended.
## Occupational settings
Vaccinated HCP
- For vaccinated HCP (who have written documentation of a complete HepB vaccine series) with subsequent documented anti-HBs ≥10 mIU/mL, testing the source patient for HBsAg is unnecessary. No postexposure prophylaxis for HBV is necessary, regardless of the source patient's HBsAg status. - For vaccinated HCP (who have written documentation of a complete HepB vaccine series) without previous anti-HBs testing, the HCP should be tested for anti-HBs and the source patient (if known) should be tested for HBsAg as soon as possible after the exposure. Anti-HBs testing should be performed using a method that allows detection of the protective concentration of anti-HBs (≥10 mIU/mL). Testing the source patient and the HCP should occur simultaneously; testing the source patient should not be delayed while waiting for the HCP anti-HBs test results, and likewise, testing the HCP should not be delayed while waiting for the source patient's HBsAg results.
-If the HCP has anti-HBs <10 mIU/mL and the source patient is HBsAg-positive or has an unknown HBsAg status, the HCP should receive 1 dose of HBIG and be revaccinated as soon as possible after the exposure. HepB vaccine may be administered simultaneously with HBIG at a separate anatomical injection site (e.g., separate limb). The HCP should then receive the second 2 doses of HepB vaccine to complete the second series (likely 6 doses total when accounting for the original series) according to the vaccination schedule. So the HCP's vaccine response status can be documented for future exposures, anti-HBs testing should be performed 1-2 months after the final vaccine dose. -If the HCP has anti-HBs <10 mIU/mL and the source patient is HBsAg-negative, the HCP should receive an additional single HepB vaccine dose, followed by repeat anti-HBs testing 1-2 months later. HCP whose anti-HBs remains <10 mIU/mL should undergo revaccination with two more doses (likely 6 doses total when accounting for the original series). So the HCP's vaccine response status can be documented for future exposures, anti-HBs testing should be performed 1-2 months after the final dose of vaccine. -If the HCP has anti-HBs ≥10 mIU/mL at the time of the exposure, no postexposure HBV management is necessary, regardless of the source patient's HBsAg status. - For vaccinated HCP with anti-HBs <10 mIU/mL after two complete HepB vaccine series, the source patient should be tested for HBsAg as soon as possible after the exposure. If the source patient is HBsAg-positive or has unknown HBsAg status, the HCP should receive 2 doses of HBIG [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref]. The first dose should be administered as soon as possible after the exposure, and the second dose should be administered 1 month later. HepB vaccine is not recommended for the exposed HCP who has previously completed two HepB vaccine series. If the source patient is HBsAg-negative, neither HBIG nor HepB vaccine is necessary [fig_ref] BOX 2 [/fig_ref].
## Unvaccinated hcp
- For unvaccinated or incompletely vaccinated HCP, the source patient should be tested for HBsAg as soon as possible after the exposure. Testing unvaccinated or incompletely vaccinated HCP for anti-HBs is not necessary and is potentially misleading, because anti-HBs ≥10 mIU/mL as a correlate of vaccine-induced protection has only been determined for persons who have completed an approved vaccination series (107) ( anti-HBs testing of HCP who received HBIG should be performed after anti-HBs from HBIG is no longer detectable (6 months after administration), it might be necessary to defer anti-HBs testing for a period longer than 1-2 months after the last vaccine dose in these situations.
-HCP with anti-HBs ≥10 mIU/mL after receipt of the primary vaccine series are considered immune. Immunocompetent persons have long-term protection and do not need further periodic testing to assess anti-HBs levels. -HCP with anti-HBs <10 mIU/mL after receipt of the primary series should be revaccinated. For these HCP, administration of a second complete series on an appropriate schedule, followed by anti-HBs testing 1-2 months after the final dose, is usually more practical than conducting serologic testing after each additional dose of vaccine. So the HCP's vaccine response status can be documented for future exposures, anti-HBs testing should be performed 1-2 months after the final vaccine dose. - If the source patient is HBsAg-negative, the HCP should complete the HepB vaccine series according to the vaccination schedule. So the HCP's vaccine response status can be documented for future exposures, anti-HBs testing should be performed approximately 1-2 months after the final vaccine dose.
-HCP with anti-HBs ≥10 mIU/mL after receipt of the primary vaccine series are considered immune. Immunocompetent persons have long-term protection and do not need further periodic testing to assess anti-HBs levels. -HCP with anti-HBs <10 mIU/mL after receipt of the primary series should be revaccinated. For these HCP, administration of a second complete series on an appropriate schedule, followed by anti-HBs testing 1-2 months after the final dose, is usually more practical than conducting serologic testing after each additional dose of vaccine. So the HCP's vaccine response status can be documented for future exposures, anti-HBs testing should be performed 1-2 months after the final vaccine dose.
## Clinical management of exposed hcp
- HCP who have anti-HBs <10 mIU/mL (or who are unvaccinated or incompletely vaccinated) and sustain an exposure to a source patient who is HBsAg-positive or has an unknown HBsAg status should undergo baseline testing for HBV infection as soon as possible after the exposure, and follow-up testing approximately 6 months later. Testing immediately after the exposure should consist of total anti-HBc, and follow-up testing approximately 6 months later should consist of HBsAg and total anti-HBc. - HCP exposed to a source patient who is HBsAg-positive or has an unknown HBsAg status do not need to take special precautions to prevent secondary transmission during the follow-up period; however, they should refrain from donating blood, plasma, organs, tissue, or semen (10). The exposed HCP does not need to modify sexual practices or refrain from becoming pregnant [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref]. If an exposed HCP is breastfeeding, she does not need to discontinue [bib_ref] CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection..., Schillie [/bib_ref]. No modifications to an exposed HCP's patient-care responsibilities are necessary to prevent transmission to patients based solely on exposure to a source patient who is HBsAg-positive or has an unknown HBsAg status.
## Previously vaccinated hcp
- Providers should only accept written, dated records as evidence of HepB vaccination. - An increasing number of HCP have received routine HepB vaccination during childhood. No postvaccination serologic testing is recommended after routine infant or adolescent HepB vaccination. Because vaccine-induced anti-HBs wanes over time, testing HCP for anti-HBs years after vaccination might not distinguish vaccine nonresponders from responders. Pre-exposure assessment of current or past anti-HBs results upon hire or matriculation, followed by one or more additional doses of HepB vaccine for HCP with anti-HBs <10 mIU/mL and retesting anti-HBs, if necessary, helps to ensure that HCP will be protected if they have an exposure to HBVcontaining blood or body fluids (Box 5; [fig_ref] FIGURE 3: Pre-exposure evaluation for health care personnel previously vaccinated with complete, ≥3-dose HepB... [/fig_ref].
-HCP who cannot provide documentation of 3 doses of HepB vaccine should be considered unvaccinated and should complete the vaccine series. Postvaccination serologic testing for anti-HBs is recommended 1-2 months after the third vaccine dose. HCP who are inadvertently tested before receiving 3 documented doses of HepB vaccine and have anti-HBs ≥10 mIU/mL should not be considered immune because anti-HBs ≥10 mIU/mL is a known correlate of protection only when testing follows a documented 3-dose series. Health care facilities are encouraged to try to locate vaccine records for HCP and to enter all vaccine doses in their state immunization information system.
## Nonoccupational settings
## Hbsag-positive source
This section provides recommendations for management of persons who are exposed to HBV through a distinct, identifiable exposure to blood or body fluids that contain blood, in nonoccupational settings [fig_ref] TABLE 6: Postexposure management after distinct nonoccupational percutaneous or mucosal exposure to blood or... [/fig_ref]. The exposed person does not need to undergo postvaccination serologic testing following vaccination based solely on being exposed.
- Exposed persons who have written documentation of a complete HepB vaccine series and who did not receive postvaccination testing should receive a single dose of HepB vaccine. - Exposed persons who are in the process of being vaccinated but who have not completed the vaccine series should receive a dose of HBIG and complete the HepB vaccine series (it is not necessary to restart the HepB vaccine series). HepB vaccine may be administered simultaneously with HBIG at a separate anatomical injection site (e.g., separate limb). - Exposed unvaccinated persons should receive both HBIG and HepB vaccine as soon as possible after exposure (preferably within 24 hours). HepB vaccine may be administered simultaneously with HBIG at a separate anatomical injection site (e.g., separate limbs). Studies are limited on the maximum interval after exposure during which postexposure prophylaxis is effective, but the interval is unlikely to exceed 7 days for percutaneous exposure and 14 days for sexual exposures. The HepB vaccine series should be completed according to the vaccination schedule.
## Hbsag-unknown source
- Exposed persons with written documentation of a complete HepB vaccine series require no further treatment. - Exposed persons who are in the process of being vaccinated but who are not fully vaccinated should complete the HepB vaccine series (it is not necessary to restart the vaccination series). - Exposed unvaccinated persons should receive the HepB vaccine series with the first dose administered as soon as possible after exposure, preferably within 24 hours. Studies are limited on the maximum interval after exposure during which postexposure prophylaxis is effective, but the interval is unlikely to exceed 7 days for percutaneous exposure and 14 days for sexual exposures. The vaccine series should be completed according to the vaccination schedule.
## Immunization management issues
Prevaccination Testing
## Testing for hbv infection
- Testing for HBV infection (consisting of testing for HBsAg, anti-HBs, and anti-HBc) is also recommended for the following persons: -persons born in countries of high and intermediate HBV endemicity (HBsAg prevalence ≥2%); -U.S.-born persons not vaccinated as infants whose parents were born in countries with high HBV endemicity (≥8%); -persons needing immunosuppressive therapy, including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatologic or gastroenterologic disorders; and -donors of blood, plasma, organs, tissues, or semen. - All pregnant women should be tested for HBsAg during each pregnancy. Pregnant women with positive HBsAg tests should be tested for HBV DNA.
## Postvaccination serologic testing
- Serologic testing for immunity is not necessary after routine vaccination of infants, children, or adults. - Testing for anti-HBs after vaccination is recommended for the following persons whose subsequent clinical management depends on knowledge of their immune status (Box 7): -infants born to HBsAg-positive women and infants born to women whose HBsAg status remains unknown Guidance for health care institutions: Health care institutions may measure anti-HBs upon hire or matriculation for HCP who have documentation of a complete HepB vaccine series in the past (e.g., as part of routine infant or adolescent vaccination). HCP with anti-HBs <10 mIU/mL should receive one or more additional doses of HepB vaccine and retesting [fig_ref] FIGURE 3: Pre-exposure evaluation for health care personnel previously vaccinated with complete, ≥3-dose HepB... [/fig_ref]. Institutions that decide to not measure anti-HBs upon hire or matriculation for HCP who have documentation of a complete HepB vaccine series in the past should ensure timely assessment and postexposure prophylaxis following an exposure [fig_ref] BOX 2 [/fig_ref].
Considerations: The risk for occupational HBV infection for vaccinated HCP might be low enough in certain settings so that assessment of anti-HBs status and appropriate follow-up should be done at the time of exposure to potentially infectious blood or body fluids. This approach relies on HCP recognizing and reporting blood and body fluid exposures and therefore may be applied on the basis of documented low risk, implementation, and cost considerations. Certain HCP occupations have lower risk for occupational blood and body fluid exposures (e.g., occupations involving counseling versus performing procedures), and nontrainees have lower risks for blood and body fluid exposures than trainees. Some settings also will have a lower prevalence of HBV infection in the patient population served than in other settings, which will influence the risk for HCP exposure to HBsAg-positive blood and body fluids. should not be a barrier to vaccination, and the first HepB vaccine dose should be administered immediately after collection of the blood for serologic testing. -Persons who test negative for HBsAg should be considered susceptible to HBV infection and should be counseled about precautions to prevent HBV infection and the need to obtain HBIG postexposure prophylaxis for any known or likely exposure to an HBsAg-positive source (10). - Testing HCP with documentation of complete HepB vaccination for anti-HBs upon hire or matriculation (i.e., pre-exposure assessment of prior response to HepB vaccination), followed by one or more additional doses of HepB vaccine for HCP with anti-HBs <10 mIU/mL, helps to ensure that HCP will be protected if they have an exposure to HBV-containing blood or body fluids. - Anti-HBs levels of ≥10 mIU/mL are generally considered seroprotective; however, different assays have different assay cutoff values based on which reported levels of anti-HBs might vary depending on the assay used. Refer to the package insert of the test for the determination of actual/ correct levels of anti-HBs antibodies.
## Revaccination
- Revaccination (i.e., booster dose, challenge dose, or revaccination with a complete series) is not generally recommended for persons with a normal immune status who were vaccinated as infants, children, adolescents, or adults. Available data do not suggest a maximum number of booster doses. Revaccination when anti-HBs is <10 mIU/mL is recommended for the following persons: -Infants born to HBsAg-positive mothers. HBsAgnegative infants with anti-HBs <10 mIU/mL should be revaccinated with a single dose of HepB vaccine, and retested 1-2 months later. Infants whose anti-HBs remains <10 mIU/mL following single dose revaccination should receive two additional doses of HepB vaccine on a vaccine schedule to complete the second series, followed by anti-HBs testing 1-2 months later. Alternatively, these infants may be revaccinated with a second 3-dose series and retested (HBsAg and anti-HBs) 1-2 months after the final dose of vaccine. including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatologic or gastroenterologic disorders - Donors of blood, plasma, organs, tissues, or semen * Serologic testing comprises testing for hepatitis B surface antigen (HBsAg), antibody to HBsAg, and antibody to hepatitis B core antigen. † Denotes persons also recommended for hepatitis B vaccination. Serologic testing should occur prior to vaccination. Serologic testing should not be a barrier to vaccination of susceptible persons. The first dose of vaccine should typically be administered immediately after collection of the blood for serologic testing.
-HCP. Completely vaccinated HCP with anti-HBs <10 mIU/mL should receive an additional dose of HepB vaccine, followed by anti-HBs testing 1-2 months later. HCP whose anti-HBs remains <10 mIU/mL should complete the second series (usually 6 doses total), followed by repeat anti-HBs testing 1-2 months after the final dose. Alternatively, it might be more practical for very recently vaccinated HCP with anti-HBs <10 mIU/mL to receive the second complete series (usually 6 doses total), followed by anti-HBs testing 1-2 months after the final dose. -Hemodialysis patients. For hemodialysis patients treated in outpatient centers, the need for booster doses should be assessed by annual anti-HBs testing. A booster dose should be administered when anti-HBs levels decline to <10 mIU/mL. Anti-HBs testing 1-2 months following the booster dose to assess response is not recommended. -Other immunocompromised persons. For other immunocompromised persons (e.g., HIV-infected persons, hematopoietic stem-cell transplant recipients, and persons receiving chemotherapy), the need for booster doses has not been determined. Annual anti-HBs testing and booster doses should be considered for persons with an ongoing risk for exposure.
## Interrupted schedules and minimum dosing intervals
- For all ages, when the HepB vaccine schedule is interrupted, the vaccine series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be separated by an interval of at least 8 weeks. If only the third dose has been delayed, it should be administered as soon as possible. The final dose of vaccine must be administered at least 8 weeks after the second dose and should follow the first dose by at least 16 weeks; the minimum interval between the first and second doses is 4 weeks. Inadequate doses of HepB vaccine or doses received after a shorter-thanrecommended dosing interval should be readministered, using the correct dosage or schedule. - Vaccine doses administered ≤4 days before the minimum interval or age are considered valid. Because of the unique accelerated schedule for Twinrix, the 4-day guideline does not apply to the first 3 doses of this vaccine when administered on a 0-day, 7-day, 21-30-day, and 12-month schedule (new recommendation). - In infants, administration of the final dose is not recommended before age 24 weeks.
## Other immunization management issues
- No differences in immunogenicity have been observed when one or 2 doses of HepB vaccine produced by one manufacturer are followed by doses from a different manufacturer [bib_ref] A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection..., Mast [/bib_ref]. Whenever feasible, the same vaccine should be used for the subsequent doses; however, if a different brand is administered, the dose should be considered valid and does not need to be repeated. - Providers should only accept dated records as evidence of HepB vaccination. - Although vaccinations should not be postponed if records cannot be found, an attempt to locate missing records should be made by contacting previous health care providers, reviewing state or local immunization information systems, and searching for a personally held record. If records cannot be located within a reasonable time, these persons should be considered susceptible and started on the age-appropriate vaccination schedule. An anti-HBs ≥10 mIU/mL is a serologic correlate of protection only when following a documented, complete series.
## Box 7. persons recommended to receive postvaccination serologic testing* following a complete series of hepb vaccination
- Infants born to hepatitis B surface antigen (HBsAg)positive mothers or mothers whose HBsAg status remains unknown (e.g., when a parent or person with lawful custody safely surrenders an infant confidentially shortly after birth infants safely surrendered at or shortly after birth) † - Health care personnel and public safety workers - Hemodialysis patients and others who might require outpatient hemodialysis (e.g., predialysis, peritoneal dialysis, and home dialysis) - HIV-infected persons - Other immunocompromised persons (e.g., hematopoietic stem-cell transplant recipients or persons receiving chemotherapy) - Sex partners of HBsAg-positive persons * Postvaccination serologic testing for persons other than infants born to HBsAg-positive (or HBsAg-unknown) mothers consists of anti-HBs. † Postvaccination serologic testing for infants born to HBsAg-positive (or HBsAg-unknown) mothers consists of anti-HBs and HBsAg. Persons with anti-HBs <10 mIU/mL after the primary vaccine series should be revaccinated. Infants born to HBsAg-positive mothers or mothers with an unknown HBsAg status should be revaccinated with a single dose of HepB vaccine and receive postvaccination serologic testing 1-2 months later. Infants whose anti-HBs remains <10 mIU/mL following single dose revaccination should receive two additional doses of HepB vaccine, followed by postvaccination serologic testing 1-2 months after the final dose. Based on clinical circumstances or family preference, HBsAgnegative infants with anti-HBs <10 mIU/mL may instead be revaccinated with a second, complete 3-dose series, followed by postvaccination serologic testing performed 1-2 months after the final dose of vaccine. For others with anti-HBs <10 mIU/mL after the primary series, administration of 3 additional HepB vaccine doses on an appropriate schedule, followed by anti-HBs testing 1-2 months after the final dose, is usually more practical than serologic testing after ≥1 dose of vaccine.
- In all settings, vaccination should be initiated even though completion of the series might not be ensured. - Adverse events occurring after administration of any vaccine should be reported to VAERS. Reports should be submitted to VAERS online, by facsimile, or by mail. More information about VAERS is available by calling 1-800-822-7967 (tollfree) or online at https://vaers.hhs.gov.
## Future directions
ACIP and CDC will review these recommendations as new epidemiology or other information related to HepB vaccines (including licensure of additional HepB-containing vaccines), HepB vaccine adverse events, and the experience gained in the implementation of these recommendations becomes available. Revised recommendations will be developed as needed.
[fig] FIGURE 1: Incidence of hepatitis B virus infection -National Notifiable Diseases Surveillance System, United States, 1980 [/fig]
[fig] FIGURE 2: Acute : anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to hepatitis B e antigen; anti-HBs = antibody to hepatitis B surface antigen; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV DNA = hepatitis B virus deoxyribonucleic acid; IgM = immunoglobulin class M. [/fig]
[fig] *: Source: CDC. Travelers health: infectious diseases related to travel. Atlanta, GA: US Department of Health and Human Services, CDC; 2017. [/fig]
[fig] BOX 5: Testing anti-HBs for health care personnel (HCP) vaccinated in the past The issue: An increasing number of HCP have received routine hepatitis B (HepB) vaccination during childhood. No postvaccination serologic testing is recommended after routine infant or adolescent HepB vaccination. Because vaccine-induced antibody to hepatitis B surface antigen (anti-HBs) wanes over time, testing HCP for anti-HBs years after vaccination might not distinguish vaccine nonresponders from responders. [/fig]
[fig] FIGURE 3: Pre-exposure evaluation for health care personnel previously vaccinated with complete, ≥3-dose HepB vaccine series who have not had postvaccination serologic testing* Measure antibody to hepatitis B surface antigen (anti-HBs) [/fig]
[fig] BOX 6: Persons recommended to receive serologic testing prior to vaccination* • Household, sexual, or needle contacts of hepatitis B surface antigen (HBsAg)-positive persons † • HIV-positive persons † • Persons with elevated alanine aminotransferase/ aspartate aminotransferase of unknown etiology † • Hemodialysis patients † • Men who have sex with men † • Past or current persons who inject drugs † • Persons born in countries of high and intermediate hepatitis B virus (HBV) endemicity (HBsAg prevalence ≥2%) • U.S.-born persons not vaccinated as infants whose parents were born in countries with high HBV endemicity (≥8%) • Persons needing immunosuppressive therapy, [/fig]
[table] TABLE 1: Typical interpretation of test results for hepatitis B virus infection [/table]
[table] TABLE 2: Recommended doses of hepatitis B vaccine, by group and vaccine typeAbbreviation: N/A = not applicable. * Pediarix is approved for use in persons aged 6 weeks through 6 years (prior to the 7th birthday). † Twinrix is approved for use in persons aged ≥18 years. § Adult formulation administered on a 2-dose schedule. [/table]
[table] TABLE 3: Hepatitis B vaccine schedules for infants, by infant birthweight and maternal HBsAg status [/table]
[table] TABLE 4: Hepatitis B vaccine schedules for children, adolescents, and adults [/table]
[table] anti -: HBs ≥10 mIU/mL anti-HBs <10 mIU/mL anti-HBs <10 mIU/mL anti-HBs ≥10 mIU/mL Administer 1 dose of HepB vaccine, postvaccination serologic testing Administer 2 more doses of HepB vaccine, postvaccination serologic testing anti-HBs <10 mIU/mL anti-HBs ≥10 mIU/mL No action for hepatitis B prophylaxis (regardless of source patient hepatitis B surface antigen status) Source: Adapted from CDC. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization of adults. MMWR 2006;55(No. RR-16). * Should be performed 1-2 months after the last dose of vaccine using a quantitative method that allows detection of the protective concentration of anti-HBs (≥10 mIU/mL) (e.g., enzyme-linked immunosorbent assay [ELISA]). [/table]
[table] TABLE 6: Postexposure management after distinct nonoccupational percutaneous or mucosal exposure to blood or body fluidsAbbreviations: HepB = hepatitis B; HBsAg = hepatitis B surface antigen; HBIG = hepatitis B immune globulin. * Exposures include percutaneous (e.g., bite or needlestick) or mucosal exposure to blood or body fluids, sex or needle-sharing contact, or victim of sexual assault/abuse.(e.g., infants safely surrendered shortly after birth). Postvaccination serologic testing should consist of testing for anti-HBs and HBsAg; -HCP and public safety workers at risk for blood or body fluid exposure; -hemodialysis patients (and other persons who might require outpatient hemodialysis), HIV-infected persons, and other immunocompromised persons (e.g., hematopoietic stem-cell transplant recipients or persons receiving chemotherapy), to determine the need for revaccination and the type of follow-up testing; and -sex partners of HBsAg-positive persons, to determine the need for revaccination and for other methods of protection against HBV infection. • Testing should be performed 1-2 months after administration of the final dose of the vaccine series using a method that allows determination of a protective concentration of anti-HBs (≥10 mIU/mL).-Persons found to have anti-HBs concentrations of ≥10 mIU/mL after the primary vaccine series are considered to be immune. -Immunocompetent persons have long-term protection and do not need further periodic testing to assess anti-HBs levels. -Immunocompromised persons might need annual testing to assess anti-HBs concentrations (See Revaccination). -Persons found to have anti-HBs concentrations of <10 mIU/mL after the primary vaccine series should be revaccinated. Administration of all doses in the second series, on an appropriate schedule, followed by anti-HBs testing 1-2 months after the final dose, is usually more practical than serologic testing after one or more doses of vaccine (except for when revaccinating infants born to HBsAg-positive mothers). -Persons who do not have a protective concentration of anti-HBs after revaccination should be tested for HBsAg. -If the HBsAg test result is positive, the person should receive appropriate management, and any household, sexual, or needle-sharing contacts should be identified and vaccinated. Prevaccination testing (consisting of anti-HBc, HBsAg, and anti-HBs) to identify infected persons is recommended for household, sexual, or needle-sharing contacts of HBsAg-positive persons; serologic testing [/table]
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https://www.cdc.gov/hepatitis/hbv/pdfs/prenatalhbsagtesting.pdf
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Summary Hepatitis B virus (HBV) is transmitted via blood or sexual contact. Persons with chronic HBV infection are at increased risk for cirrhosis and liver cancer and require medical care. This report updates and summarizes previously published recommendations from the Advisory Committee on Immunization Practices (ACIP) and CDC regarding the prevention of HBV infection in the United States. ACIP recommends testing all pregnant women for hepatitis B surface antigen (HBsAg), and testing HBsAg-positive pregnant women for hepatitis B virus deoxyribonucleic acid (HBV DNA); administration of HepB vaccine and hepatitis B immune globulin (HBIG) for infants born to HBV-infected women within 12 hours of birth, followed by completion of the vaccine series and postvaccination serologic testing; universal hepatitis B vaccination within 24 hours of birth, followed by completion of the vaccine series; and vaccination of children and adolescents aged <19 years who have not been vaccinated previously. ACIP recommends vaccination of adults at risk for HBV infection, including universal vaccination of adults in settings in which a high proportion have risk factors for HBV infection and vaccination of adults requesting protection from HBV without acknowledgment of a specific risk factor. These recommendations also provide CDC guidance for postexposure prophylaxis following occupational and other exposures. This report also briefly summarizes previously published American Association for the Study of Liver Diseasest guidelines for maternal antiviral therapy to reduce perinatal HBV transmission
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cf1a950abccb734b1dd5a106697c46f5ba1a4d83
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pubmed
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Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition
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Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition
This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition' . The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.
# Introduction
Depression is a highly prevalent mental disease that is prone to recurrence and chronicity, and the WHO forecasted that this disease would be second only to heart disease as a cause of loss of healthy years by 2020. Nevertheless, due to its pathological features, the treatment of depression has not been systematized, but is dependent on the experience of individual pathologists. As an attempt to overcome such circumstances, ceaseless efforts have been made worldwide for the development of an evidence-based clinical practice guideline that would suggest therapeutic recommendations systematically [bib_ref] Kasper S; the Executive Committee for the Korean Medication Algorithm Project for..., Lee [/bib_ref].
The treatment guideline development team judged that the Republic of Korea currently has, at least, the minimum infrastructure needed for producing an evidencebased clinical practice guideline. This decision was based on the improved national environment, in which rapidly growing information and communication networks now provide up-to-date knowledge on treatment, which can be accessed and applied efficiently. In 2005, the Republic of Korea Government began to take note of the seriousness of major depressive disorder (MDD) and realized that a guideline would be essential for the improv ed and systematic treatment of depression, and at last decided to build a national depression clinical research center as a national health and medical treatment technology infrastructure development project. Our research team developed the "Evidence-based, Pharmacological Treatment Guideline for Depression in Korea" in 2008, and developed the "Evidence-based, Non-pharmacological Treatment Guideline for Depression in Korea" in 2010 [bib_ref] Evidence-based, non-pharmacological treatment guideline for depression in Korea, Park [/bib_ref]. Due to the limitations of the initial pharmacological treatment guideline, the accumulation of new clinical information with time, and the emphasis on the importance of a guideline reflecting the current local clinical situation, the "Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition" was released in 2012. In an attempt to inform Korean practitioners of the recommendations made in the revised edition, tients, such as the initiation of antidepressant treatment, efficacy and side effects of treatment, increase in drug dosage, and augmentation, combination, and switching of medication.
## Adaptation process
The clinical practice guideline adaptation manual (version 1.0), which was originally developed by the ADAPTE Collaboration, translated under the official approval of the original Bureau of Clinical Research Support Center, and modified to fit the current clinical environment of Korea, was used for the adaptation and revision of this new guideline. The guideline went through most of the processes proposed in the modified manual.
## Search of treatment guidelines
A comprehensive search of the National Guideline Clearinghouse, NHS Evidence, Guidelines International Network, and PubMed was conducted. 2,526 articles were identified, and among them, only the guidelines prepared by governments, states, or learned societies were selected from the search list. Based on these inclusion criteria, 21 depression treatment guidelines were selected.
## Evaluation of treatment guidelines
The 21 studies on treatment guidelines for depression were selected and evaluated by a working group composed of a psychiatrist, a specialist on preventive medicine, and a clinical psychologist, using the AGREE II Tool. The selected studies were assessed for all of the 6 domains of AGREE II, that is, the scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. The total score was converted to a percentile, and depending on the converted scores, weighted values were assigned as follows: 3 points for a score 60 and above, 2 points for 40 and above but less than 60, 1 point for a score below 40. The points were then summed (with the total of 18 points). Among the studies, 12 articles were found to be of good quality and were finally selected as shown in [fig_ref] Table 1: Twelve clinical practice guidelines for depression Formal title, Development group, Year of... [/fig_ref]. The consistency of the evidence itself, the interpretation of evidence, and the recommendations in each treatment guideline were reviewed. The scientific feasibility of the treatment guidelines was also reviewed and integrated by examining the validity, the standard level and the consistency of the evidence, and the concordance with other treatment guidelines.
## Recommendation grades
Expert panel meetings were held for the selection of recommendation statements. A total of 12 experts participated in the evaluation, scoring each statement on a scale of 1 to 9 (1, most inappropriate and 9, most appropriate). Panel meetings were held face to face after preliminary evaluation, results and problems were reviewed and the recommendations were amended, with a second evaluation taking place [bib_ref] Going from evidence to recommendations, Guyatt [/bib_ref].
## Treatment guideline preparation
Once the content of the adapted treatment guideline was decided upon, all past processes were recorded in the guideline draft in detail. The main principles of the drafting process are as follows: The process is transparent and accurate, the content of reference studies is reflected accurately and the studies are appropriately referenced, and it is acknowledged that the original treatment guideline developers have made great contribution. This guideline was prepared based on these principles.
## External expert review and approval
The guideline draft was reviewed by five experts (peer review), and the results of the reviews were also reflected in this guideline. A public hearing was held to collect the stakeholders' opinions. Finally the approval of the Korean Neuropsychiatric Association was obtained on April 13, 2011.
## Key questions and recommendations
Key question 1. What is the first-line treatment agent among antidepressants?
## Evidence
In order to be considered a first-line antidepressant, the antidepressant must have the same efficacy as tricyclic antidepressants (TCAs), a favorable tolerance level, and a high safety level even when taken in large doses. As there is sufficient evidence that selective serotonin reuptake inhibitors (SSRIs) satisfy these qualifications, the New Zealand guidelines group, National Institute for Health and Clinical Excellence (NICE), British Association for Psychopharmacology (BAP), and the Clinical Research Center for Depression guidelines have strongly recommended SS-RIs as a first-line treatment agent [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. Furthermore, the Canadian Network for Mood and Anxiety Treatments (CAN-MAT), American Psychiatric Association (APA), and Northern Sydney Central Coast Mental Health Drug & Alcohol (NSCC-MHDA) and University of Sydney CADE Clinic guidelines have recommended serotonin and norepinephrine reuptake inhibitors (SNRIs), norepinephrine and dopamine reuptake inhibitors (NDRIs) and norepinephrine and specific serotonergic antidepressants (NaSSAs) as first-line antidepressants [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. TCAs are as effective as SSRIs; however, TCAs have many adverse effects, poor tolerability, and high discontinuation rates. Therefore, TCAs are not recommended as first-line treatment agents [bib_ref] A meta-analysis of the efficacy and tolerability of paroxetine versus tricyclic antidepressants..., Montgomery [/bib_ref] [bib_ref] Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its..., Puech [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref]. However, patients with melancholic depression or patients who have responded well to TCAs previously are recommended to use TCAs as first-line treatment agents.
## Recommendations
SSRIs, SNRIs, NDRIs, and NaSSAs are strongly recommended as first-line treatment agents. However, TCAs are weakly recommended as first-line agents, depending on patient factors and medication costs. The APA guideline described SSRIs as superior in their safety profile and tolerability. The BAP and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines described SSRIs as having better tolerability than TCAs, and having a lower discontinuation rate [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Initial antidepressant choice in primary care: effectiveness and cost of fluoxetine vs..., Simon [/bib_ref] [bib_ref] Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review, Vaswani [/bib_ref]. In addition, the New Zealand guidelines group reviewed 13 studies on the effects of antidepressants and concluded that SSRIs were superior in tolerability to other antidepressants such as TCAs and venlafaxine.
## Recommendations
In patients with low tolerability to antidepressant medication, SSRIs are weakly recommended as a treatment agent.
## Key question 3. what factors influence the choice of antidepressant medication?
## Evidence
The NICE, CANMAT, BAP, Hong Kong, ACP, NSCCMHDA and University of Sydney CADE Clinic, and WFSBP guidelines have recommended considering the potential side effects of the medication and previous history of side effects when on that medication [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The APA, BAP, Hong Kong, ACP, and WFSBP guidelines have recommended considering the preference of and acceptability to the patient [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The CANMAT, APA, Hong Kong, ACP, and WFSBP guidelines have also recommended considering the cost of treatment [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. Furthermore, the CANMAT guideline has also recommended considering the age, sex, severity of the illness, availability of medication, and discontinuation symptoms [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] , while the BAP, NSCCMHDA and University of Sydney CADE Clinic, and WFSBP guidelines have recommended considering adherence to medication and family history of medication [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. Finally, the WFSBP guideline has also recommended considering the physician's experience with a given drug [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref].
## Recommendations
It is strongly recommended that the potential side effects of the medication, patient history of having side effects when taking medication, drug interaction, previous treatment response, preference of and acceptability to the patient, cost of treatment, and co-existing diseases all be considered when selecting antidepressants.
## Recommendations
It is strongly recommended that antidepressants be augmented with antipsychotic medication in psychotic depression.
## Key question 4-3.
Which antidepressant is most efficacious in the treatment of seasonal depression?
## Evidence
The NICE, CANMAT, APA, and BAP guidelines noted that taking bupropion may prevent major depressive episodes in the winter [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. The BAP and WFSBP guidelines have recommended sertraline (28) and fluoxetine [bib_ref] Multicenter, placebo-controlled study of fluoxetine in seasonal affective disorder, Lam [/bib_ref] for the treatment of seasonal depression [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The NICE guideline maintained that evidence on antidepressants being effective in treating seasonal depression is insufficient; however, the evidence supports that antidepressants are effective in preventing depression.
The WFSBP guideline described SSRIs as having efficacy in treating seasonal depression; however, SSRIs take longer to treat symptoms than light therapy and have more side effects [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Multicenter, placebo-controlled study of fluoxetine in seasonal affective disorder, Lam [/bib_ref] [bib_ref] Effects of fluoxetine versus bright light in the treatment of seasonal affective..., Ruhrmann [/bib_ref].
## Recommendations
Although there is not much evidence on the efficacy of antidepressants in the treatment of seasonal depression, SSRIs and bupropion may be weakly recommended as a treatment modality.
The NICE and APA guidelines have described moclobemide as more efficacious than placebo. The NICE guideline reported that an HRSD score improvement of over 50% was superior to placebo. The APA guideline reported that 6 mg per day of transdermal selegiline for 6 weeks was shown to be more efficacious in 177 MDD patients compared to placebo [bib_ref] A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal..., Amsterdam [/bib_ref] [bib_ref] Selegiline transdermal system for the treatment of major depressive disorder: an 8-week,..., Feiger [/bib_ref]. The NICE guideline noted that evidence of tolerability is not sufficient.
## Recommendations
It is strongly recommended that MAOIs are more efficacious than placebo in the treatment of depression.
Key question 5-3. Are SSRIs (including escitalopram) more efficacious than placebo in the treatment of depression?
## Evidence
The New Zealand guidelines group, NICE, APA, BAP, Hong Kong, WFSBP, and Clinical Research Center for Depression guidelines have all described SSRIs to be superior to placebo in treating depression . In particular, the NICE guideline described SSRIs as having greater efficacy than placebo with HDRS improvement of more than 50%, with similar effects in moderate, severe, and extremely severe depression. The BAP guidelines described SSRIs as having a 61% response rate, whereas placebos had a 50% response rate [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. The WFSBP guideline also suggested as evidence, double-blind studies reporting SSRIs as being more efficacious than placebos [bib_ref] Symptom reduction and suicide risk in patients treated with placebo in antidepressant..., Khan [/bib_ref] [bib_ref] Tollefson GD. Meta-analysis of randomised controlled trials of fluoxetine v. placebo and..., Bech [/bib_ref]. However, the NICE guideline described the difference in remission rate to be non-significant, and although a significant difference was shown in moderate and extremely severe depression, the effect was not clinically relevant.
## Recommendations
It is strongly recommended that SSRIs are more efficacious than placebo in the treatment of depression.
## Key question 5-4.
Are SNRIs (venlafaxine, duloxetine) more efficacious than placebo in the treatment of depression?
## Evidence
The NICE and APA guidelines have described duloxetine and venlafaxine as being more efficacious than placebo. Three studies that compared the efficacy of duloxetine and placebo reported duloxetine to be superior, and the effect size was also statistically superior. At the end of treatment, duloxetine seemed to be efficacious in the improvement of HDRS compared to placebo. However, pain associated with depression showed no significant difference. The discontinuation rate at the early stages of treatment was twice as high for duloxetine compared to placebo, but the discontinuation due to ineffectiveness was twice as high for placebo.
## Recommendations
It is strongly recommended that duloxetine and venlafaxine are more efficacious than placebo in the treatment of depression.
## Key question 5-5.
Are NaSSAs (mirtazapine) more efficacious than placebo in the treatment of depression?
## Evidence
The APA and Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines have described mirtazapine as having superior efficacy compared to placebo. A meta-analysis comparing 6 studies reported that when mirtazapine was taken for 6-8 weeks, superior treatment efficacy was observed compared to placebo [bib_ref] Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the..., Bech [/bib_ref]. Furthermore, the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guideline identified mirtazapine as having superior antidepressant effects compared to placebo, based on many doubleblind studies and meta-analyses (level 1).
## Recommendations
It is strongly recommended that mirtazapine is more efficacious than placebo in the treatment of depression.
Key question 5-6. Are NDRIs (bupropion) more efficacious than placebo in the treatment of depression?
## Evidence
The APA and the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines reported bupropion to be more efficacious than placebo. Bupropion showed superior efficacy in the treatment of depression in the acute phase compared to placebo [bib_ref] Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL, Modell [/bib_ref] , and all three forms of bupropion are more efficacious than placebo [bib_ref] 15 years of clinical experience with bupropion HCl: from bupropion to bupropion..., Fava [/bib_ref]. In addition, the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guideline found bupropion to be more efficacious than placebo, based on many double-blind studies (level I).
## Recommendations
It is strongly recommended that bupropion is more efficacious than placebo in the treatment of depression.
## Key question 5-7.
Are serotonin antagonist and reuptake inhibitors (SARIs, trazodone) more efficacious than placebo in the treatment of depression?
## Evidence
The APA and Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines described trazodone as having a superior antidepressant effect over placebo. Trazodone is still widely used, and shows better antidepressant effects compared to placebo [bib_ref] Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the..., Bech [/bib_ref] [bib_ref] Bupropion in depression: a tri-center placebo-controlled study, Pitts [/bib_ref]. Therefore, trazodone is recommended as more efficacious than placebo.
## Recommendations
It is strongly recommended that trazodone is more efficacious than placebo in the treatment of depression.
Key question 6. Is there a difference among the efficacies of antidepressants?
Key question 6-1. When compared to other antidepressants, do TCAs have a different antidepressant efficacy?
## Evidence
The NICE, APA, and BAP guidelines have described amitriptyline to be equal or slightly more effective than other antidepressants (SSRIs, SNRIs, MAOIs) [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. Especially in the case of inpatients, amitriptyline showed a slightly higher efficacy than other TCAs or SSRIs [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref] [bib_ref] Amitriptyline v. the rest: still the leading antidepressant after 40 years of..., Barbui [/bib_ref] [bib_ref] Amitriptyline versus other types of pharmacotherapy for depression, Guaiana [/bib_ref]. In addition, in melancholic depression and severe depression, its efficacy was superior to SSRIs [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref]. However, many side effects have been reported, and treatment can also be terminated due to the side effects.
## Recommendations
It is strongly recommended that TCAs show a similar efficacy to other antidepressants. [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref]. A meta-analysis on 12 reversible inhibitor of MAOA studies reported that moclobemide did not show a difference in efficacy compared to imipramine and clomipramine in admitted patients with severe depression or psychotic depression [bib_ref] Moclobemide and tricyclic antidepressants in severe depression: meta-analysis and prospective studies, Angst [/bib_ref].
## Recommendations
It is strongly recommended that MAOIs show equal efficacy to other antidepressants and moclobemide also shows equal efficacy.
Key question 6-3. When compared to other antidepressants, do SSRIs have a different antidepressive efficacy?
## Evidence
The New Zealand guidelines group, NICE, CANMAT, APA, Hong Kong, and ACP guidelines described SSRIs as having similar antidepressant effects to other agents but better tolerability [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. More than ten meta-analyses have reported SSRIs to be as effective as TCAs [bib_ref] A meta-analysis of the efficacy and tolerability of paroxetine versus tricyclic antidepressants..., Montgomery [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and..., Anderson [/bib_ref] [bib_ref] Fluoxetine versus other types of pharmacotherapy for depression, Cipriani [/bib_ref] [bib_ref] Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants..., Macgillivray [/bib_ref] [bib_ref] Antidepressants versus placebo for depression in primary care, Arroll [/bib_ref] , and many studies have reported that there is not much evidence that other antidepressants are more effective than SSRIs [bib_ref] Fluoxetine versus other types of pharmacotherapy for depression, Cipriani [/bib_ref] [bib_ref] Are SSRIs really more effective for anxious depression?, Panzer [/bib_ref] [bib_ref] SSRIs versus other antidepressants for depressive disorder, Geddes [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors versus tricyclic and heterocyclic antidepressants: comparison of drug..., Barbui [/bib_ref] [bib_ref] Efficacy of escitalopram in the treatment of major depressive disorder compared with..., Kennedy [/bib_ref] [bib_ref] Comparative benefits and harms of second-generation antidepressants: background paper for the American..., Gartlehner [/bib_ref]. Furthermore, the New Zealand guidelines group reported that escitalopram is superior to other SSRIs and venlafaxine [bib_ref] Efficacy of escitalopram in the treatment of major depressive disorder compared with..., Kennedy [/bib_ref]. SSRIs are also relatively safe when taken in large amounts, so they are recommended as a first-line treatment and also to patients with a risk of suicide. However, some studies have reported that SN-RIs are superior to SSRIs in the remission of symptoms [bib_ref] The effect of venlafaxine compared with other antidepressants and placebo in the..., Bauer [/bib_ref].
## Recommendations
It is strongly recommended that SSRIs show similar efficacy to other antidepressants. . The CANMAT guideline described venlafaxine to be superior to duloxetine, fluoxetine, and pooled SSRIs, and duloxetine to be superior to paroxetine and pooled SSRIs [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. The APA guideline reported venlafaxine and duloxetine to be as effective as SSRIs [bib_ref] A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of..., Perahia [/bib_ref] [bib_ref] Efficacy of duloxetine and selective serotonin reuptake inhibitors: comparisons as assessed by..., Thase [/bib_ref]. A few studies have recommended SNRIs as more beneficial than SSRIs [bib_ref] The effect of venlafaxine compared with other antidepressants and placebo in the..., Bauer [/bib_ref]. However, there is evidence that patients taking venlafaxine discontinue the drug due to its side effects. In addition, whereas venlafaxine has proven to have an efficacy equal to TCA, there are not yet systematic studies comparing the efficacy of duloxetine and TCAs [bib_ref] The effect of venlafaxine compared with other antidepressants and placebo in the..., Bauer [/bib_ref] [bib_ref] Efficacy and tolerability of venlafaxine compared with selective serotonin reuptake inhibitors and..., Smith [/bib_ref].
A meta-analysis comparing 105 studies on the difference in efficacy among antidepressants reported that no specific difference exists among the agents.
## Recommendations
It is strongly recommended that SNRIs have a similar antidepressive efficacy compared to other antidepressants.
Key question 6-5. When compared to other antidepressants, do NaSSAs (mirtazapine) have a different antidepressive efficacy?
## Evidence
The NICE, CANMAT, APA, BAP, ACP, WFSBP, Clinical Research Center for Depression, and the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guidelines have described mirtazapine as having equal treatment efficacy to other antidepressants [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The NICE guideline described the possibility of reaching remission and decreasing depressive symptoms was greater compared to SSRIs, but no clinical significance was observed. However, mirtazapine was described to be less prone to early discontinuation compared to other antidepressants. The APA and Clinical Research Center for Depression guidelines described mirtazapine as having earlier onset of treatment efficacy compared to fluoxetine, paroxetine, and sertraline [bib_ref] Meta-analysis of placebo-controlled trials with mirtazapine using the core items of the..., Bech [/bib_ref] [bib_ref] Mirtazapine compared with paroxetine in major depression, Benkert [/bib_ref] , but no significant difference was observed in the response rate. The APA guideline described mirtazapine as having equal efficacy to SSRIs.
## Recommendations
It is strongly recommended that mirtazapine has a similar anti-depressive efficacy as other antidepressants.
Key question 6-6. When compared to other antidepressants, do NDRIs (bupropion) have a different antidepressive efficacy?
## Evidence
The APA guideline described SSRIs to be more effective in patients diagnosed with depression and anxiety compared to bupropion [bib_ref] Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment..., Papakostas [/bib_ref]. However bupropion is effective for symptoms of fatigue and drowsiness and is FDA approved for cessation of smoking, and does not cause too much weight gain.
## Recommendations
Bupropion may be weakly recommended to be effective as other antidepressants.
Key question 6-7. When compared to other antidepressants, do SARIs (trazodone) have a different antidepressive efficacy?
## Evidence
The APA and Clinical Research Center for Depression guidelines reported trazodone to have an efficacy equal to that of TCAs and other antidepressants. However, the CANMAT guideline described trazodone as not having a superior antidepressive efficacy compared to mirtazapine [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] Which antidepressants have demonstrated superior efficacy? a review of the evidence, Montgomery [/bib_ref] , and the APA guideline described trazodone as showing inferior efficacy when treating severe depression or depression with severe psychomotor retardation compared to other antidepressants [bib_ref] Effectiveness of antidepressants: meta-analysis of dose-effect relationships in randomised clinical trials, Bollini [/bib_ref] [bib_ref] A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and..., Rudolph [/bib_ref].
## Recommendations
Trazodone may be weakly recommended to show similar antidepressive efficacy compared to other antidepressants.
## Key question 7.
When is the appropriate time to assess treatment efficacy if symptoms do not improve with antidepressant treatment?
## Evidence
The NICE, CANMAT, and WFSBP guidelines have recommended 2-4 weeks as the appropriate time for assessment, and the BAP, Hong Kong, and Clinical Research Center for Depression guidelines have recommended at least 4 weeks before assessment [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The New Zealand guidelines group and TDMHMR in collaboration with Texas universities guidelines recommended 4-6 weeks, the APA guideline recommended 4-8 weeks, and the ACP guideline recommended 6-8 weeks [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref].
## Recommendations
When there is no improvement or only mild improvement of symptoms (25%), it is strongly recommended that treatment ef- (62). Phenelzine was reported to show an increased treatment response with an increase in dosage in the moderate-to high-dose range [bib_ref] High dose tranylcypromine therapy for refractory depression, Amsterdam [/bib_ref].
## Recommendations
It is strongly recommended that when there is no response to first-line treatment with MAOIs, increasing the dose may help treatment.
Key question 9-3. When treatment with SSRIs (including escitalopram) does not result in a treatment response, does increasing the dosage help achieve treatment response?
## Evidence
The APA guideline reported that a higher dosage of SSRIs is more effective. MDD patients were assigned randomly to 0, 10, 20, 40, or 60 mg/day, and it was reported that the groups taking 10-20 mg showed more improvement than the placebo-treated group, but less improvement than the group taking 40-60 mg [bib_ref] Moclobemide twice daily in the treatment of major depressive episode: a double-blind,..., Gagiano [/bib_ref]. However, the groups taking 20, 30, and 40 mg showed more side effects than the placebo group. The BAP guideline reported 20 mg of escitalopram as having better efficacy than 10 mg (13). On the other hand, the Clinical Research Center for Depression guideline indicated that increasing the dosage of fluoxetine and sertraline in treatment-resistant MDD patients did not significantly improve symptoms compared to maintaining the same dosage in such patients [bib_ref] Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients, Burke [/bib_ref] [bib_ref] Citalopram dose-response revisited using an alternative psychometric approach to evaluate clinical effects..., Bech [/bib_ref]. Furthermore, a previous study reported that an increase in the dosage of paroxetine did not significantly improve symptoms [bib_ref] What constitutes an adequate antidepressant trial for fluoxetine?, Schweizer [/bib_ref].
## Recommendations
It is strongly recommended that when there is no response to (3). The CANMANT guideline also referenced a meta-analysis of 8 randomized controlled trials that reported when switching from SSRIs to other antidepressants, significant differences in treatment efficacy were not shown between antidepressants [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref].
## Recommendations
When patients do not respond to SSRIs, it is strongly recommen-ded that switching to a non-SSRI antidepressant will help treatment.
## Key question 11. how efficacious is the combination treatment of two antidepressants?
Key question 11-1. Is the combination treatment of TCAs and another antidepressant efficacious?
## Evidence
The BAP guideline reported that the combination treatment of amitriptyline and moclobemide was more efficacious than amitriptyline therapy alone [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. The APA guideline reported that the combination treatment of TCAs and SSRIs shows a higher remission rate compared to therapy with either TCAs or SSRIs [bib_ref] Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a..., Nelson [/bib_ref].
## Recommendations
There is strong evidence that when treatment response to firstline therapy is not sufficient, combination treatment with TCAs and another antidepressant is helpful.
## Key question 11-2. is the combination treatment of maois and another antidepressant efficacious?
## Evidence
The NICE and BAP guidelines reported that randomized control trials on the combination treatment of MAOIs and another antidepressant have been insufficient [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]. In particular, the number of controlled trials on the benefits or potential interactions of the combination treatment of TCAs and MAOIs in treatment-resistant depression is insufficient [bib_ref] Combined use of tricyclic antidepressants and monoamine oxidase inhibitors, Lader [/bib_ref].
## Recommendations
When treatment response to first-line therapy is insufficient, the combination treatment of MAOIs and another antidepressant is strongly not recommended.
## Key question 11-3. is the combination treatment of ssris and another antidepressant efficacious?
## Evidence
The APA, BAP, NSCCMHDA and University of Sydney CADE Clinic, Clinical Research Center for Depression, and Hong Kong guidelines have recommended the combination treatment of SSRIs and another antidepressant [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref]. The efficacy of the combination treatment of mirtazapine and SSRIs was proven in a placebo-controlled study [bib_ref] A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine, Carpenter [/bib_ref]. The BAP guideline reported that the combination of reboxetine, bupropion, and TCAs with SSRIs are the most widely used [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref]
## Recommendations
It is strongly recommended that when treatment response to first-line therapy is insufficient, the combination treatment of SSRIs and another antidepressant is helpful.
## Key question 11-4. is the combination treatment of snris and another antidepressant efficacious?
## Evidence
The APA guideline reported that the combination treatment of venlafaxine and mirtazapine will achieve a remission rate of 13.7% in patients that did not previously respond to 3 different medications [bib_ref] Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for..., Mcgrath [/bib_ref]. On the other hand, the Korean Society for Depressive and Bipolar Disorders and Korean College of Neuropsychopharmacology guideline reported that there is not much evidence on the effectiveness of the combination of venlafaxine and SSRIs. Further, when SSRIs that can suppress the metabolism of venlafaxine by CYP2D6 are taken in combination with venlafaxine, the blood level of venlafaxine can increase, and as a result, increased blood pressure, serotonin syndrome, and severe anticholinergic side effects may occur; hence, the combination of the agents must be performed with caution.
## Recommendations
It is strongly recommended that when the treatment response to first-line therapy is insufficient, the combination treatment of SNRIs and another antidepressant is helpful.
## Key question 11-5.
Is the combination treatment of NASSAs (mirtazapine) and another antidepressant efficacious?
## Evidence
The CANMAT, BAP, and Clinical Research Center for Depression guidelines described the combination treatment of mirtazapine or mianserin and other antidepressants (bupropion, venlafaxine, SSRIs, TCAs) as helpful [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref]. The CANMAT and APA guidelines have noted that the combination treatment of mirtazapine and SSRIs was shown to be superior in a placebo-controlled study [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine, Carpenter [/bib_ref].
## Recommendations
It is strongly recommended that when the treatment response to first-line therapy is insufficient, the combination treatment of NaSSAs and another antidepressant is helpful.
Key question 11-6. Is the combination treatment of NDRIs (bupropion) and another antidepressant efficacious?
## Evidence
The CANMAT, APA, BAP, WFSBP, and the Clinical Research Center for Depression guidelines all reported that the combination treatment of bupropion and SSRIs is efficacious [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. When unresponsive to citalopram, bupropion was shown to be superior to buspirone in effectiveness and tolerability when used in combination with citalopram [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The combination treatment of SSRIs and bupropion was also shown to have superior efficacy to either agent used as monotherapy [bib_ref] Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression, Lam [/bib_ref]. The CANMAT guideline noted that many open-label studies and cohort studies have reported bupropion to be efficacious, but randomized controlled trials have not reported such efficacy [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] To combine or not to combine? a literature review of antidepressant combination..., Dodd [/bib_ref].
The New Zealand guidelines group, NICE, APA, TDMHMR in collaboration with Texas universities, and WFSBP guidelines have recommended that adult patients who have responded to antidepressant treatment should continue more than 6 months of antidepressant therapy in order to prevent relapse [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The APA guideline recommended that patients who were successfully treated in the acute phase should continue treatment for 4-9 months. The TDMHMR in collaboration with Texas universities guideline recommended continuing therapy for 6-9 months after remission. The WFSBP guideline recommended continuing therapy for more than 9 months, considering the patient's psychiatric history, and if there are persisting symptoms, treatment should be continued until all symptoms resolve [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref].
## Recommendations
It is strongly recommended that treatment be continued for at least 6 months after remission.
## Key question 13-2.
How long should antidepressant treatment be continued in maintenance therapy?
## Evidence
The Hong Kong, NSCCMHDA and University of Sydney CADE Clinic, WFSBP, and Clinical Research Center for Depression guidelines have recommended that patients with recurrent MDD continue treatment for 3 yr [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. The APA guideline has recommended maintenance therapy for patients who have experienced 3 or more depressive episodes, while the Hong Kong and NSCCMHDA and University of Sydney CADE Clinic guidelines have recommended maintenance therapy of 3-6 months or 1 yr after the first depressive episode [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref].
## Recommendations
It is strongly recommended that maintenance therapy be continued for at least 3 yr for recurrent MDD.
## Key question 14.
What are the withdrawal symptoms of antidepressants and the management of such symptoms?
## Evidence
The NICE, APA, ACP, and NSCCMHDA and University of Sydney CADE Clinic guidelines have described the withdrawal symptoms of antidepressants to include an increase in mood fluctuation (for example, hypersensitivity), gastrointestinal symptoms (nausea), neuromotor abnormalities (ataxia), vasomotor abnormalities (sweating), neurosensory abnormalities (sensory abnormalities), insomnia and other neurological problems [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. The NSCCMHDA and University of Sydney CADE Clinic guideline described general withdrawal symptoms of SS-RIs as flu-like symptoms, a shock-like sensation, dizziness, dreaming excessively, insomnia, and tearing. The general withdrawal symptoms of TCAs were described as flu-like symptoms and insomnia [bib_ref] Clinical practice recommendations for depression, Malhi [/bib_ref]. The APA and ACP guidelines reported that paroxetine may have a long-term discontinuation syndrome, and venlafaxine may have similar symptoms as well [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. Most of the guidelines have recommended a slow tapering down of antidepressants or retaking the previous antidepressant or switching to an antidepressant that has a long half-life.
## Recommendations
It is strongly recommended that antidepressants be tapered slowly as to prevent withdrawal symptoms. When withdrawal symptoms appear, it is strongly recommended that the previous medication be taken again or that an antidepressant in the same line with a longer half-life be administered.
## Key question 15. do antidepressants influence the suicide of mdd patients?
## Evidence
The CANMAT, APA, BAP, Hong Kong, and WFSBP guidelines have reported that there is no clear evidence on whether antidepressants increase suicide-related behaviors in adults [bib_ref] Evidencebased guidelines for treating depressive disorders with antidepressants: a revision of the..., Anderson [/bib_ref] [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] WFSBP Task Force on Unipolar Depressive Disorders. World Federation of Societies of..., Bauer [/bib_ref]. However, suicidal risks may increase in patients under 30 yr old who are receiving initial treatment, and the APA guideline has quoted the results of a meta-analysis reporting that suicidal ideation and rates were statistically 1.5-2.5 times higher in patients 25 yr old and under, compared to control groups. On the other hand, the ACP guideline quoted a meta-analysis reporting no evidence that antidepressants increase suicide risks, but the risk of suicide attempts that are not fatal may increase [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref] [bib_ref] Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug..., Gunnell [/bib_ref].
## Recommendations
Although the evidence that antidepressants increase the suicide rate is insufficient, it is strongly recommended that clinicians show caution in light of the suicide risk of patients 25 yr old and under. [bib_ref] Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the..., Lam [/bib_ref] [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref]. It was also recommended to switch to bupropion when sexual side effects arise from other antidepressants [bib_ref] Strategies for managing antidepressantinduced sexual dysfunction: systematic review of randomised controlled trials, Taylor [/bib_ref]. Furthermore, mirtazapine was reported to cause sexual side effects at a similarly low rate to bupropion. The ACP guideline described paroxetine as causing sexual side effects; however, the exact rate has not yet been reported [bib_ref] Clinical Efficacy Assessment Subcommittee of American College of Physicians. Using second-generation antidepressants..., Qaseem [/bib_ref].
## Recommendations
It is strongly recommended that bupropion be prescribed to patients who complain of sexual side effects, and mirtazapine can also be weakly recommended.
# Discussion
A clinical practice guideline can be defined as a systematic description that helps clinicians and patients choose their health management program in a specific clinical situation. The present guideline was developed to reduce the discrepancies in clinical treatment, inappropriate levels of treatment, and treatment costs by improving the quality of treatment in Korea. Not only the USA and UK, but also Canada, New Zealand, and Singapore are developing their own evidence-based guidelines. Guidelines that have been developed by evidence-based methods are becoming the mainstream treatment modality worldwide for the following reasons: First, given the huge amount of published research these days, no one individual can keep up with the rate of development of medical knowledge; second, treatment recommendations may be contradictory among experts, and if clinical practice is only based on the judgment of the practitioner, different recommendations may be made in the same clinical situation.
In summary, our evidence-based treatment guideline has made certain recommendations considered appropriate to the current clinical situation of Korea [fig_ref] Table 2: http [/fig_ref]. The revised edition of the treatment guideline is considered to comprise new clinical information, and to reflect the current clinical situation of Korea, when compared to the previous version. Furthermore, the Evidence-based, Non-pharmacological Treatment Guideline for Depression in Korea (4) has also been developed, which strengthens the holistic approach of the guidelines to the treatment of depression when used together. The next step for the treatment guideline development team to take may be harmonizing the pharmacological and non-pharmacological treatment guidelines to a single comprehensive guideline, in order to complete the holistic approach to treating depression. Until further development of specific methodologies for the pharmacological treatment of depression is achieved in Korea, we recommend the wide distribution of the Evidence-based Pharmacological Treatment Guideline for Depression in Korea, Revised Edition, so that it is available to all clinical practitioners. The guideline is considered to be helpful when selecting the appropriate pharmacological treatment for MDD patients in Korea.
[table] Table 1: Twelve clinical practice guidelines for depression Formal title, Development group, Year of publication, (Reference number) Abbreviation [/table]
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This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition'. The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended.
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Head and neck melanoma (excluding ocular melanoma): United Kingdom National Multidisciplinary Guidelines
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Head and neck melanoma (excluding ocular melanoma): United Kingdom National Multidisciplinary Guidelines
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the United Kingdom. This paper provides consensus recommendations on the management of melanomas arising in the skin and mucosa of the head and neck region on the basis of current evidence.
# Introduction
Cutaneous melanoma, also known as cutaneous malignant melanoma, is a malignant tumour of neural crestderived cutaneous melanocytes. The incidence of melanoma has been increasing rapidly for the last few decades in most parts of the world. It is the fifth considerable effort expended in raising public and professional awareness over that period. Although melanoma is the major cause of skin cancer mortality, it is usually curable if treated at an early stage. Melanoma in its advanced stages remains largely resistant to currently available treatments, although in the last five years, new targeted biological agents and immunotherapies have offered the potential for improved survival.
## Aetiology and risk factors
Melanomas can arise in pre-existing naevi, or de novo in normal skin. Like most tumours, the aetiology of melanoma is complex and not fully understood. It is, however, thought to be caused by ultraviolet radiation (UVR) in susceptible individuals. It is estimated that around 86 per cent of melanomas in the UK in 2010 were linked to exposure to UVR from the sun and sun-beds. [bib_ref] Cancers attributable to solar (ultraviolet) radiation exposure in the UK in 2010, Parkin [/bib_ref] Fair-skinned individuals who burn easily in the sun, have fair or red hair, and have a tendency to freckle are about three times more likely to develop melanoma. A number of case-control studies conclude that intense burning sun exposure of unacclimatised white skin is a major risk factor for cutaneous melanoma. Migration studies show that exposure to intense UVR at a young age may be particularly important. This is in contradistinction to squamous cell and basal cell carcinomas, which are associated with chronic, long-term sun exposure. Patients with xeroderma pigmentosum have a significantly higher risk of all types of skin cancer, including melanoma, as a result of inability to repair the DNA damage induced by UVR.
## Recommendation
- At-risk individuals should be warned about the correlation between UVR exposure and skin cancer, and should be given advice on UVR protection (R)
While it is understood that melanoma is related to UVR exposure, it is not clear why the body site distribution of melanoma is different to other sun-related cancers such as cutaneous squamous cell carcinoma. This suggests that the pattern of UVR exposure is important, with sites that are intermittently exposed being more at risk than continually exposed sites. The gaps in our knowledge of the aetiology have recently been critically evaluated.
Other risk factors include a large number of banal naevi, a tendency to freckle, and more atypical or dysplastic naevi.About 2 per cent of melanoma patients have a positive family history in one or more first degree relatives. The major melanoma susceptibility gene identified to date is CDKN2A gene. Mutations in this gene are found in 10-30 per cent of melanoma patients with a positive family history. Melanoma is more prevalent in those of high socio-economic status, but the converse applies to mortality.
## Clinical presentation
Cutaneous melanoma is divided into subtypes on the basis of clinical features and pathology.
Superficial spreading melanoma (SSM). This is the most frequently encountered type of melanoma; characteristically an asymmetrical pigmented lesion with irregular borders, irregular pigmentation and sometimes an irregular outline. Patients may have noted growth, a change in sensation and/or colour, crusting, bleeding or inflammation of the lesion. The duration of the symptoms varies from a few months to several years. Nodular melanoma (NM). The second most common type of melanoma is NM. This usually has a shorter presentation and a greater tendency to bleed and/or ulcerate.
Lentigo maligna melanoma (LMM). The next in frequency is the type that occurs most often in sundamaged skin on the head and neck of older patients. This is the only variety that has a clearly recognised and often lengthy pre-invasive (in situ) lesion termed lentigo maligna (LM) before progressing in some instances to an invasive melanoma (LMM).
Acral lentiginous melanoma (ALM). The least common type of melanoma in the UK is the ALM. This occurs on sites, including the palms, soles and beneath the nails. It is the most common melanoma found in African and Asian populations.
Desmoplastic neurotropic melanoma. This type is associated with higher local recurrence than other forms of melanoma. This is thought to be a consequence of its propensity for peri-neural spread. Desmoplastic neurotropic melanoma is predominantly found in the head and neck.
## Assessment and staging
Suspicious pigmented lesions are best examined in a good light with or without magnification and should be assessed using the seven-point checklist [bib_ref] An evaluation of the revised seven-point checklist for the early diagnosis of..., Healsmith [/bib_ref] [fig_ref] TABLE I SEVEN: POINT CHECKLIST FOR PIGMENTED SKIN LESIONS [/fig_ref] or ABCDE systems [fig_ref] TABLE I SEVEN: POINT CHECKLIST FOR PIGMENTED SKIN LESIONS [/fig_ref]. The presence of any major feature in the seven-point checklist, or any of the features in the ABCDE system, is an indication for referral. The presence of minor features should Clinical diagnosis of melanoma can be difficult and the accuracy of diagnosis varies according to a clinician's level of experience, with reports of variation in sensitivity from 50 to 86 per cent. High magnification dermatoscopy is more sensitive than non-dermatoscopic diagnosis, when used by those trained and experienced in the technique. [bib_ref] Is dermoscopy (epiluminescence microscopy) useful for the diagnosis of melanoma? Results of..., Bafounta [/bib_ref] Hand-held (lower magnification) dermatoscopy improves diagnostic accuracy in those trained to be 'expert', but it may decrease diagnostic sensitivity of 'non-expert' or untrained dermatologists.
Diagnostic biopsy. The thickness of cutaneous melanoma greatly influences both its treatment and its prognosis. It is essential, therefore, to obtain a full-thickness biopsy of suspected lesions. Excisional biopsy is the preferred technique, and is aimed at excising the lesion with a 2-5 mm peripheral margin, including a cut-off of subdermal fat. This allows accurate assessment of the tumour thickness and depth of penetration, without transgressing tumour boundaries. Excisional biopsy may not be practical when the lesion is large or located near structures such as an eyelid or lip. Punch biopsy is an alternative where excision biopsy could lead to significant disfigurement. A punch biopsy is usually performed with a 2-4 mm biopsy punch at the thickest or highest part of the lesion. Incisional biopsy is not usually recommended, but the indications are the same as those for punch biopsy. Again, it should be performed at the thickest or highest part of the lesion and must reach the full depth of the lesion
## Recommendations
- Dermatoscopy can aid in the diagnosis of cutaneous melanoma (R) - Histological examination after biopsy is essential to confirm the diagnosis and the tumour thickness (G) - Excisional biopsy is method of choice (G)
Staging. The latest revisions to the staging of cutaneous melanoma were published in the 7th Edition of the American Joint Committee on Cancer (AJCC) in 2009 [fig_ref] TABLE I SEVEN: POINT CHECKLIST FOR PIGMENTED SKIN LESIONS [/fig_ref].Of note, primary tumour mitotic rate (mitoses/mm 2 ) is now considered an important independent prognostic indicator, with an inverse correlation between mitotic rate and survival. The mitotic rate replaces Clark's level of invasion as a primary criterion for separating T1 tumours into T1a and T1b.
Anatomical staging Imaging considerations. Staging investigations for regional lymph node metastases are often performed, and may comprise computed tomography (CT), magnetic resonance imaging (MRI), and/or ultrasound, depending upon local protocols. The use of scans to detect distant metastasis is indicated in patients with high-risk melanoma (stages IIC, IIIB, IIIC and stage IIIA with a macroscopic sentinel lymph node), and in patients with new All other visceral metastases Normal Any distant metastases Elevated * Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed) † Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension symptoms, anaemia, elevated lactate dehydrogenase or a chest X-ray abnormality. Computed tomography scanning is used for the evaluation of potential metastatic sites in the lungs, bones, liver and lymph nodes. Imaging of the brain is recommended in patients with stage IV, but is optional in stage III disease. Positron emission tomography (PET)-CT is more accurate than CT or MRI alone in the diagnosis of metastases. It should complement conventional CT and MRI imaging in patients who have distant metastases and where surgical resection is being considered.
## Recommendations
- Staging investigations can be performed for both regional and distant disease (R) - Scanning (CT and/or MRI) is recommended for patients with high-risk melanoma (G) - Patients with signs or symptoms of disease relapse should be investigated by imaging (R) - Imaging of the brain should be performed in patients who have stage IV disease (G)
Unknown primary. The patient presenting with regional or visceral metastatic melanoma of unknown primary (MUP) origin should be seen by a dermatologist for a skin examination, an ophthalmologist for examination of the eye, and a head and neck surgeon for visualisation of the upper aerodigestive tract. Staging investigations should be carried out, including PET-CT to detect occult metastases. In 10-20 per cent of patients with regional or visceral melanoma metastases, the primary melanoma is never found. Such patients should be treated as if they have regional or visceral metastases from a known primary melanoma. [bib_ref] Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma, Lee [/bib_ref] It has been suggested that the most likely explanation for MUP is immune-induced regression of the primary tumour, and this may be the reason for the slightly better outcomes in such patients.
## Recommendation
- Patients with a melanoma of unknown primary origin should be thoroughly examined and investigated for a potential primary source (R)
## Management
Surgery for primary disease Wide local excision. This remains the most effective treatment for primary cutaneous melanoma. [bib_ref] Revised UK guidelines for the management of cutaneous melanoma 2010, Marsden [/bib_ref] The optimal width of excision margins has been contentious. [bib_ref] Surgical excision margins for primary cutaneous melanoma, Sladden [/bib_ref] [bib_ref] Primary mucosal melanoma of head and neck: prognostic value of clear margins, Penel [/bib_ref] Current treatment guidelines are based on a relatively small number of prospective randomised trials. [bib_ref] 2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than..., Gillgren [/bib_ref] [bib_ref] Excision margins in high-risk malignant melanoma, Thomas [/bib_ref] [bib_ref] Long term results of a randomized study by the Swedish Melanoma Study..., Cohn-Cedermark [/bib_ref] The current recommended excision margins for cutaneous melanoma in the UK are as follows:
- [fig_ref] TABLE I SEVEN: POINT CHECKLIST FOR PIGMENTED SKIN LESIONS [/fig_ref] Any
[formula] T N > N0 M0 IIIA T1-4a N1a M0 T1-4a N2a M0 IIIB T1-4b N1a M0 T1-4b N2a M0 T1-4b N1b M0 T1-4b N2b M0 T1-4b N2c M0 IIIC T1-4b N1b M0 T1-4b N2b M0 T1-4b N2c M0 Any T N3 M0 IV [/formula]
Any T Any N M1 IV Any T Any N M1 * Clinical staging includes microstaging of the primary melanoma and clinical and/or radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases † Pathological staging includes microstaging of the primary melanoma and pathological information about the regional lymph nodes after partial or complete lymphadenectomy. Pathological stage 0 or IA patients are the exception; they do not require pathological evaluation of their lymph nodes It should be stressed that these recommendations are for cutaneous melanomas in all body sites; in the head and neck region, anatomical restrictions and cosmetic considerations may preclude even a 1 cm margin. In these circumstances, however, the width of excision should remain uniform. For example, if a clear margin of only 8 mm is possible near to an eyelid or an ear, the rest of the peripheral surgical margins should also be 8 mm.
## Recommendations
- Primary cutaneous invasive melanoma should be excised with a surgical margin of at least 1 cm (G) - The maximum recommended excision margin is 3 cm (R) - The actual margin of excision depends upon the depth of the melanoma and its anatomical site (G)
Mohs micrographic surgery (MMS). Mohs micrographic surgery may have a role in the primary treatment of cutaneous melanoma of the head and neck, especially that of the face. [bib_ref] Mohs micrographic surgery for the treatment of malignant melanoma, Whalen [/bib_ref] There is growing evidence of the efficacy of MMS in comparison to traditional surgery but the majority of reports compare MMS with historical controls. Further study, in the form of prospective comparative trials, is required before firm recommendations can be made regarding the use of MMS.
Reconstruction. When possible, the surgical defect after wide local excision should be closed primarily. If primary closure is not possible, reconstruction by local flaps or skin grafts will be required. Local flaps are the preferred option when the surgical defect is on the face, because of a superior aesthetic outcome. Rarely, distant flaps will be required for complex or very large surgical defects. If there is any doubt as to the adequacy of surgical clearance, definitive reconstruction should be delayed pending histological confirmation.
Surgery for regional disease The regional lymph node basin in head and neck cutaneous melanoma comprises the nodes found in the parotid gland (superficial portion), neck levels I-V, the occipital nodes, mastoid nodes and pre-auricular nodes. There may be clinically apparent lymphadenopathy, representing metastatic melanoma, or occult metastases in the head and neck nodes.
Clinical lymphadenopathy. When patients present with a neck mass or a radiologically identified suspicious node(s) a tissue diagnosis should be obtained. The preferred stepwise diagnostic algorithm to follow is: (1) palpable lymph node in the neck or radiologically identified suspicious node; (2) ultrasound-guided or clinically-guided FNA; (3) ultrasound-guided core biopsy; (4) open biopsy. Fine needle aspiration is more accurate when performed with ultrasound guidance, and this should be subsequently performed if a clinically guided FNA is non-diagnostic. If an open biopsy is performed, the incision should be placed in a manner which permits subsequent excision of the biopsy tract if a neck dissection is necessary. If metastatic melanoma is confirmed, lymphadenectomy of the involved nodal basin should be performed.
The extent of lymphadenectomy performed for melanoma is determined by the location of the primary, the location of the neck disease, and the general fitness of the patient. If parotid lymphadenopathy is present, a neck dissection should also be performed as a high proportion of patients with parotid lymph node involvement will have occult cervical metastases. If neck disease is present without parotid involvement then the location of the primary should be considered. If the draining basin of that primary site is likely to pass through the parotid gland, a concomitant superficial parotidectomy should be considered. It is reasonable to perform a selective neck dissection for some melanoma sites that have metastasised to the neck when there is low volume, mobile lymphadenopathy. For example, omitting excision of level IA and IB neck nodes for a well-lateralised occipital melanoma would be accepted management.
## Recommendations
- Ultrasound-guided FNA or core biopsy of suspected lymphadenopathy is more accurate than 'blind' biopsy (R) - Open biopsy should only be performed if FNA or core biopsy is inadequate or equivocal (R) - Prior to lymph node dissection, staging by CT scan should be carried out (R) - If parotid disease is present without neck involvement, both parotidectomy and neck dissection should ideally be performed (R) - If neck disease is present without parotid involvement, parotidectomy should be considered if the lymphatic drainage of the primary site is likely to have passed through the parotid gland (R)
Occult lymph nodal disease. The most accurate means of staging the regional lymph nodes in head and neck melanoma is by sentinel lymph node biopsy (SLNB). This staging tool has a learning curve and involves the administration of a radiocolloid into the site of the excision biopsy. Pre-operative lymphoscintigraphy identifies the approximate location of the sentinel nodes and the intra-operative use of blue dye and a gamma probe aids in location of the sentinel node(s). The removed sentinel nodes are histologically examined with multiple sections and immunohistochemical stains for the presence of occult metastases. Sentinel lymph node biopsy identification of regional lymph node metastasis should be followed by lymphadenectomy of the at-risk nodal basin. Whether or not SLNB is performed for staging the regional lymph nodes is a matter for local policy. Sentinel lymph node biopsy provides highly accurate staging information but there is controversy as to whether or not it improves disease-specific survival. The long-term results of the Multicentre Selective Lymphadenectomy Trial-I (MSLT-I) indicate that SLNB is associated with improved disease-free survival for patients with intermediate thickness (1.2-3.5 mm) and thick (≥3.5 mm) melanomas, [bib_ref] Final trial report of sentinel-node biopsy versus nodal observation in melanoma, Morton [/bib_ref] but this has been questioned in a recent editorial in the British Medical Journal. [bib_ref] Where is the evidence base for benefits of sentinel node biopsy in..., Thomas [/bib_ref] Furthermore, there is the question of biological false-positivity. [bib_ref] Prognostic false-positivity of the sentinel node in melanoma, Thomas [/bib_ref] Some clinical trials require information on disease stage and an SLNB can provide this information. Sentinel lymph node biopsy has replaced elective lymph node dissection in melanoma and there are few indications to perform the latter.
The Options Grid Collaborative, based at Dartmouth University, is an organisation which attempts to improve shared decision-making between healthcare professionals and patients, their carers and families. They produced, in collaboration with the National Institute for Health and Care Excellence, three tools to try and help patients with practical decisionmaking in managing melanoma. These can be found at http://optiongrid.org
## Recommendations
- There is no role for elective lymph node dissection (R) - Sentinel lymph node biopsy can be considered in stage IB and above by specialist skin cancer multidisciplinary teams (G) - Patients should be made aware that sentinel lymph node biopsy is a staging procedure, and should understand that it has, as yet, no proven therapeutic value (R)
Metastatic disease. Distant melanoma metastases occur preferentially and earliest in intra-abdominal organs, liver, lung, brain and bone. Whilst these are the commonest sites, metastases to almost every organ and tissue have been reported.
Distant metastases can be divided into two groups: metastases already established at presentation of the primary (stage IV disease) and metastases that subsequently become apparent. Metastases at presentation carry the worst prognosis, while for delayed metastases the prognosis improves in direct proportion to the time taken for the metastasis to develop. In practice the questions to be addressed are what, if any, improvement in survival time may be gained from treatment of metastatic disease and what symptomatic improvement will occur?
Treating metastases in patients with distant metastases confirmed at presentation (stage 4 disease) has proved very disappointing. Survival rates in such individuals have not improved over the last two decades.
Resection of late-appearing metastases to non-liver intra-abdominal organs or gastro-intestinal mucosa yields the best improvement with a disease-free survival in the region of 23 months compared with a median survival of only 12 months if untreated. [bib_ref] Clinical outcome after surgical resection of lung metastases from melanoma, Conill [/bib_ref] Patients undergoing surgical resection of late-appearing metastatic melanoma to the liver also have improved disease-free survival compared with untreated patients. [bib_ref] Liver resection and ablation for metastatic melanoma: a single center experience, Doussot [/bib_ref] [bib_ref] A 20-year experience of hepatic resection for melanoma: is there an expanding..., Faries [/bib_ref] Surgical resection of pulmonary metastases and solitary brain metastases from melanoma may yield a survival advantage of a few months more than any other method of dealing with these lesions. Stereotactic radiosurgery (SRS) for brain metastases also offers some patients extended survival. Early treatment of spinal cord secondaries can preserve mobility. Bone metastases are associated with short survival irrespective of treatment.
Biological markers have been studied extensively in metastatic melanoma with regard to prognosis and as a guide to resectability of metastases. Of these, lactate dehydrogenase (LDH) and the c-kit mutation may be helpful. A high serum LDH level suggests a large disease burden and a poor result from treatment of metastases.
Aggressive surgical treatment of distant metastases from melanoma at any site must be carried out on highly selected patients and, even then, it is best regarded as a palliative procedure, usually improving survival by only a matter of months. Nevertheless, quite long remissions may be obtained in fit patients with apparently solitary, or oligometastatic, disease.
## Non-surgical treatment
Primary tumour. There is no established role for primary radiotherapy (RT) (instead of surgery) in the management of early stage (stages Ia, b and IIa, b, c) malignant melanoma, other than in elderly patients with extensive facial LMM. It is unlikely that this situation will change in the foreseeable future. Similarly, chemotherapy, biological agents and immunotherapy have no proven place in the management of early stage melanoma. [bib_ref] Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma, Sasse [/bib_ref] Regional disease. In patients with stage III (nodal) or IV (M1) disease, the prognosis is significantly worse. Surgery remains the key initial treatment with the goal of securing local control, even in the setting of metastatic disease. There is no established role for RT O A AHMED, C KELLY S138 in the management of patients with micrometastatic nodal disease (N1a, N2a). These patients are treated with surgery alone (±entry into studies of adjuvant systemic therapies). Recent adjuvant trials in malignant melanoma have included those testing immunotherapies (interferon, interleukin-2, peptide gp100:209-217(210 M), Canvaxin TM ) and anti-angiogenic agents, such as bevacizumab (Avastin). [bib_ref] Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma, Sasse [/bib_ref] For patients with macrometastatic nodal disease (N1b, N2b), there is no consensus that RT is beneficial following surgery, but for patients with cervical lymph node disease it is frequently used. There is no currently defined role for chemoradiation in this setting. The findings of the Phase III TROG 02.01 trial suggest that entry to an adjuvant systemic therapy trial may be a preferable alternative to adjuvant RT. [bib_ref] Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at..., Henderson [/bib_ref] Distant metastases. Patients with established metastatic melanoma are treated with palliative intent and should be referred to specialist melanoma units.
The chemotherapy management options for metastatic melanoma have greatly expanded in the last five years with the introduction of biologically targeted agents. [bib_ref] Rapid evolution of combination therapy in melanoma, Curti [/bib_ref] About 50 per cent of melanomas show a mutation in the BRAF gene, with valine substituted for glutamate at codon 600, and this mutation is known as V600E or V600K. If this mutation is present then patients will have a 60-70 per cent chance of responding to a BRAF inhibitor drug such as vemurafenib 23 or dabrafenib. Those patients who develop the most slowly but continued response to these BRAF inhibitors appear to achieve a more sustained response when compared with those patients who develop a very rapid tumour clearance. One potential sideeffect of these drugs, which must be monitored, is the development of squamous cell carcinoma of the skin.
The second major advance in the management of metastatic melanoma was the introduction of immunotherapy. Ipilimumab is a monoclonal antibody which targets cytotoxic T lymphocyte-associated protein 4 (CTLA-4) which is a protein receptor which can be made to switch off cytotoxic T lymphocytes (CTLs) by melanoma cells. Ipilimumab removes this brake on the immune response and allows the CTLs to recognise and destroy melanoma cells. This agent's efficacy does not depend on the patient's BRAF status. Although the response rate is only 15-20 per cent, in those patients who do show a response this can be sustained for some considerable time. There are hopes that some patients may have even been cured but follow-up has generally not been long enough to establish this.
There is much interest in metastatic melanoma at present, with numerous trials underway, especially in combining targeted therapies where by blocking two different steps in the same pathway a much greater melanoma cell kill may result. Another drug which blocks a specific pathway target is trametinib which is a MEK inhibitor. When combined with dabrafenib, there is both a progression free survival benefit and an overall survival benefit. Another MEK inhibitor cobimetinib, shows benefit when given with vemurafenib, when compared with giving vemurafenib alone.
Nivolamab is also a novel agent. It is a programmed death 1 (PD-1) checkpoint inhibitor which also shows complimentary benefit in metastatic melanoma when given together with ipilimumab, compared with each drug alone and this is now proposed as a standard of care in those patients who have wild-type BRAF, i.e. not showing a BRAF mutation. If this regimen does become standard of care it may not remain so for very long as the field is advancing so quickly.
For patients who become refractory to ipilimumab, and to the BRAF and MEK inhibitors there is a further new agent pembrolizumab, which targets the PD-1 receptor, and can extend progression-free survival.
Palliative RT is often used in metastatic disease (stages IV, M1a-c). Radiotherapy dose fractionation is non-standard in most of these treatments. Commonly used regimens include 8 Gy single fraction, 20 Gy in five fractions, 30 Gy in six fractions (alternate days), the latter fractionation being used most commonly for all brain RT for brain metastasis, and a host of local variations in different RT departments. There is no accepted role for the use of concomitant chemotherapy (although temozolomide has been tested with RT in cerebral metastases). There is emerging evidence that SRS can be beneficial in those patients who have a small number of brain metastases, usually less than three, where very focused high-dose RT can be given to the metastases, with very little dose to the surrounding brain.
## Recommendations
- All patients with cutaneous melanoma should have their original tumour checked for BRAF status, and their subsequent targeted biological therapy based on this (R) - Patients who develop brain metastases should be considered for stereotactic radiosurgery (R)
## Mucosal melanoma (upper aerodigestive tract)
Introduction Mucosal melanoma of the upper aerodigestive tract is a rare malignancy with a poor prognosis. Management recommendations are based upon retrospective case series, few of which exceed 100 patients. Mucosal melanoma accounts for less than 1 per cent of all melanomas, and less than 10 per cent of all head and neck melanomas. The median age of patient presentation is the sixth decade, but case reports span the age range. The function of melanocytes in mucosa is uncertain. The most common sites of head and neck mucosal melanoma are the nasal and oral cavities. Pharyngeal, laryngeal and oesophageal melanomas are exceedingly rare. Melanocytes in the nasal cavity can be found in the respiratory epithelium, nasal glands, nasal septum, and the middle and inferior turbinates. In oral mucosa, melanocytes are located along the tips and peripheries of the rete pegs. Unlike cutaneous melanoma, no risk factors for the development of this disease have been identified, though cigarette smoke and other air pollutants may play a role. It is thought that a preceding atypical melanocytic hyperplasia occurs in a significant proportion.
## Clinical presentation
Sinonasal melanoma presents in the same way as other sinonasal malignancies and is primarily influenced by site of origin. Nasal obstruction, followed by discharge and bleeding, predominates. The commonest site is the anterior portion of the nasal septum. Oral mucosal melanoma most often presents as a painless mass, which may or may not be pigmented. Ulceration and bleeding are also common. The majority occur on the alveolar gingiva and palate.
## Assessment and staging
Endoscopic assessment and imaging, as appropriate to the primary site, is necessary, following which staging is performed [fig_ref] TABLE V TNM: STAGING SYSTEM FOR MUCOSAL MELANOMAS I-Primary tumour [/fig_ref].
## Management
The prevailing opinion is that localised disease is best managed with primary surgery which aims to achieve clear surgical margins. [bib_ref] Primary mucosal melanoma of head and neck: prognostic value of clear margins, Penel [/bib_ref] Craniofacial resection for skull base extension from sinonasal melanoma is associated with poor survival and is seldom justified. Radical surgical excision involving severe functional deficits should not be performed in the context of established metastatic disease.
Reports indicate high rates of local recurrence (31-85 per cent), regional recurrence, and distant metastasis (25-50 per cent) as well as poor five-year survival rates (13-48 per cent), and a median survival of less than two years, for head and neck mucosal melanoma. The predominant mode of treatment failure is local recurrence, and this usually occurs within a year of initial treatment. It is frequently accompanied by the appearance of regional and distant metastases. Distant metastasis is associated with short survival time.
While the view of mucosal melanoma as a 'radioresistant' tumour has been challenged, the role of post-operative RT remains unclear. Its use has been reported to improve local control. Short-course, hypofractionated schedules (e.g. 30 Gy in six fractions over two weeks, 50 Gy in 20 fractions), to relatively small volumes, compared with other head and neck practice are frequently employed. Adjuvant chemotherapy and biological therapeutic strategies have been employed with encouraging response rates. For metastatic disease, unfortunately only a tiny percentage of mucosal melanomas show a BRAF mutation; therefore it is usually not appropriate to use BRAF inhibitors, so chemotherapy in the form of biological agents has to depend on immunotherapy with ipilimumab 24 or the newer agents such as pembrolizumab, although to date there has been no specific study of the latter agent's efficacy specifically in mucosal melanoma.
## Key points
- Cutaneous melanoma is the fifth commonest cancer in the UK; the incidence of melanoma doubled in the three decades following 1970 - Despite widely used checklists, the clinical diagnosis of melanoma can be difficult and a biopsy is needed for diagnosis - The thickness of cutaneous melanoma greatly influences both its treatment and its prognosis - Staging includes microstaging of the primary melanoma and clinical/radiological evaluation for metastases - Mucosal melanoma is a poor prognostic disease - Wide local excision, with appropriate margins based on the thickness of the tumour, with or without lymph node dissection of the involved nodal basins, is the mainstay of treatment for primary cutaneous melanoma - Excision of localised mucosal melanoma with clear margins is the mainstay of treatment, but radical excision with functional compromise has not shown oncological benefits. Advances in immunotherapy have revolutionised the management of distant metastases Deep soft tissue, cartilage, bone, overlying skin T4b
Brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, mediastinal structures N-Regional lymph nodes NX Regional lymph nodes cannot be assessed N0
No regional lymph node metastasis N1
Regional lymph node metastasis
[table] TABLE I SEVEN: POINT CHECKLIST FOR PIGMENTED SKIN LESIONS [/table]
[table] TABLE II THE: ABCDE CHECKLIST FOR PIGMENTED SKIN LESIONS [/table]
[table] TABLE III TNM: STAGING SYSTEM FOR CUTANEOUS MELANOMA [/table]
[table] TABLE IV CLINICAL: AND PATHOLOGICAL STAGING FOR CUTANEOUS MELANOMASClinical staging * Pathological staging † [/table]
[table] TABLE V TNM: STAGING SYSTEM FOR MUCOSAL MELANOMAS I-Primary tumour [/table]
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Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the United Kingdom. This paper provides consensus recommendations on the management of melanomas arising in the skin and mucosa of the head and neck region on the basis of current evidence. Recommendations • At-risk individuals should be warned about the correlation between ultraviolet radiation (UVR) exposure and skin cancer, and should be given advice on UVR protection. (R) • Dermatoscopy can aid in the diagnosis of cutaneous melanoma. (R) • Histological examination after biopsy is essential to confirm the diagnosis and the tumour thickness. (G) • Excisional biopsy is method of choice. (G) • Staging investigations can be performed for both regional and distant disease. (R) • Scanning (computed tomography (CT) and/or magnetic resonance imaging) is recommended for patients with high-risk melanoma. (G) • Patients with signs or symptoms of disease relapse should be investigated by imaging. (R) • Imaging of the brain should be performed in patients who have stage IV disease. (G) • Patients with melanoma of unknown primary should be thoroughly examined and investigated for a potential primary source. (R) • Primary cutaneous invasive melanoma should be excised with a surgical margin of at least 1 cm. (G) • The maximum recommended excision margin is 3 cm. (R) • The actual margin of excision depends upon the depth of the melanoma and its anatomical site. (G) • Ultrasound-guided fine needle aspiration (FNA) or core biopsy of suspected lymphadenopathy is more accurate than ‘blind’ biopsy. (R) • Open biopsy should only be performed if FNA or core biopsy is inadequate or equivocal. (R) • Prior to lymph node dissection, staging by CT scan should be carried out. (R) • If parotid disease is present without neck involvement, both parotidectomy and neck dissection should ideally be performed. (R) • There is no role for elective lymph node dissection. (R) • Sentinel lymph node biopsy (SLNB) can be considered in stage IB and above by specialist skin cancer multidisciplinary teams. (G) • Patients should be made aware that SLNB is a staging procedure, and should understand that it has, as yet, no proven therapeutic value. (R) • All patients with cutaneous melanoma should have their original tumour checked for BRAF gene status, and their subsequent targeted biological therapy based on this. (R) • Patients who develop brain metastases should be considered for stereotactic radio-surgery. (R)
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Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines
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Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines
Childhood renal osteodystrophy (ROD) is the consequence of disturbances of the calcium-regulating hormones vitamin D and parathyroid hormone (PTH) as well as of the somatotroph hormone axis associated with local modulation of bone and growth cartilage function. The resulting growth retardation and the potentially rapid onset of ROD in children are different from ROD in adults. The biochemical changes of ROD as well as its prevention and treatment affect calcium and phosphorus homeostasis and are directly associated with the development of cardiovascular disease in pediatric renal patients. The aims of the clinical and biochemical surveillance of pediatric patients with CRF or on dialysis are prevention of hyperphosphatemia, avoidance of hypercalcemia and keeping the calcium phosphorus product below 5 mmol 2 /l 2 . The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2-3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.
# Introduction
Chronic renal failure is associated with specific abnormalities of skeletal homeostasis, commonly called renal osteodystrophy (ROD), which if not treated appropriately during the critical phases of skeletal growth can result in bone deformities and a disturbed growth pattern. The main factors for the development of ROD are disturbances in the calcium phosphate homeostasis, in vitamin D and parathyroid hormone metabolism as well as alterations in the somatotroph axis, i.e., on the endocrine and paracrine levels. In recent years it has been recognized that the spectrum of renal bone disease covers 'high-' as well as 'low-turnover' conditions. As a consequence of chronic renal failure itself and of the treatment of renal bone disease, high plasma phosphate levels and an elevated calcium phosphorus product are common. These are important risk factors for the development of vascular calcification and cardiovascular morbidity and mortality in young adults who have been on renal replacement therapy since childhood [bib_ref] Coronary-artery calcification in young adults with end-stage renal disease who are undergoing..., Goodman [/bib_ref] [bib_ref] Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal..., Oh [/bib_ref]. Because aluminium-containing phosphate binders are no longer indicated in children, aluminium-related osteopathy is not considered in these recommendations.
The European Pediatric Peritoneal Working Group (EPPWG) was established in 1999 by pediatric nephrologists with a major interest in peritoneal dialysis and has, among others, published guidelines on chronic and acute peritoneal dialysis [bib_ref] European Paediatric Peritoneal Dialysis Working Group Guidelines by an Ad Hoc European..., Watson [/bib_ref] [bib_ref] The choice of dialysis solutions in pediatric chronic peritoneal dialysis: guidelines by..., Schröder [/bib_ref] [bib_ref] European Paediatric Peritoneal Dialysis Working Group (2002) Guidelines by an ad hoc..., Fischbach [/bib_ref] [bib_ref] The choice of dialysis solutions in chronic peritoneal dialysis: guidelines by an..., Schröder [/bib_ref]. The group incorporates pediatric nephrologists from 12 European countries. One of the functions of the group is to establish expert guidance in important clinical areas associated with chronic renal failure and dialysis [now the European Pediatric Dialysis Working Group (EPDWG)] in conjunction with other members of the multidisciplinary team. These guidelines were initiated and discussed at meetings of the group and developed by e-mail discussion to develop consensus of opinion based upon cumulative clinical experience and reported studies.
## Recommendations
## Recommendation 1
Clinical, biochemical and radiological markers of renal bone disease should be monitored regularly. The clinical markers of renal bone disease to be prevented are signs of overt rickets, slipped femoral epiphysis and disturbances of growth. The biochemical markers are plasma phosphate, calcium, alkaline phosphatase, bicarbonate and intact parathyroid hormone (PTH). The minimal frequency of measurements (and target ranges) for biochemical markers in a stable phase vary according to renal function [fig_ref] Table 1: Frequency of measurements for biochemical and radiological markers of renal osteodystrophy [/fig_ref]. If the patient has active ROD, additional blood samples may be required.
Plasma calcium must be adjusted for albumin levels (= corrected calcium) or by measuring ionized (free) calcium, in patients with hypoalbuminemia or acid-base disorders. Ionized calcium values are often available on blood gas analysis systems with calcium-sensitive electrodes, but correct values are only obtained in validated conditions. Alkaline phosphatase as a marker for osteoblast activity has particular importance in both low and high-turnover bone disease with elevated or low alkaline phosphatase serum levels, respectively.
PTH should be monitored monthly in advanced CRF (GFR <15 ml/min/1.73m 2 ) because of its rapid changes. Different assays are available for the measurement of PTH. In principle, intact PTH(1-84) (iPTH) should be measured because it is believed to represent the active hormone. For this purpose, two-site assays were developed at the end of the 1980s [bib_ref] Measurement of intact human parathyrin by an extracting twosite immunoradiometric assay, Blind [/bib_ref]. However, PTH fragments accumulating in end-stage renal disease may also show biological activity. Furthermore, recent research using plasma samples from healthy and renal patients analyzed by HPLC and the iPTH assay demonstrated cross-reactivity of the intact PTH-assay with a PTH-fragment (PTH7-84). Therefore, new assays were developed that detect only PTH molecules with a complete N-terminal end, called "whole-PTH" assays [bib_ref] Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid..., Gao [/bib_ref]. In adult and pediatric dialysis patients, these "whole PTH" assays yielded 30-60% lower PTH levels than the intact PTH assay. Despite theoretical considerations, no significant improvement in the distinction between the different forms of renal bone disease using the "whole PTH" assays has yet been demonstrated in clinical practice [bib_ref] Influence of PTH assay methodology on differential diagnosis of renal bone disease, Reichel [/bib_ref] [bib_ref] Parathyroid hormone and its fragments in children with chronic renal failure, Waller [/bib_ref] [bib_ref] Similar predictive value of bone turnover using first-and second-generation immunometric PTH assays..., Salusky [/bib_ref] [bib_ref] Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy, Martin [/bib_ref]. Radiological signs of renal bone disease, which alone are not sensitive enough to indicate therapy-adaptations, include signs of hyperparathyroidism and growth zone lesions. Periosteal resorption zones and metaphyseal changes are the most obvious signs. In late adolescent and young adult patients, Looser zones as specific signs of osteomalacia may be found. The sites and expression of bone lesions are age-dependent according to the age-dependent growth and remodeling at different sites of the skeleton. In pre-school children, the metaphysis of the distal radius and ulna may present only minor abnormalities, whereas more severe lesions may be seen at the upper and lower femoral epiphysis. Adynamic bone disease shows no specific radiological changes. However, extraosseous calcifications, fractures or osteopenia may indicate adynamic bone disease.
Histological evaluation of bone biopsy specimens remain the "gold standard" in assessment of renal osteodystrophy. However, due to its invasive nature, bone biopsies are not performed in clinical practice, but they remain an important tool for research [bib_ref] Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy, Martin [/bib_ref].
## Recommendation 2
Metabolic acidosis should be corrected (evidence). Chronic metabolic acidosis leads to increased bone resorption and inhibits endochondral bone formation in animal experiments [bib_ref] Optimal correction of acidosis changes progression of dialysis osteodystrophy, Lefebvre [/bib_ref] [bib_ref] Histologic and dynamic change induced by chronic metabolic acidosis in the rat..., Carbajo [/bib_ref]. Infants with isolated chronic metabolic acidosis show growth retardation [bib_ref] Histologic and dynamic change induced by chronic metabolic acidosis in the rat..., Carbajo [/bib_ref]. In adult hemodialysis patients, negative aspects of chronic metabolic acidosis on metabolism have been reported [bib_ref] Nutrition, acid-base status and growth in early childhood, Kalhoff [/bib_ref]. Therefore, metabolic acidosis should be corrected by a stepwise approach: The first step is optimization of the dialysis regimen both for HD-and PD-patients [bib_ref] The choice of dialysis solutions in pediatric chronic peritoneal dialysis: guidelines by..., Schröder [/bib_ref] [bib_ref] Nutrition, acid-base status and growth in early childhood, Kalhoff [/bib_ref]. Since the introduction of HCO 3 -based PD solutions [bib_ref] Metabolic acidosis of chronically hemodialyzed patients, Kovacic [/bib_ref] , metabolic acidosis is a less frequent problem. In combination with a daytime-dwell, patients may even be at risk for alkalosis [bib_ref] Clinical experience with a 39 mmol/l bicarbonate-buffered peritoneal dialysis solution, Feriani [/bib_ref]. However, if these adaptations do not result in correction of the metabolic acidosis, sodium bicarbonate should be administered orally. Whenever possible, formulations that dissolve in the small intestine should be used. The use of sodium citrate increases the risk of aluminium absorption [bib_ref] Calcium citrate markedly enhances aluminum absorption from aluminum hydroxide, Coburn [/bib_ref]. Acidosis should be corrected to the normal range of the local laboratory.
## Recommendation 3
The plasma-phosphate level should be kept within the normal age-specific range (evidence). In children with chronic renal failure, hyperphosphatemia is observed at GFR levels below 40 ml/min/1.73m 2 [bib_ref] Nutrition and growth in relation to severity of renal disease in children, Norman [/bib_ref] and almost always in children on dialysis. Hyperhosphatemia has several deleterious effects on PTH secretion [bib_ref] The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in..., Slatopolsky [/bib_ref] [bib_ref] Parathyroid hormone gene expression in hypophosphatemic rats, Kilav [/bib_ref] , parathyroid cell proliferation [bib_ref] Parathyroid cell proliferation in normal and chronic renal failure rats. The effects..., Naveh-Many [/bib_ref] and soft tissue (vascular) calcification [bib_ref] Coronary-artery calcification in young adults with end-stage renal disease who are undergoing..., Goodman [/bib_ref] [bib_ref] Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal..., Oh [/bib_ref].
Increased phosphate levels stimulate PTH secretion in vitro [bib_ref] Glucose charged dialysate for children on hemodialysis: acute dialytic changes, Almaden [/bib_ref] and in vivo [bib_ref] The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in..., Slatopolsky [/bib_ref] independent of calcium and 1,25(OH) 2 vitamin D 3 levels. This effect of phosphate on PTH secretion occurs via post-transcriptional processes by regulating pre-pro-PTH mRNA stability . Furthermore, a reduction of serum-phosphate results in a parallel reduction of PTH levels without change in serum calcium . Hyperphosphatemia accelerates parathyroid cell proliferation [bib_ref] Parathyroid cell proliferation in normal and chronic renal failure rats. The effects..., Naveh-Many [/bib_ref] , which can result in nodular hyperplasia and severe hyperparathyroid bone disease necessitating parathyroidectomy (see below).
Increased plasma phosphate levels have a profound effect on soft tissue and vascular calcification, which are often observed in young patients on or even after dialysis [bib_ref] Coronary-artery calcification in young adults with end-stage renal disease who are undergoing..., Goodman [/bib_ref] [bib_ref] Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal..., Oh [/bib_ref] , increasing the risk of cardiovascular morbidity and mortality. found an increased risk of death for serum phosphate exceeding 2.09 mmol/l in adult patients; other studies described a much lower phosphate level (~1.4-1.6 mmol/l) at which a higher incidence of calcifications was found [bib_ref] Coronary-artery calcification in young adults with end-stage renal disease who are undergoing..., Goodman [/bib_ref]. The histology of the calcification pattern is quite distinct from the process of atherosclerosis. In renal patients, extensive calcification of the tunica media occurs even after short periods of dialysis, as shown by investigations of the epigastric artery in adult patients . Experimental work gave evidence for an active role of phosphate in this process as phosphate induces osteoblastic marker followed by calcification in cultured smooth muscle cells . Dialysis patients are at risk of heart failure. Although this is a multifactorial process, it was demonstrated in animal experiments that high plasma phosphate levels per se accelerated cardiac fibrosis [34].
## Recommendation 4
If plasma phosphate is elevated, phosphate intake should be limited to the recommended levels. Dietary intake of protein and as a consequence of phosphate in western countries usually exceeds the recommended intake at least in adolescent dialysis patients. Therefore, dietary counseling should be performed by a trained dietician . If the dietary records show a protein intake above the recommended level for pediatric dialysis patients, the patients and their parents should be trained to reduce their phosphate intake. This may start with the reduction of dairy products and/or substitution with special low-phosphorus products and a reduction of meat intake.
## Recommendation 5
In case of hyperphosphatemia, the dialysis efficacy should be optimized (evidence). Phosphate is slowly transported via the peritoneal membrane into the dialysate . The dialysate to plasma ratio (D/P) for phosphate is volume and time related; after 4 h in standard peritoneal equilibration tests, this ratio reaches the value of 0.5-0.6, which is a much lower ratio than for urea, which is usually nearly 1. Therefore, an increase in phosphate removal should consider not only an increase in dwell volume to 1,000-1,400 ml/m 2 BSA, but also dwell time optimization, avoiding a too short dwell time. A daytime dwell should be added. The details of a dialysis regimen optimization has been described elsewhere [bib_ref] European Paediatric Peritoneal Dialysis Working Group (2002) Guidelines by an ad hoc..., Fischbach [/bib_ref]. However, due to the low clearance of phosphate achievable even with an optimized PD regimen, dietary phosphate restriction and the use of oral phosphate binders are almost always necessary.
The dialytic phosphate removal kinetic during a hemodialysis session differs from urea kinetic: after an early initial drop the phosphatemia decrease only slowly . Therefore, it is admitted that the hemodialysis phosphate purification capacity is directly impacted by the duration of the dialysis session, because the phosphate shift from the intracellular to the vascular compartment is time-dependent. Therefore, longer dialysis sessions
## Recommendation 6
For control of hyperphosphatemia, aluminium-free phosphate binders should be administered (evidence). Phosphate binders are necessary to reduce phosphate absorption from the gut. Ca-containing phosphate binders, i.e., calcium carbonate (CaCO 3 , elemental calcium content 40%) or calcium acetate (CaAc, elemental calcium content 25%) should be used as the first line. No data are published on the efficacy and safety of calcium acetate/ magnesium carbonate compound phosphate binders in pediatric patients. The upper intake level of elemental calcium is suggested to be 2,500 mg/day for healthy children above 4 years of age. Whereas for adult dialysis patients the DOQI guidelines suggest to limit the elemental calcium intake to 2,000 mg/day, no safe upper level can be given for the pediatric age band. However, a positive calcium balance in the range of +200-+300 mg in the growing skeleton should be maintained. In contrast, a too high calcium load should be avoided, because one of the identified risk factors for soft tissue calcification in pediatric CRI patients was cumulative calcium intake [bib_ref] Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal..., Oh [/bib_ref] [bib_ref] Glucose charged dialysate for children on hemodialysis: acute dialytic changes, Almaden [/bib_ref].
Calcium-containing phosphate binders are started at approximately 500 mg per 200 mg phosphate content of the diet (0-1 years, 1-2500 mg; 1-4 years, 2-3500 mg/ day; 5-8 years, 3-4500 mg/day; 9-18 years, 5500 mg). An alternative approach is a start dose of approximately 50 mg/kg/day, which is well below the doses given in clinical studies. Phosphate binders are then adjusted to normalize serum-phosphate and calcium. CaCO 3 can be crushed to fine powder, or a 10% solution can be used for administration in infants, often via a feeding tube. The phosphate binders should be taken with meals, because fecal excretion of phosphate was higher when calcium acetate was given with meals instead of in between meals [bib_ref] Effect of the time of administration of calcium acetate on phosphorus binding, Schiller [/bib_ref]. Biochemically, CaAc has a higher phosphate binding capacity, which is independent of the pH. The higher efficacy of CaAc, calculated on a weight basis compared to CaCO 3 , for phosphate control was also shown in clinical practice in adult and pediatric patients [bib_ref] Calcium acetate versus calcium carbonate as oral phosphate binder in pediatric and..., Wallot [/bib_ref] [bib_ref] Calcium acetate versus calcium carbonate as phosphate-binding agents in chronic haemodialysis, Pflanz [/bib_ref]. Unfortunately, compliance of the patients with the intake of phosphate binders is often poor and should be checked regularly. It may be helpful if the patient is involved in selecting the flavor and size of the phosphate binder and has regular contact with the dietician at clinic appointments. Snacks during the day are often a source of additional phosphate and require additional phosphate binders.
Patients treated with Ca-containing phosphate binders and active vitamin D metabolites are particularly at risk for the development of hypercalcemia. Therefore, in case of hypercalcemia, active vitamin D metabolites should be stopped (see recommendation 12). If hypercalcemia, the most common side-effect of Ca-containing phosphate binder therapy, persists or the calcium phosphorus product exceeds 5.0 mmol 2 /l 2 with the use of Ca-containing phosphate binders, the calcium content in the dialysis fluid should be reduced [bib_ref] European Paediatric Peritoneal Dialysis Working Group (2002) Guidelines by an ad hoc..., Fischbach [/bib_ref]. Furthermore, the dose of the calcium-containing phosphate binders should be reduced whenever possible or they should be replaced by Ca-and aluminium-free phosphate binders, because epidemiological studies have shown a direct relationship between serum phosphate and calcium phosphorus product on mortality [bib_ref] Death risk in hemodialysis patients: the predictive value of commonly measured variables..., Lowrie [/bib_ref]. The only commercially available aluminium-and calcium-free phosphate binder is Sevelamer. This compound is usually taken orally as capsules, but anecdotally can be delivered via enteral tubes by dissolving the capsule in 5 ml water (instruction Fa genzyme). Aluminium-containing phosphate binders or calcium citrate increase intestinal aluminium absorption and should not be used in pediatric dialysis patients. An alternative phosphate binder that is available is lanthanum carbonate, which has a high affinity for phosphate, and is minimally absorbed in the intestine. In a randomized study in adult patients, lanthanum carbonate controlled plasma phosphate levels well and induced less adynamic bone disease than CaCO 3 [bib_ref] A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium..., D'haese [/bib_ref]. However, no long-term data on the effect of lanthanum on bone, on which surface lanthanum can accumulate [bib_ref] Incorporation of 140-lanthanum into bones, teeth and hydroxyapatite, Fernandez-Gavarron [/bib_ref] , and its safety profile for use in children are available yet.
## Recommendation 7
Vitamin D deficiency should be avoided (evidence). In early renal failure, an increase of PTH correlates positively with 25(OH)-vitamin D 3 levels [bib_ref] Calcium metabolism in early chronic renal failure: implications for the pathogenesis of..., Reichel [/bib_ref]. Renal synthesis of 1,25(OH) 2 D 3 is impaired in chronic renal dis-ease. However, extrarenal cells, i.e., macrophages and osteoblasts, are also capable of 1,25(OH) 2 D 3 production [bib_ref] Extrarenal production of calcitriol in chronic renal failure, Dusso [/bib_ref]. In contrast to the kidney, the extra-renal synthesis is strictly substrate dependent. It has been shown that supplementation with vitamin D 3 in elderly CRF patients with 25(OH)-vitamin D 3 levels between 20 and 50 pg/ml decreased PTH serum concentrations [bib_ref] Serum vitamin D concentrations among elderly people in Europe, Van Der Wielen [/bib_ref]. Furthermore, 25-OH-vitamin D 3 , but not 1,25(OH) 2 D 3 , improved muscular function and phosphate content [bib_ref] 25-hydroxycholecalciferol stimulation of muscle metabolism, Birge [/bib_ref]. Therefore, vitamin D deficiency should be prevented.
## Recommendation 8
Marked hyperparathyroidism should be prevented in children with CRF prior to dialysis (evidence). Due to the risk of persisting bone disease and the development of parathyroid adenoma, an increase in PTH above normal to slightly elevated levels should be prevented in children with CRF. Therefore, low doses of active vitamin D metabolites should be given in time. In adult patients this treatment regimen has resulted in controlled iPTH without negative aspects [bib_ref] Low-dose calcitriol prevents the rise in 1,84-iPTH without affecting serum calcium and..., Ritz [/bib_ref]. In children with moderate renal failure (GFR >30 ml/min/1.73 m 2 ), normal levels of PTH in association with strictly controlled phosphate levels are associated with a normal ratio of intact PTH to "whole" PTH and normal levels of alkaline phosphatase, indicating a physiological PTH secretion and unremarkable bone turnover [bib_ref] Parathyroid hormone and its fragments in children with chronic renal failure, Waller [/bib_ref]. In such patients, slight catch-up growth with PTH levels at the upper limit of normal was reported [bib_ref] Catch-up growth with normal parathyroid hormone levels in chronic renal failure, Waller [/bib_ref]. In a sub-group analysis, improved growth was restricted to patients with enteral feeding tubes.
## Recommendation 9
PTH levels should be kept at two to three times the upper limit of the normal range in end-stage renal disease (evidence). Grossly elevated PTH concentrations (>four times the upper normal range) in the presence of normal or high serum calcium and high alkaline phosphatase are almost always associated with high-turnover bone disease [bib_ref] Catch-up growth with normal parathyroid hormone levels in chronic renal failure, Waller [/bib_ref] [bib_ref] Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD, Salusky [/bib_ref]. The exception is intermittent therapy with high-dose active vitamin D metabolites, because 1,25(OH) 2 vitamin D 3 directly inhibits osteoblastic function and proliferation. Hyperphosphatemia can occur in hyperparathyroid bone disease because of excessive bone resorption.
However, in pediatric dialysis patients low and even normal levels of PTH are reported to be associated with low turnover bone disease [bib_ref] Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD, Salusky [/bib_ref]. A PTH concentration higher than in healthy subjects is needed to stimulate bone turnover due to resistance of the skeleton to PTH in advanced renal failure. If PTH falls into the (low) normal range, the risk of hypercalcemia increases [bib_ref] Correlation among markers of renal osteodystrophy in pediatric hemodialysis patients, Piscitelli [/bib_ref]. Hyperphosphatemia and hypercalcemia can develop in low turnover bone disease because the skeleton is unable to take up enough phosphate and calcium. Low bone turnover or adynamic bone disease is increasingly observed in adult [bib_ref] Is intermittent oral calcitriol safe and effective in renal secondary hyperparathyroidism?, Klaus [/bib_ref] as well as in pediatric PD patients [bib_ref] Catch-up growth with normal parathyroid hormone levels in chronic renal failure, Waller [/bib_ref]. Risk factors for adynamic bone disease are high calcium intake (Ca-containing phosphate binders), therapy with high doses of active vitamin D metabolites, peritoneal dialysis using dialysis fluid with high calcium content and age (adolescents after the growth spurt). Biochemically, hypercalcemia and/or PTH levels within or below the normal range are indicative of low turnover bone disease [bib_ref] Catch-up growth with normal parathyroid hormone levels in chronic renal failure, Waller [/bib_ref] [bib_ref] Correlation among markers of renal osteodystrophy in pediatric hemodialysis patients, Piscitelli [/bib_ref] , which may adversely affect growth in dialysed children [bib_ref] Frequency of adynamic bone disease and aluminum storage in Italian uraemic patients-retrospective..., Ballanti [/bib_ref]. Therefore, active vitamin D therapy should be reduced or stopped if PTH falls below the low normal range [bib_ref] Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD, Salusky [/bib_ref] [bib_ref] Is intermittent oral calcitriol safe and effective in renal secondary hyperparathyroidism?, Klaus [/bib_ref] [bib_ref] Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD, Kuizon [/bib_ref]. If PTH remains below normal despite normal calcium and phosphate levels, the dialysate should be changed to low calcium solutions (1.0 or 1.25 mmol/l) to stimulate PTH secretion [bib_ref] Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD, Kuizon [/bib_ref] , if this is not already used as the standard solution [bib_ref] European Paediatric Peritoneal Dialysis Working Group (2002) Guidelines by an ad hoc..., Fischbach [/bib_ref].
## Recommendation 10
If PTH is elevated in children with CRF or if PTH is elevated more than two to three times normal in the presence of Pi <2 mmol/l in dialyzed children, active vitamin D metabolites should be administered orally (evidence). Treatment with active vitamin D metabolites results in biochemical and/or histological improvement in patients with high-turnover bone disease. Doses of 1,25(OH) 2 vitamin D 3 or 1a-(OH) vitamin D 3 usually range from 0.1 g/day to 0.75 g/day, with a starting dose of 20-40 ng/kg. High doses often induce hypercalcemia, necessitating the reduction or discontinuation of vitamin D therapy (see hypercalcemia).
As to the mode of administration of the active vitamin D metabolites, intravenous or oral therapy, have the same efficacy [bib_ref] Calcitriol pulse therapy is not more effective than daily calcitriol therapy in..., Ardissino [/bib_ref]. Therefore, the oral route should be preferred in children on dialysis. Doses should be given in the evening, because fewer episodes of hypercalcemia have been reported compared to taking the vitamin D metabolites in the morning [bib_ref] Chronotherapy of high-dose active vitamin D3 in haemodialysis patients with secondary hyperparathyroidsm:..., Tsuruoka [/bib_ref]. Intermittent therapy was shown to be effective to suppress elevated PTH serum levels [bib_ref] Is intermittent oral calcitriol safe and effective in renal secondary hyperparathyroidism?, Klaus [/bib_ref]. However, recent data indicate that large intermittent 1,25(OH) 2 vitamin D 3 doses adversely affect bone turnover [bib_ref] Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD, Salusky [/bib_ref] [bib_ref] Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD, Kuizon [/bib_ref] [bib_ref] Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol..., Goodman [/bib_ref] and chondrocyte activity [bib_ref] Intermittent and continuous exposure to 1,25(OH)2D3 have different effects on growth plate..., Klaus [/bib_ref] resulting in low turnover bone disease and in reduced growth [bib_ref] Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol..., Goodman [/bib_ref] [bib_ref] Intermittent and continuous exposure to 1,25(OH)2D3 have different effects on growth plate..., Klaus [/bib_ref] [bib_ref] Daily but not pulse calcitriol therapy improves growth in experimental uremia, Mehls [/bib_ref] [bib_ref] Growth in children with chronic renal failure on intermittent versus daily calcitriol, Schmitt [/bib_ref]. In addition, episodes of hypercalcemia occur with similar frequency with the intermittent or oral administration of vitamin D metabolites [bib_ref] Calcitriol pulse therapy is not more effective than daily calcitriol therapy in..., Ardissino [/bib_ref] [bib_ref] No difference in intestinal strontium absorption after oral or IV calcitriol in..., Ardissino [/bib_ref] ; furthermore, the intermittent mode of administration was not shown to be more effective in suppressing PTH levels in adult [bib_ref] Comparison of intermittent and continuous oral administration of calcitriol in dialysis patients:..., Herrmann [/bib_ref] and pediatric [bib_ref] Calcitriol pulse therapy is not more effective than daily calcitriol therapy in..., Ardissino [/bib_ref] patients in prospective, randomized trials. For the above mentioned reasons, intermittent high-dose vitamin D therapy should be avoided in pediatric patients.
Three newer vitamin D analogs, so called "non-hypercalcemic" vitamin D analogs (doxercalciferol, paricalcitol and 22-oxa-calciferol), have been introduced in clinical use in adult patients with secondary hyperparathyroidism due to CRF. Despite their ability to induce less hypercalcemia in animal experiments, only one clinical study with a head-to-head comparison of the new vitamin D analogue (paricalcitol) is available demonstrating a borderline reduction of hypercalcemia or a decrease in calcium phosphorus product [bib_ref] Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism, Sprague [/bib_ref]. No data are available for their use in children.
Agents that specifically enhance the sensitivity of the calcium-sensing receptor, called calcimimetics, used in combination with active vitamin D metabolites in adult dialysis patients resulted in a persistent decrease of PTH levels without elevated calcium phosphorus product [bib_ref] Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis, Block [/bib_ref]. If plasma Ca or Pi is high in the presence of elevated PTH, the calcimimetics may become first choice. However, no data for pediatric patients are available.
## Recommendation 11
Treatment with growth hormone should not be started in the presence of severe hyperparathyroid bone disease. It is well established that the uremic growth retardation is at least in part due to disturbed pulsatile secretion of growth hormone as well as a peripheral growth hormone resistance [bib_ref] Derangements of the somatotropic hormone axis in chronic renal failure, Tönshoff [/bib_ref]. After correction of metabolic acidosis and normalization of caloric intake, administration of recombinant human growth hormone increases growth velocity resulting in catch-up growth and in improved final height [bib_ref] Effect of growth hormone treatment on the adult height of children with..., Haffner [/bib_ref]. Growth hormone directly stimulates growth cartilage proliferation and metabolism and osteoblast activity [bib_ref] Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal..., Wang [/bib_ref] [bib_ref] Regulation of bone mass by growth hormone, Olney [/bib_ref]. This growth promoting effect of GH was suspected to increase the metaphyseal instability induced by severe hyperparathyroidism. In hyperparathyroid bone disease, i.e., osteitis fibrosa, a fibrous layer is formed at the metaphyseal junction of the growth plate with the bone tissue. This can lead to epiphyseal slipping resulting in gross deformities of the affected long bones [bib_ref] Slipped capital femoral epiphysis associated with renal failure osteodystrophy, Loder [/bib_ref]. Therefore, parathyroid hormone, as well as calcium and phosphate levels, should be treated towards the recommended normal ranges prior to administration of GH. However, in a recent prospective study, no increased frequency of epiphyseal slipping associated with the use of growth hormone was reported [bib_ref] Adverse events with rhGH treatment of patients with chronic renal insufficiency and..., Fine [/bib_ref]. After the start of GH administration, an increase of PTH levels was observed [bib_ref] Recombinant human growth hormone treatment of children on hemodialysis, Berard [/bib_ref] [bib_ref] Parathyroid hormone levels in pubertal uremic adolescents treated with growth hormone, Picca [/bib_ref].
## Recommendation 12
In case of hypercalcemia, active vitamin D metabolites and calcium-containing phosphate binders should be stopped and dialysate changed to low calcium solutions (evidence). Hypercalcemia and elevated calcium phosphorus product (>5.0 mmol 2 /l 2 ) should be corrected promptly [fig_ref] Figure 1: Clinical algorithm for treatment of elevated calcium phosphorus product in children with... [/fig_ref]. Vitamin D metabolites should be discontinued and in case of persisting hypercalcemia the dialysate calcium decreased to low calcium dialysate. Laboratory values should be controlled weekly until improvement is seen. One exception is hypercalcemia due to severe hyperparathyroidism and high-turnover bone disease. In addition, in patients with residual renal function, loop diuretics, i.e., furosemide may increase calcium excretion. If hypercalcemia is not corrected despite the discontinuation of active vitamin D metabolites, calciumcontaining phosphate binders should be replaced by calcium-free phosphate binders to reduce the calcium load. Hypercalcemia is reported in up to 25% of patients taking calcium-containing phosphate binders [bib_ref] Coronary-artery calcification in young adults with end-stage renal disease who are undergoing..., Goodman [/bib_ref] , see recommendation 6).
## Recommendation 13
The calcium phosphorus product should be kept within the normal range, at least below 5.0 mmol 2 /l 2 (60 mg 2 / dl 2 ) (evidence). One of the risk factors for cardiovascular Ca-free calcium-free; phos-binder phosphate binder; vit D vitamin D; ADBD adynamic bone disease morbidity was shown to be an elevated calcium phosphorus product above 5.0 mmol 2 /l 2 (see also recommendation 2). If the calcium phosphorus product is elevated above this level, phosphate and/or calcium levels should be reduced. This may be achieved by an increase in phosphate binders, reduction/stopping of active vitamin D metabolites and use of low calcium (Ca ++ 1.0-1.25 mmol/ l) dialysate.
## Recommendation 14
Parathyroidectomy has to be considered in case of severe, therapy-refractory hyperparathyroidism with radiological signs in combination with hypercalcemia and/or elevated calcium phosphorus product (evidence). Severe hyperparathyroidism may no longer react to even high doses of 1,25(OH) 2 vitamin D 3 and reduction of phosphate levels.
The clinical observations in adults show that patients with at least one parathyroid gland larger than 0.5 cm 3 or 1.0 cm in diameter usually do not respond to active vitamin D metabolites [bib_ref] Serial evaluation of parathyroid size by ultrasonography is another useful marker for..., Fukagawa [/bib_ref] [bib_ref] Relationship between parathyroid gland size and responsiveness to maxacalcitol therapy in patients..., Okuno [/bib_ref]. Therefore, persisting grossly elevated PTH levels in the presence of high-dose active vitamin D metabolites, radiological signs of hyperparathyroidism on wrist X-ray and/or high serum calcium and normal phosphate and/or elevated calcium phosphorus product indicate the need for surgical parathyroidectomy. Medical parathyroidectomy by alcohol injection was described in adult patients [bib_ref] Prognosis of parathyroid function after successful percutaneous ethanol injection therapy guided by..., Kakuta [/bib_ref] , but to our knowledge not in pediatric patients. Parathyroid hormone stimulates bone turnover and regulates calcium homeostasis, both of which are of utmost importance in the growing skeleton. Therefore, subtotal parathyroidectomy or autotransplantation of parathyroid tissue is recommended in children or adolescents, avoiding hypoparathyroidism [bib_ref] Management of disturbed calcium metabolism in uraemic patients: 2. Indications for parathyroidectomy, Schömig [/bib_ref] , review). However, these procedures carry the risk of recurrence of severe parathyroid tissue hyperplasia. The use of the new calcimimetic agents [bib_ref] The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of..., Quarles [/bib_ref] may help to prevent the most severe hyperparathyroidism and therefore modify the approach to that condition.
[fig] Figure 1: Clinical algorithm for treatment of elevated calcium phosphorus product in children with CRF. Ca-cont calcium containing; [/fig]
[table] Table 1: Frequency of measurements for biochemical and radiological markers of renal osteodystrophy [/table]
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Guidelines for Transrectal Ultrasonography-Guided Prostate Biopsy: Korean Society of Urogenital Radiology Consensus Statement for Patient Preparation, Standard Technique, and Biopsy-Related Pain Management
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Guidelines for Transrectal Ultrasonography-Guided Prostate Biopsy: Korean Society of Urogenital Radiology Consensus Statement for Patient Preparation, Standard Technique, and Biopsy-Related Pain Management
The Korean Society of Urogenital Radiology (KSUR) aimed to present a consensus statement for patient preparation, standard technique, and pain management in relation to transrectal ultrasound-guided prostate biopsy (TRUS-Bx) to reduce the variability in TRUS-Bx methodologies and suggest a nationwide guideline. The KSUR guideline development subcommittee constructed questionnaires assessing prebiopsy anticoagulation, the cleansing enema, antimicrobial prophylaxis, local anesthesia methods such as periprostatic neurovascular bundle block (PNB) or intrarectal lidocaine gel application (IRLA), opioid usage, and the number of biopsy cores and length and diameter of the biopsy needle. The survey was conducted using an Internet-based platform, and responses were solicited from the 90 members registered on the KSUR mailing list as of 2018. A comprehensive search of relevant literature from Medline database was conducted. The strength of each recommendation was graded on the basis of the level of evidence. Among the 90 registered members, 29 doctors (32.2%) responded to this online survey. Most KSUR members stopped anticoagulants (100%) and antiplatelets (76%) one week before the procedure. All respondents performed a cleansing enema before TRUS-Bx. Approximately 86% of respondents administered prophylactic antibiotics before TRUS-Bx. The most frequently used antibiotics were third-generation cephalosporins. PNB was the most widely used pain control method, followed by a combination of PNB plus IRLA. Opioids were rarely used (6.8%), and they were used only as an adjunctive pain management approach during TRUS-Bx. The KSUR members mainly chose the 12-core biopsy method (89.7%) and 18G 16-mm or 22-mm (96.5%) needles. The KSUR recommends the 12-core biopsy scheme with PNB with or without IRLA as the standard protocol for TRUS-Bx. Anticoagulants and antiplatelet agents should be discontinued at least 5 days prior to the procedure, and antibiotic prophylaxis is highly recommended to prevent infectious complications. Glycerin cleansing enemas and administration of opioid analogues before the procedure could be helpful in some situations. The choice of biopsy needle is dependent on the practitioners' situation and preferences.
# Introduction
Transrectal ultrasound-guided prostate biopsy (TRUS-Bx) is a standard test for the preoperative diagnosis of prostate cancer and is currently performed widely by radiologists and urologists. In a study of urologists in the United Kingdom, Lee et al. [bib_ref] Trans-rectal ultrasound guided biopsy of the prostate: nationwide diversity in practice and..., Lee [/bib_ref] reported numerous differences in the number of biopsy cores, protocols for prebiopsy antibiotic prophylaxis, prebiopsy enemas, and local anesthesia methods among institutions and physicians. In addition, 68% of doctors believe that their training for TRUS-Bx is insufficient [bib_ref] Trans-rectal ultrasound guided biopsy of the prostate: nationwide diversity in practice and..., Lee [/bib_ref]. In Korea, 12-core biopsy is thought to be widespread at present, but there are variations among operators with respect to the local anesthesia method, prebiopsy antibiotic use, opioid use, and other aspects during TRUS-Bx. However, guidelines for the aforementioned subjects do not yet exist. In the meeting of the Korean Society of Urogenital Radiology (KSUR) in May 2018, the members of the KSUR discussed the actual situations and opinions of the members on topics such as patient preparation and the medicines and methods used for local anesthesia. In this brief article, a consensus report of the aforementioned discussion will be presented with a review of the related literature.
# Materials and methods
## Composition of the clinical guideline development group
The KSUR convened a subcommittee consisting of one committee chief and two secretaries for guideline development in 2017. All KSUR members were included as official members of the committee.
## Topic refinement and the ksur survey
The subcommittee created several preliminary questionnaires and surveyed the members who attended the regular KSUR monthly meeting in May 2018. Based on these results and feedback, the final questionnaire items were confirmed through discussion with the subcommittee chairman, secretaries, and KSUR president. The survey was conducted using the "Naver Form" survey platform (https:// office.naver.com as "Naver form" official site, http://naver. me/50qC8iGw as our survey page [in Korean]) on January 7, 2019, through January 24, 2019, and responses were solicited from the 90 members registered on the KSUR mailing list as of 2018 (Supplementary Materials). kjronline.org
## Consensus achievement
The Delphi method was used for formal consensus in accordance with previously published guidelines [bib_ref] Korean clinical imaging guideline for hemoptysis, Kang [/bib_ref]. Twenty-six council members of the KSUR, including some of the subcommittee members, were asked to provide their level of agreement with each draft recommendation using a voting scale of 1-9 during the regular monthly meeting of the KSUR in March 2019 (where 1 denoted strong disagreement and 9 denoted strong agreement). Each voting score was allocated to one of three groups: 1-3 (disagreement), 4-6 (neutrality), and 7-9 (agreement). Consensus was defined as ≥ 75% of participants providing a score within the 7-9 range (agreement).
## Summary of literature review with consensus statements
The following recommendations for patient preparation, standard technique, and biopsy-related pain management during TRUS-Bx are summarized in [fig_ref] Table 3: Summary of KSUR GuidelinesAnticoagulants and anti-platelet agents should be discontinued at least... [/fig_ref].
## Patient preparation
## Anticoagulation: stop or continue before biopsy?
Bleeding appears as hematuria, rectal bleeding, or hematospermia, and is a common complication of TRUS-Bx; bleeding has been reported in as many as 84% of patients who undergo TRUS-Bx (5). Thus, antiplatelet medications (aspirin, clopidogrel, nonsteroidal anti-inflammatory drugs , and so on) and anticoagulation medications (heparin, warfarin, and so on) are generally required to be administered before TRUS-Bx to lower the risk of bleeding complications [bib_ref] CUA guidelines on prostate biopsy methodology, El-Hakim [/bib_ref]. The Canadian Urologic Association guideline on prostate biopsy methodology recommends that antiplatelet agents be stopped 1 to 2 weeks before TRUS-Bx and that anticoagulants be stopped 4 to 5 days prior [bib_ref] CUA guidelines on prostate biopsy methodology, El-Hakim [/bib_ref]. The Society of Interventional Radiology Consensus guideline for Periprocedural Management of Coagulation Status and Hemostasis Risk in Percutaneous Image-guided Interventions (SIR guidelines) [bib_ref] Standards of Practice Committee, with Cardiovascular and Interventional Radiological Society of Europe..., Patel [/bib_ref] stratifies percutaneous interventional procedures into three categories according to the risk of bleeding, difficulty of detection, and control of bleeding: Category 1, procedures with a low risk of bleeding or where any bleeding is easily detected and controllable; Category 2, procedures with a moderate risk of bleeding; and Category 3, procedures with a significant risk of bleeding that is difficult to detect and control. Most intra-or retroperitoneal biopsies are classified as Category 2 according to SIR guidelines, and TRUS-Bx may also be classified in this category. The SIR guidelines suggest a 5-day course of regular-dose aspirin, clopidogrel, and warfarin before Category 2 procedures with confirmation that the PT-INR is under 1.5 and the platelet count is over 50000/μL (or correction to these values).
Patients who continue taking low-dose aspirin without interruption do not show a significant increase in hemorrhage or hematuria after TRUS-Bx (9, 10). For warfarin, no statistically significant difference has been reported in the severity of postbiopsy bleeding between patients who were continuously administered before and after biopsy and those who discontinued the drug [bib_ref] Biopsy of the prostate guided by transrectal ultrasound: relation between warfarin use..., Ihezue [/bib_ref]. However, this study had limitations, including its nonrandomized design; variability in biopsy type (patients undergoing either 6-or 4-core biopsies); the possibility of life-threatening hemorrhagic complications that may have been missed due to the small sample size; the potential for recall bias, as complications were entered retrospectively 10 days after the biopsy; and the inclusion of patients kjronline.org agents should be discontinued at least 5 days prior to the procedure, and platelet counts and PT-INR levels should be monitored and adjusted to levels appropriate for the procedure (PT-INR < 1.5; platelet count > 50000/μL).
-Grade A recommendation -Evidence level 1 -Mean agreement score: 8.0 (range, 5-9) -% of respondents with agreement score ≥ 7: 88.5% (23/26)
## Cleansing enema
The main effect of the prebiopsy glycerin enema is emptying the stool from the rectum to improve the sonic window and prevent unnecessary shadowing [bib_ref] CUA guidelines on prostate biopsy methodology, El-Hakim [/bib_ref]. There is still controversy regarding the effectiveness of enema in preventing infection after biopsy. The incidence of postbiopsy bacteremia is lower in patients given an enema than in those who received no enema, independent of antibiotic administration; however, the bacteremia is asymptomatic [bib_ref] Bacteremia and bacteriuria after transrectal ultrasound guided prostate biopsy, Lindert [/bib_ref]. Carey and Korman [bib_ref] Transrectal ultrasound guided biopsy of the prostate. Do enemas decrease clinically significant..., Carey [/bib_ref] reported that the prebiopsy enema was not of significant benefit and on warfarin, which may have led to an underestimation of the severity of the hemorrhagic complications [bib_ref] CUA guidelines on prostate biopsy methodology, El-Hakim [/bib_ref]. A randomized prospective trial revealed that continuing lowdose aspirin in men undergoing TRUS-Bx did not increase the incidence of mild bleeding complications, although it prolonged the duration of self-limiting hematuria and rectal bleeding; thus, its effect on severe bleeding must be evaluated further [bib_ref] Continuing or discontinuing lowdose aspirin before transrectal prostate biopsy: results of a..., Giannarini [/bib_ref]. Therefore, there is a risk to not stopping the anticoagulant or antiplatelet based on the above studies.
All KSUR members who responded to the questionnaire stopped anticoagulants before TRUS-Bx. Approximately 76% (22 of 29) of the responding members ceased anticoagulants 1 week before the procedure. Similarly, almost all respondents except one doctor stopped antiplatelet drugs before TRUS-Bx. Most respondents (86%, 25 of 29) paused the antiplatelet drugs 1 week before the procedure.
## Recommendation
Before TRUS-Bx, anticoagulants and anti-platelet Other considerations
Use of 12-core biopsy scheme that incorporates apical and far-lateral cores is highly recommended because it appears to be optimal for CDR, NPV, and pathology concordance A 1 7.8
Length of biopsy specimen must be sufficiently long; 11.9 mm or more is suggested kjronline.org only increased the cost and inconvenience to the patient. However, several published studies subsequently reported that prebiopsy enema could reduce infectious side effects [bib_ref] Bisacodyl rectal preparation can decrease infectious complications of transrectal ultrasound-guided prostate biopsy, Jeon [/bib_ref] [bib_ref] Simple use of the suppository type povidone-iodine can prevent infectious complications in..., Park [/bib_ref] [bib_ref] Complications of transrectal ultrasound-guided prostate biopsy: impact of prebiopsy enema, Kam [/bib_ref]. Mechanical bowel preparation, such as with polyethylene glycol (PEG) solution intake, has an effect of lowering infectious side effects similar to that of a glycerin enema; however, patients considered the PEG preparation to be less comfortable [bib_ref] Transrectal-ultrasound prostatic biopsy preparation: rectal enema vs. mechanical bowel preparation, De Nunzio [/bib_ref]. All members of the KSUR who responded to the questionnaire administered an enema just before TRUS-Bx.
## Recommendation
There is no strong evidence to recommend for or against the use of an enema before TRUS-Bx; however, an enema can be administered to improve the sonic window during the biopsy or to lower the potential infectious biopsy risk. The standard bowel preparation method should be rectal enema.
-Grade B recommendation -Evidence level 2 -Mean agreement score: 7.5 (range 4-9) -% of respondents with agreement score ≥ 7: 80.1% (21/26)
## Antimicrobial prophylaxis
Antimicrobial prophylaxis reduces the risk of bacteriuria, bacteremia, and clinical infections after TRUS-Bx [bib_ref] Meta-analysis of antibiotic prophylaxis use in transrectal prostatic biopsy, Yang [/bib_ref]. Prophylactic antibiotic therapy for 1 day or even singledose prophylactic antibiotic therapy is known to lower the risk of infectious complications to 1% or less [bib_ref] Comparison of a 3-day with a 1-day regimen of an extended-release formulation..., Schaeffer [/bib_ref]. Fluoroquinolone and first-, second-, and third-generation cephalosporins are recommended for TRUS-Bx, and prophylactic antibiotics should be given 1-2 hours before the procedure [bib_ref] Meta-analysis of antibiotic prophylaxis use in transrectal prostatic biopsy, Yang [/bib_ref] [bib_ref] Infection in patients undergoing transrectal ultrasound guided prostate biopsy, Jung [/bib_ref]. The administration route (oral, intramuscular, or intravenous) does not influence the effect of the antibiotics. The postbiopsy duration of antibiotics is still controversial [bib_ref] CUA guidelines on prostate biopsy methodology, El-Hakim [/bib_ref]. A retrospective multicenter study [bib_ref] Transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the..., Nash [/bib_ref] reported that a combination of single-dose gentamicin intramuscular injection before biopsy and three-day levofloxacin oral administration after biopsy reduced the infectious complication rate by up to 90% compared to the administration of postbiopsy antibiotics only.
Most KSUR members who responded to the questionnaire (86%, 25 of 29) used antibiotic prophylaxis before TRUS-Bx. The most frequently used antibiotics were thirdgeneration cephalosporins, followed by quinolones and second-generation cephalosporins. Postbiopsy antibiotic use was also surveyed, and almost all members who responded (90%, 26 of 29) administered antibiotics up to 1 week after the procedure. One member who did not use prophylactic antibiotics administered postbiopsy antibiotics (3rd generation cephalosporins) 1 week after the biopsy.
## Recommendation
Antimicrobial prophylaxis is recommended to reduce the risk of postbiopsy infectious complications.
-Grade A recommendation -Evidence level 1 -Mean agreement score: 8.4 (range 6-9) -% of respondents with agreement score ≥ 7: 92.3% The postbiopsy duration of antibiotics is still controversial; however, KSUR members typically use a course of 5 days or less after biopsy.
-Grade I recommendation -Evidence level 5 -Mean agreement score: 7.2 (range 2-9) -% of respondents with agreement score ≥ 7: 80.1% (21/26)
# Biopsy-related pain management
## Periprostatic neurovascular bundle block
The factors affecting pain in TRUS-Bx patients vary, and the intensity of the pain is known to be influenced by the size of the ultrasound probe and the number of biopsies.
The pain that occurs when an ultrasonic transducer is inserted is known as somatic pain when the anal canal under the dentate line, which has a rich sensory nerve distribution, is expanded by the transducer. The rectal mucosa is insensitive to pain, but the prostate capsule and prostate parenchyma are very sensitive to pain, which is known to spread through the periprostatic neurovascular bundle.
Periprostatic neurovascular bundle block (PNB) was usually performed using a Chiba needle or a long spinal needle (7-inch, 22-gauge), with direct injection of 5 mL of 1-2% lidocaine in the region of the prostatic vascular pedicle at the base of the prostate just lateral to the junction between the prostate and seminal vesicle [bib_ref] Transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the..., Nash [/bib_ref]. To date, PNB has been the best proven method for reducing pain in TRUS-Bx and has been shown to reduce pain (with statistical significance) in a series of metaanalyses comparing non-anesthetic control and placebo https://doi.org/10.3348/kjr.2019.0576 kjronline.org IRLA, PNB is known to have the same effect [bib_ref] Transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the..., Nash [/bib_ref] and shows more effective pain relief [bib_ref] A meta-analysis of local anesthesia for transrectal ultrasoundguided biopsy of the prostate, Tiong [/bib_ref] [bib_ref] Local anesthetic reduces pain associated with transrectal ultrasound-guided prostate biopsy: a meta-analysis, Hergan [/bib_ref] [bib_ref] Anaesthesia in transrectal prostate biopsy: which is the most effective technique?, Maccagnano [/bib_ref] [bib_ref] Current methods of analgesia for transrectal ultrasonography (TRUS)-guided prostate biopsy --a systematic..., Lee [/bib_ref] [bib_ref] Three different techniques for administering analgesia during transrectal ultrasound-guided prostate biopsy: a..., Izol [/bib_ref]. In particular, the use of both PNB and IRLA simultaneously is described as being more effective than single treatment [bib_ref] A meta-analysis of local anesthesia for transrectal ultrasoundguided biopsy of the prostate, Tiong [/bib_ref].
Four of 29 (14%) KSUR members who responded to the questionnaire used IRLA only, and 6 doctors among the respondents used a combination of PNB and IRLA for pain management during TRUS-Bx (21%, 6 of 29).
Recommendation IRLA can be used as an ancillary method to decrease discomfort during TRUS-Bx. In particular, IRLA is recommended to be used in combination with PNB.
-Grade B recommendation -Evidence level 1 -Mean agreement score: 7.1 (range 3-9) -% of respondents with agreement score ≥ 7: 84.6% (22/26)
## Opioid analogues
Among opioid analogues, meperidine (pethidine) and fentanyl are commonly used in Korea. Generally, fentanyl is more effective and faster-acting than meperidine, but its effective duration is shorter, and it is more expensive. Among side effects, respiratory depression, nausea, and vomiting show similar frequencies between the two drugs, but the rate of cardiovascular side effects is slightly higher for meperidine. Simple comparisons are listed in [fig_ref] Table 4: Pharmacological Properties of Meperidine and Fentanyl [/fig_ref].
Opioid analogues are mainly used as an adjunct to PNB because narcotic analgesics reduce anxiety (anxiolytics) [bib_ref] Current methods of analgesia for transrectal ultrasonography (TRUS)-guided prostate biopsy --a systematic..., Lee [/bib_ref]. There is no evidence that the analgesic effect of opioid analogues is superior to that of PNBs when injected intravenously, and the analgesic effects of opioids are inferior to those of PNBs when injected intramuscularly [bib_ref] Anaesthesia in transrectal prostate biopsy: which is the most effective technique?, Maccagnano [/bib_ref] [bib_ref] Three different techniques for administering analgesia during transrectal ultrasound-guided prostate biopsy: a..., Izol [/bib_ref] [bib_ref] UP-02.137. A randomized, controlled trial comparing lidocaine periprostatic nerve block and lidocaine..., Moudouni [/bib_ref]. Although fentanyl offers no additional benefit [bib_ref] A meta-analysis of local anesthesia for transrectal ultrasoundguided biopsy of the prostate, Tiong [/bib_ref] [bib_ref] Local anesthetic reduces pain associated with transrectal ultrasound-guided prostate biopsy: a meta-analysis, Hergan [/bib_ref]. PNB has also been shown to provide similar pain control compared to sedoanalgesia (intravenous midazolam and fentanyl) or intravenous tramadol. However, PNB is a preferable method in TRUS-Bx since it is much more practical in outpatient clinics and relatively free from the side effects of midazolam, fentanyl, or tramadol.
Most KSUR members who responded to the questionnaire adopted PNB for pain management during TRUS-Bx (79%, 23 of 29).
Recommendation PNB is highly recommended to lower patient discomfort associated with TRUS-Bx.
-Grade A recommendation -Evidence level 1 -Mean agreement score: 7.8 (range 5-9) -% of respondents with agreement score ≥ 7: 84.6% (22/26)
## Intrarectal lidocaine gel application
The main function of the gel applied to the anal canal during TRUS-Bx is to reduce the pain caused by the expansion of the anal canal by enhancing anal compliance and lowering the friction between the probe and anal canal. Lidocaine-containing gels are expected to reduce somatic pain more effectively by dampening the sensation of the anal canal and by adding local anesthetic effects to the surrounding prostate capsule and parenchyma via absorption through the rectal mucosa [bib_ref] Local anesthetic reduces pain associated with transrectal ultrasound-guided prostate biopsy: a meta-analysis, Hergan [/bib_ref]. However, the effects of intrarectal lidocaine gel application (IRLA) have been reported to be widely variable; of 17 randomized controlled trials, 12 reported no difference in pain relief between conventional ultrasound gel and lidocaine gel, and 5 described IRLA as reducing the pain in TRUS-Bx, relative to the effect of conventional gel [bib_ref] Anaesthesia in transrectal prostate biopsy: which is the most effective technique?, Maccagnano [/bib_ref]. In comparison with kjronline.org over PNB monotherapy when used with PNB, it should be considered for reducing patient anxiety [bib_ref] Current methods of analgesia for transrectal ultrasonography (TRUS)-guided prostate biopsy --a systematic..., Lee [/bib_ref]. Only two KSUR members (6.8%) who responded to the questionnaire used opioid analgesics, and all used opioids as a complement to PNB and/or IRLA. No respondent used opioids as the sole method of pain management during TRUS-Bx.
## Recommendation
Opioids such as meperidine or fentanyl are not usually recommended for pain relief during biopsy. However, the use of opioids can be considered for anxiolysis. This recommendation may be controversial since a consensus was not fully achieved (% of respondents with agreement score ≥ 7: 73.1%).
-Grade B recommendation -Evidence level 2 -Mean agreement score: 6.8 (range 5-9) -% of respondents with agreement score ≥ 7: 73.1% (19/26)
## Other considerations
## Number of biopsy cores and length and diameter of the biopsy needle
According to the American Urologic Association white paperand the Canadian Urological Association on Prostate Biopsy Methodology (5), a 12-core biopsy scheme including the prostate apex and bilateral far lateral peripheral zones is recommended as the standard TRUS-Bx protocol. In comparison with the standard sextant biopsy, the 12-core biopsy scheme increases the cancer detection rate (CDR), increases the negative predictive value (NPV) to lower the ratio of recurrent biopsy, and shows a similar rate for diagnosing cancer (i.e., the difference in rate is not clinically significant). These reports also indicated that there are no additional benefits in terms of CDR and NPV to performing biopsy with more than 12 cores.
The size of the biopsy needle is usually 18-gauge, and there are studies reporting that an increase in the size of the core to a 16-gauge does not cause any side effects or differences in CDR [bib_ref] Effect of needle size on cancer detection, pain, bleeding and infection in..., Mccormack [/bib_ref]. The length of the core has a great effect on the CDR [bib_ref] Effect of needle size on cancer detection, pain, bleeding and infection in..., Mccormack [/bib_ref] [bib_ref] Core length in prostate biopsy: size matters, Öbek [/bib_ref] , and one study recommended that the length of the core be greater than 11.9 mm (33). Therefore, there could be no significant difference in CDR between the 16-mm and 22-mm biopsy needles. However, the aforementioned studies compared the length of cores obtained by a fixed single-length biopsy needle, and there are no studies comparing CDR or complication rates among different biopsy needle gauges and lengths. Further studies are needed on this issue.
Most KSUR members who responded to the questionnaire (90%, 26 from 29) chose the 12-core method for TRUS-Bx. One respondent used the 10-core method. Two respondents chose 'others'; one answered that he or she obtained 10 or 12 cores depending on the situation, and the other responded that he or she obtained an additional 2 cores from the transitional zone, making 14 cores in total.
The most commonly used gauge and throw combination for the biopsy gun was the 18G 22-mm (15 of 29, 51.7%) needle, followed by the 18G 16-mm needle and 16G 16-mm biopsy needle. Four respondents chose "others" and left a comment stating "mixed use of 18G 16-mm and 18G 22-mm according to prostate size."
## Recommendation
The use of a 12-core biopsy scheme that incorporates apical and far-lateral cores is highly recommended because it appears to be optimal for CDR, NPV, and pathology concordance.
-Grade A recommendation -Evidence level 1 -Mean agreement score: 7.8 (range 5-9) -% of respondents with agreement score ≥ 7: 92.3% (24/26) Although the gauge and length of the biopsy needle seem irrelevant in CDR, the length of the biopsy specimen must be sufficiently long; 11.9 mm or more is suggested.
-Grade B recommendation -Evidence level 2 -Mean agreement score: 7.8 (range 5-9) -% of respondents with agreement score ≥ 7: 88.4% (23/26)
# Conclusion
The KSUR guideline development subcommittee presented a consensus statement with a literature review for topics including patient preparation, pain management, and biopsy scheme planning for TRUS-Bx. We recommend the 12-core biopsy scheme with the PNB ± IRLA local anesthesia method as the standard protocol for TRUS-Bx. Anticoagulants and antiplatelet agents should be discontinued at least 5 days prior to the procedure, and antibiotic prophylaxis is highly
[fig] *: Mean agreement score: mean value of agreement score from 26 council members of KSUR for each recommendation (score 1 denoted strong disagreement and score 9 denoted strong agreement), † This recommendation may be controversial since consensus was not fully achieved (% of respondents with agreement score ≥ 7: 73.1%). CDR = cancer detection rate, IRLA = intrarectal lidocaine gel application, KSUR = Korean Society of Urogenital Radiology, NPV = negative predictive value, PNB = periprostatic neurovascular bundle block, TRUS-Bx = transrectal ultrasound-guided prostate biopsy https://doi.org/10.3348/kjr.2019.0576 [/fig]
[table] Table 1: Criteria for Evidence Level for Each Evaluated Study Adapted from Choi et al. Korean J Radiol 2017;18:208-216 (2) https://doi.org/10.3348/kjr.2019.0576 [/table]
[table] Table 2: Grades of Recommendation Suggested from Korean Clinical Imaging Guidelines [/table]
[table] Table 4: Pharmacological Properties of Meperidine and Fentanyl [/table]
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https://europepmc.org/articles/pmc7082664?pdf=render
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The Korean Society of Urogenital Radiology (KSUR) aimed to present a consensus statement for patient preparation, standard technique, and pain management in relation to transrectal ultrasound-guided prostate biopsy (TRUS-Bx) to reduce the variability in TRUS-Bx methodologies and suggest a nationwide guideline. The KSUR guideline development subcommittee constructed questionnaires assessing prebiopsy anticoagulation, the cleansing enema, antimicrobial prophylaxis, local anesthesia methods such as periprostatic neurovascular bundle block (PNB) or intrarectal lidocaine gel application (IRLA), opioid usage, and the number of biopsy cores and length and diameter of the biopsy needle. The survey was conducted using an Internet-based platform, and responses were solicited from the 90 members registered on the KSUR mailing list as of 2018. A comprehensive search of relevant literature from Medline database was conducted. The strength of each recommendation was graded on the basis of the level of evidence. Among the 90 registered members, 29 doctors (32.2%) responded to this online survey. Most KSUR members stopped anticoagulants (100%) and antiplatelets (76%) one week before the procedure. All respondents performed a cleansing enema before TRUS-Bx. Approximately 86% of respondents administered prophylactic antibiotics before TRUS-Bx. The most frequently used antibiotics were third-generation cephalosporins. PNB was the most widely used pain control method, followed by a combination of PNB plus IRLA. Opioids were rarely used (6.8%), and they were used only as an adjunctive pain management approach during TRUS-Bx. The KSUR members mainly chose the 12-core biopsy method (89.7%) and 18G 16-mm or 22-mm (96.5%) needles. The KSUR recommends the 12-core biopsy scheme with PNB with or without IRLA as the standard protocol for TRUS-Bx. Anticoagulants and antiplatelet agents should be discontinued at least 5 days prior to the procedure, and antibiotic prophylaxis is highly recommended to prevent infectious complications. Glycerin cleansing enemas and administration of opioid analogues before the procedure could be helpful in some situations. The choice of biopsy needle is dependent on the practitioners' situation and preferences.
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pubmed
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Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1
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Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficient activity of the acid beta-glucosidase (GCase) enzyme, resulting in the progressive lysosomal accumulation of glucosylceramide (GlcCer) and its deacylated derivate, glucosylsphingosine (GlcSph). GCase is encoded by the GBA1 gene, located on chromosome 1q21 16 kb upstream from a highly homologous pseudogene. To date, more than 400 GBA1 pathogenic variants have been reported, many of them derived from recombination events between the gene and the pseudogene. In the last years, the increased access to new technologies has led to an exponential growth in the number of diagnostic laboratories offering GD testing. However, both biochemical and genetic diagnosis of GD are challenging and to date no specific evidence-based guidelines for the laboratory diagnosis of GD have been published. The objective of the guidelines presented here is to provide evidence-based recommendations for the technical implementation and interpretation of biochemical and genetic testing for the diagnosis of GD to ensure a timely and accurate diagnosis for patients with GD worldwide. The guidelines have been developed by members of the Diagnostic Working group of the International Working Group of Gaucher Disease (IWGGD), a non-profit network established to promote clinical and basic research into GD for the ultimate purpose of improving the lives of patients with this disease. One of the goals of the IWGGD is to support equitable access to diagnosis of GD and to standardize procedures to ensure an accurate diagnosis. Therefore, a guideline development group consisting of biochemists and geneticists working in the field of GD diagnosis was established and a list of topics to be discussed was selected. In these guidelines, twenty recommendations are provided based on information gathered through a systematic review of the literature and two different diagnostic algorithms are presented, considering the geographical differences in the access to diagnostic services. Besides, several gaps in the current diagnostic workflow were identified and actions to fulfill them were taken within the IWGGD. We believe that the implementation of recommendations provided in these guidelines will promote an equitable, timely and accurate diagnosis for patients with GD worldwide.
# Background
Gaucher disease (GD-OMIM #230800) is an autosomal recessive lysosomal storage disorder due to the deficient activity of the lysosomal hydrolase, acid beta-glucosidase (GCase; EC 3.2.1.45). The enzyme is present in the lysosomes of all nucleated cells and cleaves the beta-glucosidic linkage of glucosylceramide (GlcCer) yielding glucose and ceramide. Therefore, the deficiency of GCase leads to the progressive lysosomal accumulation of Glc-Cer and its deacylated derivate, glucosylsphingosine (GlcSph) mainly in the monocyte/macrophage system, resulting in multiorgan dysfunction.
The disease presents as a continuum of phenotypes, ranging from severe forms presenting at birth to very mild phenotypes. However, in the words of Knudson, broadly speaking, three main forms of the disease can be recognized: Type 1, non-cerebral; Type 2, cerebral acute; Type 3 cerebral chronic [bib_ref] Inborn errors of sphingolipid metabolism, Knudson [/bib_ref].
Type 1 GD (MIM No. 230800), the most common phenotype, is characterized by enlargement and dysfunction of the liver and spleen, displacement of normal bone marrow by storage cells and bone damage leading to infarctions and fractures. Although type 1 GD is considered a non-neuronopathic form, there is increasing evidence of neurological involvement in these patients (ie Parkinson syndrome, and Lewy body dementia [bib_ref] Middle-ear involvement in type I Gaucher's disease-a unique case, Khan [/bib_ref] [bib_ref] Corticobasal syndrome in a man with Gaucher disease type 1: Expansion of..., Potnis [/bib_ref] [bib_ref] In-depth phenotyping for clinical stratification of Gaucher disease, D' Amore [/bib_ref] [bib_ref] Non-neuronopathic" Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort..., Biegstraaten [/bib_ref] [bib_ref] The neurological manifestations of Gaucher disease type 1: the French Observatoire on..., Chérin [/bib_ref]. Type 2 GD (MIM No. 230900) is a rare phenotype associated with an acute neurodegenerative course and death at a very early age; while type 3, the chronic neuronopathic GD (MIM No. 231000), comprises an extremely heterogeneous group of patients who present with either attenuated or severe systemic disease associated with neurological involvement originating in childhood to early adulthood [bib_ref] The spectrum of neurological manifestations associated with Gaucher disease, Lal [/bib_ref] [bib_ref] Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes, Daykin [/bib_ref].
The human GCase is encoded by the GBA1 gene (GRCh37/hg19 Chromosome 1: 155,204,239 to 155,214,653), located on chromosome 1q21. The GBA1 gene is approximately 7.5-kb long and contains 11 exons. A highly homologous 5.5 kb-pseudogene (GBAP; MIM No. 606463; GenBank accession no. J03060.1) has been located 16 kb downstream from the active gene [bib_ref] The human glucocerebrosidase gene and pseudogene: Structure and evolution, Horowitz [/bib_ref].
GCase protein is synthesized on polyribosomes as a 55-kDa peptide, which is then translocated into the endoplasmic reticulum (ER), where it is modified by the addition of high mannose oligosaccharides and transported to the trans-Golgi network from where it is trafficked to the lysosomes [bib_ref] Biosynthesis of the Lysosomal Enzyme Glucocerebrosidase, Ericksonss [/bib_ref]. GCase protein is targeted to the lysosomal compartment through a mannose 6-phosphateindependent receptor, the lysosomal integral membrane protein type 2 (LIMP-2) [bib_ref] LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase, Reczek [/bib_ref] , a trans-membrane protein mainly found in the lysosomes and late endosomes [bib_ref] Lysosomal membrane glycoproteins. Structure, biosynthesis, and intracellular trafficking, Fukuda [/bib_ref] [bib_ref] Isolation and sequencing of a cDNA clone encoding the 85 kDa human..., Fujita [/bib_ref]. At the acidic lysosomal pH, LIMP-2 dissociates from GCase enabling enzymatic activity facilitated by the cofactor Saposin C (Sap C) [bib_ref] Effect of saposins A and C on the enzymatic hydrolysis of liposomal..., Vaccaro [/bib_ref] [bib_ref] Further studies on the reconstitution of glucosylceramidase activity by Sap C and..., Salvioli [/bib_ref] [bib_ref] Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal β-glucocerebrosidase, Abdul-Hammed [/bib_ref] [bib_ref] An evolutionary and structure-based docking model for glucocerebrosidase-saposin C and glucocerebrosidasesubstrate interactions..., Atrian [/bib_ref].
The diagnosis of GD is based on the demonstration of deficient GCase activity in cells and the identification of pathogenic variants in the GBA1 gene.
Latterly, the development of new technologies has improved the diagnostic capacity of expert laboratories. At the same time, increased access to these technologies has led to an exponential growth in the number of diagnostic laboratories that offer GD testing. However, both biochemical and genetic diagnosis of GD are challenging and to date no specific, evidence-based guidelines for the laboratory diagnosis of GD have been published.
The objective of the guidelines presented here is to provide evidence-based recommendations for the technical implementation and interpretation of biochemical and genetic testing for the diagnosis of GD to ensure a timely and accurate diagnosis for patients with GD worldwide.
# Methods
The guidelines have been developed by members of the Diagnostic Working group of the International Working Group of Gaucher Disease (IWGGD), a non-profit network established to promote clinical and basic research into GD for the ultimate purpose of improving the lives of patients with this disease.
One of the goals of the IWGGD is to support the provision of equitable access to diagnostic testing and the introduction of standardized procedures that ensure patients with GD can readily obtain an accurate diagnosis.
A guideline development group (GDG) consisting of biochemists and geneticists working in the field of GD diagnosis was therefore established and a list of guideline topics were selected for development.
A systematic literature review on GD biomarkers, biochemical diagnosis, GCase activity, molecular diagnosis and GBA1 mutations was carried out using Medline and the Cochrane Library. The literature search on molecular diagnosis and GBA1 mutations was limited to the last 20 years. The following search terms were used: "Gaucher" and "biomarkers" or "chitotriosidase or CCL18 or PARC or glucosylsphingosine, lysoGL1 or lysoGb1 or ACE or angiotensin converting enzyme or tartrate resistant acid phosphatase or TRAP or tartrate-resistant acid phosphatase"; "Gaucher" and "activity" and "fibroblasts or leukocytes" and "sensitivity or specificity or predictive value or analytical range"; "Gaucher" and "dry blood spot or dried blood spot or DBS"; "Gaucher" and "NGS"; "GBA or GBA1" and "NGS or Sanger"; "Lysosomal storage disorders" and "NGS"; "Gaucher" and "frequency and mutation"; "Gaucher" and "genotype" and "registry". Searches were limited to English language publications only.
One hundred eighty-six papers were selected as relevant.
References related to a single topic (i.e., biomarkers, enzyme activity, genetic testing) were pulled together and the GDG was divided into subgroups to critically revise references, grade them, write a draft summarizing evidence and formulate recommendations.
The group met three times virtually (December 10th, 2020; July 12th, 2021; December 21, 2021) and corresponded by email regularly for the duration of the guideline development.
All GDG members discussed the draft documents. Evidence levels were classified in accordance with the method proposed by Burns et al. [bib_ref] The Levels of Evidence and their role in Evidence-Based Medicine, Burns [/bib_ref] [fig_ref] 1: Biomarkers of GD assisting in diagnosis A [/fig_ref]. These guidelines will be revised every 2 years to update the recommendations in light of the development and validation of novel diagnostic methods.
## Topics
## Biomarkers of gaucher disease assisting in diagnosis
Biomarkers are in general chemical entities, ranging from simple metabolites to complex proteins, which indicate the presence of a biological process linked to the clinical manifestations and outcome of a particular disease. They are the focus of much research and, when available, they play a critical role in the diagnosis, monitoring of disease progression as well as the assessment of therapeutic interventions. An ideal biomarker should fulfill a number of criteria. For diagnostic purposes it should be significantly elevated in the disease with no overlap in the values obtained in untreated patients and quantification in healthy subjects. The analyte should not be influenced by factors that are unrelated to the disease. It should change in response to specific treatment. Finally, reliable, fast, and cheap methods should be available for its estimation in easily accessible biological materials (For FDA view on Biomarkers see: https:// www. fda. gov/ about-fda/ innov ation-fda/ fda-facts-bioma rkers-and-surro gate-endpo ints).
Distinct biomarkers of GD can be recognized. The first category is associated with the presence of Gaucher cells (e.g. Chitotriosidase and CCL18/PARC) while the second includes the lipid, glucosylsphingosine (GlcSph)-sometimes termed 'lysoGL1' or 'lysoGb1' in literature supported by different companies-which accumulates as a result of the deficiency of GCase activity in cells.
## Biomarkers described in gaucher diseases
Chitotriosidase Chitotriosidase is the human analogue of chitinases from lower organisms; the enzyme is released from pathological macrophages in Gaucher disease.
Sensitivity: In terms of diagnosing GD, assaying plasma chitotriosidase activity is commonly employed in many centers as a first line screening test. The activity of chitotriosidase in plasma is elevated up to 1000-fold above the mean values in a healthy reference population. In the initial studies of chitotriosidase, plasma activity was found to be elevated on average 641-fold (median control plasma, 20 nmol/mL/h; range, 4-76 nmol/mL/h; median GD plasma, 12 824 nmol/mL/h; range, 3122-65 349 nmol/mL/h) [bib_ref] Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease, Hollak [/bib_ref]. Several subsequent reports have confirmed these findings [bib_ref] Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression..., Van Dussen [/bib_ref] [bib_ref] The French Gaucher's disease registry: Clinical characteristics, complications and treatment of 562..., Stirnemann [/bib_ref] [bib_ref] Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease, Deegan [/bib_ref] [bib_ref] Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher..., Raskovalova [/bib_ref]. Generally, higher plasma chitotriosidase activity is observed in type 1 patients than patients with types 2 and 3. Increased activity has also been reported in asymptomatic/ pre-symptomatic patients identified through the screening of family members of an index case [bib_ref] Gaucher disease: Biochemical and molecular findings in 141 patients diagnosed in Greece, Dimitriou [/bib_ref].
The interpretation of plasma chitotriosidase activity is complicated by the occurrence of an intragenic 24-base pair (bp) duplication in the chitotriosidase gene CHIT1, which prevents the formation of chitotriosidase protein. This effectively null allele is frequent in most populations, and among GD patients, where one in every three individuals is a heterozygous carrier and about one in every 20 individuals is homozygous for the mutation [bib_ref] The human chitotriosidase gene-Nature of inherited enzyme deficiency, Boot [/bib_ref]. Several other mutations which affect chitotriosidase activity, have been described [bib_ref] Type 1 Gaucher disease: Null and hypornorphic novel chitotriosidase mutations -Implications for..., Grace [/bib_ref] [bib_ref] Chitotriosidase deficiency: A mutation update in an African population, Arndt [/bib_ref] [bib_ref] Human chitotriosidase polymorphisms G354R and A442V associated with reduced enzyme activity, Lee [/bib_ref] [bib_ref] Chitotriosidase deficiency in the Cypriot population: identification of a novel deletion in..., Mavrikiou [/bib_ref] [bib_ref] Chitotriosidase gene polymorphisms and mutations limit the determination of chitotriosidase expression in..., Csongrádi [/bib_ref].
Specificity: Increased plasma chitotriosidase activity is not unique to GD patients. Modest elevation of activity is also found in many different lysosomal and non-lysosomal diseases such as Niemann-Pickdisease type C, Acid sphingomyelinase deficiency, Alagille syndrome, Amyotropic lateral sclerosis, hydrops fetalis due to congenital herpes virus infection, neonatal systemic candidiasis, sarcoidosis, leprosy, arthritis, multiple sclerosis, thalassemia, chronic obstructive pulmonary disease (COPD), malaria, and atherosclerosis. Generally, although the levels of activity detected in these disorders may be within the range observed in GD (especially those patients receiving specific therapy), the values are lower than those found in GD patients. Indeed, in the absence of the intragenic duplication in CHIT1, a marked elevation of chitotriosidase activity in plasma appears to be characteristic of and diagnostic for GD [bib_ref] Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease, Hollak [/bib_ref] [bib_ref] Elevated plasma chitotriosidase activity in various lysosomal storage disorders, Guo [/bib_ref] [bib_ref] The expanding spectrum of disorders with elevated plasma chitotriosidase activity: an update, Michelakakis [/bib_ref] [bib_ref] Plasma chitotriosidase and CCL18: early biochemical surrogate markers in type B Niemann-Pick..., Brinkman [/bib_ref] [bib_ref] Plasma chitotriosidase in male Fabry patients: a marker for monitoring lipid-laden macrophages..., Vedder [/bib_ref] [bib_ref] Plasma chitotriosidase and CCL18 as surrogate markers for granulomatous macrophages in sarcoidosis, Boot [/bib_ref] [bib_ref] Increased chitotriosidase activity in serum of leprosy patients: Association with bacillary leprosy, Iyer [/bib_ref] [bib_ref] Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis, Boven [/bib_ref] [bib_ref] Strong induction of members of the chitinase family of proteins in atherosclerosis:..., Boot [/bib_ref] [bib_ref] Serial chitotriosidase activity estimations in neonatal systemic candidiasis, Labadaridis [/bib_ref] [bib_ref] Hepatosplenomegalic lipidosis: What unless Gaucher? Adult cholesteryl ester storage disease (CESD) with..., Vom Dahl [/bib_ref]. Individuals who are homozygous for this CHIT1 allele have effectively no or near-absent chitotriosidase activity.
PARC/CCL18: pulmonary and activation-regulated chemokine (PARC, systematic name CCL18), a member of the C-C chemokine family which like chitotriosidase, accumulates in the alternatively activated macrophages that accumulate in GD "Gaucher cells" [bib_ref] Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic..., Moran [/bib_ref] but appears to be actively released.
Sensitivity: A 10-to 50-fold increase in the abundance of PARC/CCL18 has been reported in plasma and serum of symptomatic GD patients compared with healthy individuals [bib_ref] Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease, Deegan [/bib_ref] [bib_ref] Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher..., Raskovalova [/bib_ref] [bib_ref] Marked elevation of the chemokine CCL18/PARC in Gaucher disease: A novel surrogate..., Boot [/bib_ref]. Increased PARC/CCL18 polypeptides release s has been reported in the asymptomatic identical twin of a patient with severe disease which were substantially lower than in the symptomatic patient. PARC/CCL18 is stable upon storage and multiple freeze thaw cycles.
Specificity: Increased concentrations that can overlap those found in GD have been described in patients with a-mannosidosis and Niemann-Pick disease type A and B [bib_ref] Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease, Deegan [/bib_ref] [bib_ref] Plasma chitotriosidase and CCL18: early biochemical surrogate markers in type B Niemann-Pick..., Brinkman [/bib_ref]. Non-lysosomal storage diseases with increased PARC/CCL18 levels include atherosclerosis, rheumatoid arthritis, beta-thalassemia, sarcoidosis [bib_ref] Plasma chitotriosidase and CCL18 as surrogate markers for granulomatous macrophages in sarcoidosis, Boot [/bib_ref] [bib_ref] Expression and cellular localization of the CC chemokines PARC and ELC in..., Reape [/bib_ref] [bib_ref] PARC/ CCL18 Is a plasma CC chemokine with increased levels in childhood..., Struyf [/bib_ref] [bib_ref] Elevated plasma chemokine CCL18/PARC in β-thalassemia, Dimitriou [/bib_ref]. So far, no genetic variations that significantly alter the concentrations of PARC/CCL18 have been described. Of note, PARC/CCL18 chemokine is not expressed in mice.
## Glucosylsphingosine (a.k.a. lysogl1, lysogb1)
Sensitivity: an average 180-fold increase in the concentration of GlcSph has been reported in plasma and serum of symptomatic type 1 GD patients compared with healthy individuals [bib_ref] Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers,..., Dekker [/bib_ref] [bib_ref] Combined analysis of plasma or serum glucosylsphingosine and globotriaosylsphingosine by UPLC-MS/MS, Beasley [/bib_ref]. A similar abnormality is noted in mice and zebrafish with deficient GCase [bib_ref] Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher..., Keatinge [/bib_ref] [bib_ref] Role of β-glucosidase 2 in aberrant glycosphingolipid metabolism: Model of glucocerebrosidase deficiency..., Lelieveld [/bib_ref] [bib_ref] Correction of pathology in mice displaying Gaucher disease type 1 by a..., Dahl [/bib_ref]. This characteristic abnormality has been confirmed by numerous laboratories worldwide (e.g. [bib_ref] Glucosylsphingosine is a key biomarker of Gaucher disease, Murugesan [/bib_ref] [bib_ref] Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and..., Rolfs [/bib_ref] ; recently reviewed in [bib_ref] Value of glucosylsphingosine (Lyso-Gb1) as a biomarker in gaucher disease: a systematic..., Revel-Vilk [/bib_ref] [bib_ref] Lyso-glycosphingolipids: Presence and consequences, Van Eijk [/bib_ref]. Specificity: More modestly increased levels of plasma GlcSph have also been noted in patients suffering from Action Myoclonus Renal Failure syndrome with a defective LIMP-2 [bib_ref] Action myoclonus-renal failure syndrome: diagnostic applications of activity-based probes and lipid analysis, Gaspar [/bib_ref] , patients with Sap C deficiency [bib_ref] Clinical, biochemical and molecular characterization of prosaposin deficiency, Motta [/bib_ref] and in some patients with Niemann-Pick disease type C [bib_ref] Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders, Ferraz [/bib_ref].
ACE (angiotensin-converting enzyme): A 2-tenfold increase in ACE has been described in serum/plasma of GD patients apparently originating from storage cells [bib_ref] Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease, Deegan [/bib_ref] [bib_ref] Elevation of serum angiotensin-converting enzyme in Gaucher's disease, Lieberman [/bib_ref] [bib_ref] Immunofluorescent detection of angiotensin-converting enzyme (ACE) in Gaucher cells, Silverstein [/bib_ref] [bib_ref] Correlation of surrogate markers of Gaucher disease. Implications for long-term follow up..., Cabrera-Salazar [/bib_ref] [bib_ref] Plasma and metabolic abnormalities in Gaucher's disease, Aerts [/bib_ref] [bib_ref] Biomarkers in Serbian patients with Gaucher disease, Šumarac [/bib_ref] [bib_ref] ACE phenotyping in Gaucher disease, Danilov [/bib_ref] [bib_ref] Glycoprotein non-metastatic protein B: an emerging biomarker for lysosomal dysfunction in macrophages, Van Der Lienden [/bib_ref]. Increased serum/plasma ACE has been reported in other disorders involving activation of the monocyte/ macrophage lineage and sarcoidosis is the most frequent and the better studied [bib_ref] Angiotensin-converting enzyme: Clinical applications and laboratory investigations on serum and other biological..., Beneteau-Burnat [/bib_ref]. Increased activity is not observed in all GD patients [bib_ref] Immunofluorescent detection of angiotensin-converting enzyme (ACE) in Gaucher cells, Silverstein [/bib_ref] up to fivefold variation in blood ACE across a population can be observed and several mutations/polymorphisms in the ACE gene have been described which result in increased ACE blood levels [bib_ref] Novel ACE mutations mimicking sarcoidosis by increasing blood ACE levels, Danilov [/bib_ref] [bib_ref] Angiotensin I-converting enzyme mutation (Trp-1197Stop) causes a dramatic increase in blood ACE, Nesterovitch [/bib_ref]. ACE activity can be repressed in patients who are take ACE inhibitors [bib_ref] Nonadherence with angiotensin-converting enzyme inhibitor therapy: a comparison of different ways of..., Struthers [/bib_ref].
TRAP (tartrate-resistant acid phosphatase): TRAP was the first biomarker to be assayed in the diagnosis of GD [bib_ref] Elevation of serum acid phosphatase in Gaucher's disease, Tuchman [/bib_ref]. TRAP is not specific for GD and the observed increase in the serum is modest. It is unstable in the blood and shows marked analytical variability [bib_ref] Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease, Deegan [/bib_ref] [bib_ref] Plasma and metabolic abnormalities in Gaucher's disease, Aerts [/bib_ref]. In interpreting TRAP serum levels, its increased activity in children as compared to adults should be taken into consideration together with its thermo-instability [bib_ref] Biochemical properties of tartrateresistant acid phosphatasein serum of adultsand children, Lam [/bib_ref].
gpNMB (glycoprotein nonmetastatic melanoma protein B): gpNMB has been identified by proteomics analysis of laser dissected Gaucher cells from GD spleens [bib_ref] Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic..., Moran [/bib_ref] [bib_ref] Glycoprotein non-metastatic protein B: an emerging biomarker for lysosomal dysfunction in macrophages, Van Der Lienden [/bib_ref] [bib_ref] Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease..., Kramer [/bib_ref]. It is selectively overexpressed by Gaucher cells that release a soluble fragment into plasma that can be conveniently detected by ELISA. The soluble fragment of gpNMB is found to be elevated over 50-fold in plasma of patients with type 1 GD [bib_ref] Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease..., Kramer [/bib_ref] and was also found to be elevated in human NPC plasma samples [bib_ref] Glycoprotein non-metastatic protein B: an emerging biomarker for lysosomal dysfunction in macrophages, Van Der Lienden [/bib_ref]. A recent investigation confirms the value of soluble gpNMB as a plasma marker of Gaucher cells and substantiates its diagnostic potential [bib_ref] Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher..., Murugesan [/bib_ref]. However further studies are needed before its role as a diagnostic biomarker is established.
Recommendation #1: Based on the data available to date, it is recommended that chitotriosidase activity, PARC/CCL18 or GlcSph concentrations can be used as a first line test when the diagnosis of GD is suspected. If chitotriosidase activity is the only assessed biomarker and the result is normal, the presence of the 24 bp duplication in the CHIT1should be excluded. In these cases, measurement of the PARC/CCL18 and/or GlcSph is recommended.
However, a suspected diagnosis of GD needs to be established by assay of GCase activity (in peripheral blood leukocytes or extracts of cultured fibroblasts), preferably supported by molecular analysis of the GBA1 gene or by the identification of biallelic pathogenetic variants in the GBA1 gene Level of evidence: II (cohort studies /case series with consistent results/ research articles) Grade: B (Recommendation)
## Biological materials and methods used to assess recommended biomarkers
Assaying chitotriosidase activity: The biological material to be used is serum and/or plasma. The enzyme in plasma is stable upon storage and multiple freeze thaw cycles, (storage: stable at room temperature for 24 h; storage at -30 after 8 months recovery 95.3-102%, data presented by Aerts et al. GD Biomarker Qualification Workshop, September 2010, FDA Campus). Although the use of DBS in the diagnosis of lysosomal storage disorders has become increasingly popular mainly due to its convenience, at present extensive studies documenting sensitivity and specificity of assaying chitotriosidase activity in this type of biological material are not yet available [bib_ref] Expanding the clinical utility of glucosylsphingosine for Gaucher disease, Saville [/bib_ref] [bib_ref] Enzymatic analysis of biomarkers for the monitoring of Gaucher patients in Colombia, Pacheco [/bib_ref] [bib_ref] Chitotriosidase determination in plasma and in dried blood spots: a comparison using..., Rodrigues [/bib_ref] [bib_ref] Successful screening for Gaucher disease in a high-prevalence population in tabuleirodo norte..., Chaves [/bib_ref]. The activity of chitotriosidase in plasma/serum can be determined using the fluorogenic substrate 4methylumbelliferyl-β-D-N,N′,N″-triacetyl-chitotrioside (4MU-C3).However, the assay is complicated by the ability of chitotriosidase to transglycosylate as well as hydrolyze this substrate and thus the reaction has nonlinear kinetics with respect to time shows non-Michaelis-Menten behaviour [bib_ref] Transglycosidase Activity of Chitotriosidase: improved enzymatic assay for the human macrophage chitinase, Aguilera [/bib_ref]. Therefore, it is essential that special care is taken to ensure that the enzyme activity is truly proportional to the amount of chitotriosidase protein and there is an urgent need to standardize the assay across laboratories.. Alternatively, a far more convenient, sensitive, and accurate detection can be achieved by measuring the activity of chitotriosidase toward the fluorogenic substrate 4-methylumbelliferyl-deoxychitobiose (4MU-dC2). Chitotriosidase shows normal Michaelis-Menten kinetics with this substrate, allowing the use of saturating substrate concentrations. Thus, a more accurate and robust assay is now available [bib_ref] Transglycosidase Activity of Chitotriosidase: improved enzymatic assay for the human macrophage chitinase, Aguilera [/bib_ref] [bib_ref] Monitoring of Gaucher patients with a novel chitotriosidase assay, Schoonhoven [/bib_ref].
Measurement of the levels of PARC/CCL18: The biological material to be used is serum and/or plasma. PARC/CCL18 is stable upon storage and multiple freeze thaw cycles (storage: stable at room temperature for 48 h; storage at-30; 8 month recovery 107-109%, data presented by be reliably estimated using SELDI-TOF but enzymelinked immunosorbent assay (ELISA) and dissociationenhanced lanthanide fluoroimmunoassay (DELFIA) can be used for reliable estimation [bib_ref] Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher..., Raskovalova [/bib_ref] [bib_ref] Marked elevation of the chemokine CCL18/PARC in Gaucher disease: A novel surrogate..., Boot [/bib_ref] [bib_ref] Limitations in quantitation of the biomarker CCL18 in Gaucher disease blood samples..., Van Breemen [/bib_ref]. Measurement of the levels of GlcSph: Different techniques can be used for detection of which LC-MS/MS is presently the most sensitive. Its levels cannot be reliably estimated using SELDI-TOF. Reliable determination of absolute concentrations of GlcSph by mass spectrometry requires use of an appropriate internal standard. The concentration of GlcSph can be measured in either plasma or serum. GlcSph can be quantified in previously frozen serum or plasma samples.
GlcSph has been reported to be also increased in DBS of GD patients [bib_ref] Expanding the clinical utility of glucosylsphingosine for Gaucher disease, Saville [/bib_ref] [bib_ref] Plasma and dried blood spot lysosphingolipids for the diagnosis of different sphingolipidoses:..., Polo [/bib_ref] [bib_ref] Gaucher disease diagnosis using Lyso-Gb1 on dry blood spot samples: time to..., Dinur [/bib_ref]. However, the outcome of extensive studies documenting specificity, stability and the impact of sample storage and shipping conditions on sensitivity of this biomarker in DBS is not yet available.
## Recommendation #2:
The biological material to be used for assessment of recommended biomarkers is serum and/or plasma. Monocentric studies report good sensitivity of DBS GlcSph assessment in identifying GD patients. However, the outcome of extensive studies documenting specificity, stability and the impact of sample storage and shipping conditions on sensitivity of this biomarker in DBS is not yet available. Recommendation #3: Chitotriosidase can be measured using fluorogenic substrates: 4-methylumbelliferylβ-D-N,N′,N″-triacetyl-chitotrioside (4MU-C3) or 4-methylumbelliferyl-deoxychitobiose (4MU-dC2), which allows a more convenient, sensitive, and accurate measurement of activity. If 4MU-C3 is used it is important to ensure that the enzyme activity is truly proportional to the amount of chitotriosidase protein and the need to standardize the assay across laboratories is urgent and is underway through the IWGGD Biomarkers & Materials working group. Recommendation #4: Both enzyme-linked immunosorbent assay (ELISA) and dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA) can be used for reliable estimation of PARC/CCL18 concentrations, while these cannot be reliably estimated using SELDI-TOF. Recommendation #5: The most sensitive technique to assess GlcSph is LC-MS/MS. Reliable determination of absolute concentrations of GlcSph by mass spectrometry requires use of an appropriate internal standard. Its levels cannot be reliably estimated using SELDI-TOF.
## Enzyme activity
The metabolic defect in Gaucher disease (GD) is an inherited deficiency of lysosomal membrane associated acid β-glucocerebrosidase (GCase) [bib_ref] The metabolism of glucocerebrosides. I purification and properties of a glucocerebroside-cleaving enzyme..., Brady [/bib_ref]. The basic function of GCase is degradation of the glycosphingolipid glucosylceramide (GlcCer), also known as glucocerebroside within acid pH to ceramide and glucose [bib_ref] Gaucher disease: new molecular approaches to diagnosis and treatment, Beutler [/bib_ref]. The gold standard for GD diagnosis is the demonstration of deficient GCase activity measured in peripheral blood leukocytes and/or cultured skin fibroblasts homogenates. Traditionally enzyme activity was measured by using the natural substrate glucocerebroside [bib_ref] A deficiency of Glucocerebrosidase in Gaucher's disease, Patrick [/bib_ref]. Nowadays, enzyme assay is carried out by the use of an artificial substrate 4-MU-β-D-glucoside. For this reason, and to avoid misinterpretation, enzyme activity assayed by the use of artificial substrate will be called BGLU.
## In what samples bglu activity can be measured?
The BGLU activity could be measured in different samples such as DBS, leukocytes, fibroblasts and in case of prenatal diagnosis in chorionic villi sampling (CVS) or cultured amniocytes [bib_ref] Laboratory and genetic evaluation of Gaucher disease, Bodamer [/bib_ref]. BGLU could be measured in DBS samples as a first-line laboratory test. Pre-analytical requirements are critical for reliable BGLU results from DBS samples. DBS can be obtained by application of 50-75 μL drops of blood obtained by venipuncture into heparin tubes and spotted on the Whatman ® 903 or S&S903 filter paper. Another option is application of the same amount of blood after finger prick on filter paper collection device onto printed circles [bib_ref] Rapid diagnostic testing procedures for lysosomal storage disorders: alpha-glucosidase and beta-galactosidase assays..., Gasparotto [/bib_ref]. DBS should be dried for 4 h at room temperature avoiding direct illumination, and then packed in a sealed plastic bag with desiccant, and stored at 4 °C until analysis [bib_ref] The stability of markers in dried-blood spots for recommended newborn screening disorders..., Adam [/bib_ref]. Exposure of DBS to both heat and humidity can destroy enzyme functions rapidly. Moreover, an incomplete mixed blood before spotting can result in significant variation on enzyme activity [bib_ref] The effect of preparation, storage and shipping of dried blood spots on..., Elbin [/bib_ref].
The use of DBS as first line laboratory test offers many advantages over leukocytes or fibroblasts samples including easy collection methodologies, need of a small amount of blood, and simpler transportation as samples can be shipped via regular mail at room temperature. If the DBS sample is treated appropriately, the BGLU remain stable at least for 21 days [bib_ref] The use of dried blood spot samples in the diagnosis of lysosomal..., Reuser [/bib_ref] [bib_ref] Reliability of enzyme assays in dried blood spots for diagnosis of 4..., Ceci [/bib_ref] [bib_ref] Gaucher and Niemann-Pick diseases-enzymatic diagnosis in dried blood spots on filter paper:..., Chamoles [/bib_ref]. DBS has limitations for measurement of BGLU activity. The volume of blood applied, hematocrit, recent blood transfusions and other preanalytical steps such as drying time, homogeneity and extraction of the analyte influences the quality of the DBS sample [bib_ref] Use of dried blood spot specimens to monitor patients with inherited metabolic..., Moat [/bib_ref]. To ensure integrity of BGLU activity and to avoid false positive results, another lysosomal enzyme should be measured as a control enzyme with approximately same stability at room temperature. The value of the control (reference) sample should generally lie between the mean ± twostandard deviations [bib_ref] Towards quality assurance in the determination of lysosomal enzymes: a two-centre study, Lukacs [/bib_ref]. Different studies have shown good sensitivity and specificity, above 95%. However, enzyme testing in DBS has a low positive predictive value (of < 45% on average) [bib_ref] A comparative effectiveness study of newborn screening methods for four lysosomal storage..., Sanders [/bib_ref] [bib_ref] Newborn screening for lysosomal disorders in Brazil: a pilot study using customized..., Bender [/bib_ref] [bib_ref] High risk screening for Gaucher disease in patients with splenomegaly and/or thrombocytopenia..., Huang [/bib_ref] [bib_ref] Implementation of second-tier tests in newborn screening for lysosomal disorders in North..., Burlina [/bib_ref] [bib_ref] The New York pilot newborn screening program for lysosomal storage diseases: report..., Wasserstein [/bib_ref] [bib_ref] Successful newborn screening for Gaucher disease using fluorometric assay in China, Kang [/bib_ref] [bib_ref] Simultaneous testing for 6 lysosomal storage disorders and x-adrenoleukodystrophy in dried blood..., Tortorelli [/bib_ref] [bib_ref] Pilot study of newborn screening for six lysosomal storage diseases using Tandem..., Elliott [/bib_ref] [bib_ref] Validity of β-d-glucosidase activity measured in dried blood samples for detection of..., Stroppiano [/bib_ref].
Patient leukocytes or cultured skin fibroblast homogenates are the gold standard for measurement of BGLU activity. Leukocytes as the BGLU source are obtained by separation from approximately 5-10 ml of blood, drawn from the patient in potassium EDTA or heparin tubes. Moreover, skin fibroblasts should be used when patients have received blood transfusions or when discordant results are obtained with white blood cells. The shipment of blood samples to the reference laboratory should be carried out at 4 °C [bib_ref] Human leukocyte acid hydrolases: Characterization of eleven lysosomal enzymes and study of..., Kolodny [/bib_ref]. The isolation of leukocytes from the whole blood should be completed within 24 h after blood collection using dextran sedimentation or the ammonium chloride lysis method [bib_ref] Changes in the carbohydrate metabolism of mitogenicellay stimulated human peripheral lymphocytes I...., Roos [/bib_ref] [bib_ref] A microassay for Gaucher's disease, Peters [/bib_ref] [bib_ref] Enzyme kinetics and inhibition parameters of human leukocyte glucosylceramidase, Karatas [/bib_ref] [bib_ref] Studies on the fibrinogen, dextran and phytohemagglutinin methods of isolating leukocytes, Skoog [/bib_ref]. The pellet of isolated leukocytes can be stored for at least 20 days at − 20 °C before enzyme activities are determined [bib_ref] Enzyme kinetics and inhibition parameters of human leukocyte glucosylceramidase, Karatas [/bib_ref].
Homogenates prepared from cultured fibroblasts are labour intensive, since they require a skin biopsy (requiring no more than local anesthesia) transport in particular medium followed by transfer to medium for a primary cell culture of skin fibroblasts (avoiding the risk of contamination). The time taken for adequate fibroblast outgrowth to obtain a confluent cell monolayer varies but is generally about three weeks. Shipment of cultured fibroblasts should be at ambient room temperature, avoiding freezing, in a tube, dish or sealed flask (T25 or T75) containing culture media [bib_ref] Fibroblasts of skin fragments as a tool for the investigation of genetic..., Coelho [/bib_ref]. There are some potential interfering factors in the assays: excessive transport time, lack of viable cells, bacterial or mycoplasma contamination, exposure of the specimen to temperature extremes (freezing or > 30 °C).
The use of gold standard samples requires a homogenisation step with a metal tip sonicator, and total protein measurement of the homogenate [bib_ref] Human leukocyte acid hydrolases: Characterization of eleven lysosomal enzymes and study of..., Kolodny [/bib_ref] [bib_ref] A rapid and sensitive method for the quantitation of microgram quantities of..., Bradford [/bib_ref].
Recommendation #6: BGLU activity can be measured in dried blood spots (DBS) samples as a firstline test. However, GD diagnosis should never be rely solely on DBS enzyme activity measurement. Patient leukocytes or cultured skin fibroblast homogenates are the gold standard for measurement of BGLU activity and confirmation of GD diagnosis; skin fibroblasts, while more laborious and expensive to obtain, have the advantage that they can be cryopreserved in liquid nitrogen almost indefinitely and if adequately aliquoted, can be used repeatedly for study Level of evidence: II, III and IV (Well-designed cohort, case-control study, case reports) Grade: B (Recommendation)
## How gcase activity can be measured?
BGLU activity can be measured using fluorometric methods, tandem mass spectrometry or by digital microfluidics platforms. Fluorometric methods are based on the artificial substrate 4-methylumbelliferyl-β-Dglucopyranoside (4-MUG). They are mostly performed in microtiter plates [bib_ref] An improved high-throughput dried blood spot screening method for Gaucher disease, Olivova [/bib_ref] [bib_ref] Comparison of various β-glucosidase assays used to diagnose Gaucher's disease, Chiao [/bib_ref]. The sample is put into a reaction mixture of acidic pH, sodium deoxytaurocholate, and the fluorogenic substrate, 4-methylumbelliferyl β-D-glucopyranoside (4-MUG). Sodium deoxytaurocholate is added in order to inhibit the non-lysosomal isoenzyme BGLU activity [bib_ref] Gaucher and Niemann-Pick diseases-enzymatic diagnosis in dried blood spots on filter paper:..., Chamoles [/bib_ref] [bib_ref] An improved fluorometric leukocyte β-glucosidase assay for Gaucher's disease, Daniels [/bib_ref] [bib_ref] Sodium taurocholate effect on β-glucosidase activity: a new approach for identification of..., Magalhães [/bib_ref] [bib_ref] Biochemical study on β-glucosidase in individuals with Gaucher's disease and normal subjects, Michelin [/bib_ref]. Fluorometric enzyme assays for BGLU onto digital microfluidic platforms have the potential for simple, rapid and high-throughput selective screening of BGLU activity [bib_ref] Rapid assays for Gaucher and Hurler diseases in dried blood spots using..., Sista [/bib_ref] [bib_ref] Multiplex newborn screening for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases using..., Sista [/bib_ref] [bib_ref] Neonatal screening for four lysosomal storage diseases with a digital microfluidics platform:..., Neto [/bib_ref] [bib_ref] Lysosomal storage disorder screening implementation: findings from the first six months of..., Hopkins P V [/bib_ref]. Beside digital microfluidic fluorometry, there are other available compact digital microfluidic platforms (e.g. electro-wetting based digital microfluidics) [bib_ref] Digital microfluidics comes of age: high-throughput screening to bedside diagnostic testing for..., Millington [/bib_ref].
Tandem mass spectrometry enzyme assays with (LC-MS/MS) or without (MS/MS) liquid chromatography are based on non-fluorometric synthetic substrates [bib_ref] Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn..., Li [/bib_ref] [bib_ref] Multiplex enzyme assay screening of dried blood spots for lysosomal storage disorders..., Zhang [/bib_ref] [bib_ref] Direct multiplex assay of enzymes in dried blood spots by tandem mass..., Gelb [/bib_ref]. This approach may be particularly suitable for highthroughput analyses with a large number of individuals at-risk and/or for newborn screening for GD [bib_ref] Pilot study of newborn screening for six lysosomal storage diseases using Tandem..., Elliott [/bib_ref] [bib_ref] Tandem mass spectrometry assay of β-glucocerebrosidase activity in dried blood spots eliminates..., Wolf [/bib_ref] [bib_ref] Lysosomal storage disorder 4+1 multiplex assay for newborn screening using tandem mass..., Orsini [/bib_ref]. All three technologies (approaches) are suitable for selective screening BGLU activity [bib_ref] A comparative effectiveness study of newborn screening methods for four lysosomal storage..., Sanders [/bib_ref].
Recommendation #7: BGLU activity could be measured using artificial substrate with fluorometric methods, tandem mass spectrometry or by digital microfluidics platform. The fluorometric method is accepted as the gold standard assay in leukocyte/ fibroblast lysates. Tandem mass spectrometry or digital microfluidics platforms are generally used for DBS samples in screening studies. Level of evidence: II, III and IV (Well-designed cohort, case-control study, case reports) Grade: B (Recommendation)
## What is the role of enzymatic activity in gd?
Enzyme determinations in DBS samples are useful screening tests in clinically suspected individuals. Samples with BGLU activity below cut-off values require confirmation by measuring BGLU activity in gold standard samples: homogenates of leukocytes or fibroblasts [bib_ref] Reliability of enzyme assays in dried blood spots for diagnosis of 4..., Ceci [/bib_ref]. Whenever subjects present suggestive GD symptoms they must be reassessed even in the presence of normal BGLU from DBS testing [bib_ref] Validity of β-d-glucosidase activity measured in dried blood samples for detection of..., Stroppiano [/bib_ref]. An enzyme activity result of less than 15% of normal activity in homogenates of leukocytes or fibroblasts is diagnostic of GD [bib_ref] A review of Gaucher disease pathophysiology, clinical presentation and treatments, Stirnemann [/bib_ref]. Residual enzyme activity does not correlate with disease severity. Enzyme testing is not suitable for identification of carriers of GD nor of saposin C deficiency [bib_ref] Biochemical study on β-glucosidase in individuals with Gaucher's disease and normal subjects, Michelin [/bib_ref] [bib_ref] Gaucher disease: The metabolic defect, pathophysiology, phenotypes and natural history, Baris [/bib_ref] [bib_ref] Twenty-five years of biochemical diagnosis of Gaucher disease: the Egyptian experience, Fateen [/bib_ref]. Heterozygotes may have half-normal enzyme activity, but overlapping with activity levels of healthy controls, rendering enzymatic testing for carrier status unreliable [bib_ref] Use of 4-heptylumbelliferyl-β-d-glucoside to identify Gaucher's disease heterozygotes, Butcher [/bib_ref] [bib_ref] Phenotype variations in Gaucher disease, Mistry [/bib_ref] [bib_ref] Gaucher's disease: report of 11 cases with review of literature, Essabar [/bib_ref].
## Recommendation #8:
The DBS samples are useful as a first line test in clinically suspected individuals. Samples with BGLU activity below cut-off values always require confirmation by measuring BGLU activity in gold standard samples: homogenates of leukocytes or fibroblasts. The demonstration of deficient (below 15% of mean normal activity) BGLU enzyme activity in leukocyte and/or skin fibroblast homogenates confirms GD diagnosis. Residual enzyme activity does not correlate with disease severity and the test is not suitable for diagnosis of heterozygotes of GD nor of saposin C deficiency. Level of evidence: II, III and IV (Well-designed cohort, case-control study, case reports) Grade: B (Recommendation)
## How to validate gcase assay in the lab?
To ensure the quality of BGLU testing performance, each laboratory should establish its own Quality Management (QM) system according to ISO15189 and participate in both internal and external quality assessments. The internal audit program monitors operations throughout the testing process and the quality system. For quality control purposes, it is necessary to include an appropriate blank and at least one affected control and one normal control sample for each run of enzyme assays. All assays should be performed in duplicate. The cut-off range, normal range, and disease range should be established by the laboratory based on its own analysis. The inter-laboratory variance of numerical enzyme activity determinations could be large [bib_ref] Recommendations on Diagnosis, Treatment, and Monitoring for Gaucher Disease, Martins [/bib_ref]. Reproducibility was demonstrated by intra-(n = 6) and inter-assay (n = 10) results using threshold of %CV < 15. Therefore, quality assurance and improvement in diagnostic proficiency have become essential in this area [bib_ref] Inherited metabolic disorders: quality management for laboratory diagnosis, Verma [/bib_ref]. The enzyme assay is made in house by each laboratory based on the original published methods. It implies differences in units (pmol/h/disk, μmol/h/l, μmol/h/mg protein), disease cutoff; reference range, limit of detection (LOD) and limit of quantitation (LOQ). For this reason, laboratory reports from reference labs should include an interpretation of the result that reflects the conclusion of the result as normal or deficient, possible limitations of the test, and recommendations for additional testing if applicable.
The European Research Network for Evaluation and Improvement of Screening, Diagnosis, and Treatment of Inherited Disorders of Metabolism (ERNDIM) serves as an external proficiency testing program for clinical diagnostic laboratories, providing lyophilized fibroblasts for eight lysosomal storage diseases (LSD) enzymes. For laboratories testing lysosomal enzymes on DBS, the Newborn Screening Quality Assurance Program (NSQAP) at Centers for Disease Control and Prevention (CDC) provides quality control (QC) materials, proficiency testing (PT) services, and technical support in collaboration with the Newborn Screening Translation Research Initiative (NSTRI) at CDC [bib_ref] Enzymatic screening and diagnosis of lysosomal storage diseases, Yu [/bib_ref] [bib_ref] Quality of analytical performance in inherited metabolic disorders: the role of ERNDIM, Fowler [/bib_ref]. A highly homologous pseudogene, GBAP (96% identity), is located 16 kb downstream of the GBA1 gene [bib_ref] The human glucocerebrosidase gene and pseudogene: Structure and evolution, Horowitz [/bib_ref]. The high degree of homology, which reaches 96% in exonic regions, and the proximity between GBA1 and GBAP favours the occurrence of recombination events resulting in complex gene-pseudogene rearrangements [bib_ref] Sequence of two alleles responsible for Gaucher disease, Hong [/bib_ref] [bib_ref] Heterogeneity of mutations in the acid β-glucosidase gene of Gaucher disease patients, Latham [/bib_ref].
The nascent GCase polypeptide is composed of 536 amino acids, including 39 that encode a signal sequence that is later cleaved after it directs the polypeptide to transit the endoplasmic reticulum. Historically, GBA1 variants were numbered from the first residue after the cleavage of the signal peptide as amino acid number one. This legacy nomenclature is still used (herein reported between brackets and without the prefix p.), although it does not comply with contemporary nomenclature standards of the Human Genome Variation Society (HGVS).
## What is the role of genetic testing in the diagnosis of gd?
The identification of biallelic pathogenetic variants in the GBA1 gene confirms the diagnosis of GD. Genetic testing is performed in subjects displaying absent or low residual BGLU activity in cells to support the diagnosis and provide appropriate genetic counseling to family members.
Genetic testing can be done as a primary test for GD diagnosis. However, since many GBA1 variants are private, the chances of finding variants of uncertain significance (VUS) are quite high [bib_ref] Gaucher disease: Biochemical and molecular findings in 141 patients diagnosed in Greece, Dimitriou [/bib_ref] [bib_ref] Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher..., Filocamo [/bib_ref] [bib_ref] Analysis and classification of 304 mutant alleles in patients with type 1..., Koprivica [/bib_ref] [bib_ref] Mutation prevalence among 51 unrelated Spanish patients with Gaucher disease: identification of..., Alfonso [/bib_ref] [bib_ref] Identification and functional characterization of five novel mutant alleles in 58 Italian..., Miocić [/bib_ref] [bib_ref] Genetic and clinical features of patients with Gaucher disease in Hungary, Erdos [/bib_ref] [bib_ref] Molecular analysis of Turkish Gaucher disease patients: identification of novel mutations in..., Emre [/bib_ref] [bib_ref] Spectrum of GBA mutations in patients with gaucher disease from Slovakia: identification..., Mattošová [/bib_ref] [bib_ref] Clinical and genetic characteristics of Korean patients with Gaucher disease, Jeong [/bib_ref] [bib_ref] Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación..., Ortiz-Cabrera N V [/bib_ref] [bib_ref] Clinical and molecular characteristics of patients with Gaucher disease in Southern China, Feng [/bib_ref] [bib_ref] Gaucher disease: Single gene molecular characterization of one-hundred Indian patients reveals novel..., Sheth [/bib_ref] [bib_ref] Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene, Lepe-Balsalobre [/bib_ref] [bib_ref] Novel pathogenic mutations in the glucocerebrosidase locus, Duran [/bib_ref]. In this case, confirmation of diagnosis through the assessment of enzymatic activity in patient's cells is mandatory.
Variants should be classified following the American College of Medical Genetics (ACMG) criteria and in the case of VUS, pathogenicity should be assessed by functional analysis.
In addition, molecular testing of known familial variants represents the most reliable method to identify GD carriers since enzymatic activity does not discriminate between carriers and normal subjects [bib_ref] Use of 4-heptylumbelliferyl-β-d-glucoside to identify Gaucher's disease heterozygotes, Butcher [/bib_ref].
According to The Human Gene Mutation Database (HGMD-Professional 2021.1), 540 variants of the GBA1 gene have been reported to date, although not all of them are linked to GD. Indeed, 403 of them have been associated with GD.
Diverse variants have been reported: missense and nonsense variants, splice junction variants, deletions and insertions of one or more nucleotides and complex alleles (complex rearrangements) resulting from gene conversion or gene fusion with the downstream pseudogene GBAP. However, missense and nonsense variants, are the most frequently identified in GD patients worldwide [bib_ref] Gaucher disease: Mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA), Hruska [/bib_ref].
The frequency distribution of GBA1 variants differs across ethnic groups. While 4 pathogenetic variants (N370S; L444P, c.84-85 insG; IVS + 1G > A) account for 90% of alleles within Ashkenazi Jews, they account only for about 50-75% of alleles in non-Jewish populations. In addition, about 10% of patients present large deletions/ recombinant alleles [bib_ref] Gaucher disease: Biochemical and molecular findings in 141 patients diagnosed in Greece, Dimitriou [/bib_ref] [bib_ref] Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher..., Filocamo [/bib_ref] [bib_ref] Analysis and classification of 304 mutant alleles in patients with type 1..., Koprivica [/bib_ref] [bib_ref] Mutation prevalence among 51 unrelated Spanish patients with Gaucher disease: identification of..., Alfonso [/bib_ref] [bib_ref] Identification and functional characterization of five novel mutant alleles in 58 Italian..., Miocić [/bib_ref] [bib_ref] Genetic and clinical features of patients with Gaucher disease in Hungary, Erdos [/bib_ref] [bib_ref] Molecular analysis of Turkish Gaucher disease patients: identification of novel mutations in..., Emre [/bib_ref] [bib_ref] Spectrum of GBA mutations in patients with gaucher disease from Slovakia: identification..., Mattošová [/bib_ref] [bib_ref] Clinical and genetic characteristics of Korean patients with Gaucher disease, Jeong [/bib_ref] [bib_ref] Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación..., Ortiz-Cabrera N V [/bib_ref] [bib_ref] Clinical and molecular characteristics of patients with Gaucher disease in Southern China, Feng [/bib_ref] [bib_ref] Gaucher disease: Single gene molecular characterization of one-hundred Indian patients reveals novel..., Sheth [/bib_ref] [bib_ref] Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene, Lepe-Balsalobre [/bib_ref] [bib_ref] Novel pathogenic mutations in the glucocerebrosidase locus, Duran [/bib_ref] [bib_ref] Report of the Spanish Gaucher's disease registry: clinical and genetic characteristics, Giraldo [/bib_ref] [bib_ref] Gaucher disease in Tunisia: High frequency of the most common mutations, Cherif [/bib_ref] [bib_ref] An update of Gaucher mutations distribution in the Ashkenazi Jewish population: prevalence..., Bronstein [/bib_ref] [bib_ref] Patients with type 1 Gaucher disease in South Florida, USA: Demographics, genotypes,..., Orenstein [/bib_ref] [bib_ref] Gaucher disease types 1 and 3: Phenotypic characterization of large populations from..., Grabowski [/bib_ref] [bib_ref] Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients, Horowitz [/bib_ref] [bib_ref] Gaucher disease mutations in non-Jewish patients, Beutler [/bib_ref] [bib_ref] Mutation analysis in 46 British and Irish patients with Gaucher's disease, Hatton [/bib_ref].
Recommendation #10: Molecular analysis of the GBA1 gene should always be performed when biomarker results or phenotype are at odds with the enzymology and is highly recommended in subjects with BGLU activity below normal reference intervals in cells to further support/confirm the diagnosis of GD and provide genetic counseling. Testing of familial variants and genetic counseling should be made available to all at risk family members. Recommendation #11: Genetic testing could be done as a primary test (before testing enzymatic activity). However, results should be interpreted with caution since GBA1 testing is challenging (see below), depending on the method used the detection of large deletions and/or recombinant alleles will not be possible and VUS are often identified. Therefore, confirmation of diagnosis through the assessment of enzymatic activity in patient's cells is mandatory. Recommendation #12: Genetic testing is the most reliable method to detect heterozygous carriers and it should be made available to family members at risk of being a carrier. Recommendation #13: In all cases, molecular testing should be accompanied by a pre and post-test genetic counseling delivered by a counsellor experienced in GD to ensure informed choices. Level of evidence: II and IV (retrospective cohort studies or case series with consistent results) Grade: B (Recommendation)
## How should molecular testing be performed?
Long template specific PCR amplification of the GBA1 gene (and not the pseudogene) followed by Sanger sequencing allows the identification of single base pair variants and most recombinant alleles leading to molecular diagnosis of GD about 95-98% of cases [bib_ref] Gaucher disease: Biochemical and molecular findings in 141 patients diagnosed in Greece, Dimitriou [/bib_ref] [bib_ref] Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher..., Filocamo [/bib_ref] [bib_ref] Analysis and classification of 304 mutant alleles in patients with type 1..., Koprivica [/bib_ref] [bib_ref] Mutation prevalence among 51 unrelated Spanish patients with Gaucher disease: identification of..., Alfonso [/bib_ref] [bib_ref] Identification and functional characterization of five novel mutant alleles in 58 Italian..., Miocić [/bib_ref] [bib_ref] Genetic and clinical features of patients with Gaucher disease in Hungary, Erdos [/bib_ref] [bib_ref] Molecular analysis of Turkish Gaucher disease patients: identification of novel mutations in..., Emre [/bib_ref] [bib_ref] Spectrum of GBA mutations in patients with gaucher disease from Slovakia: identification..., Mattošová [/bib_ref] [bib_ref] Clinical and genetic characteristics of Korean patients with Gaucher disease, Jeong [/bib_ref] [bib_ref] Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación..., Ortiz-Cabrera N V [/bib_ref] [bib_ref] Clinical and molecular characteristics of patients with Gaucher disease in Southern China, Feng [/bib_ref] [bib_ref] Gaucher disease: Single gene molecular characterization of one-hundred Indian patients reveals novel..., Sheth [/bib_ref] [bib_ref] Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene, Lepe-Balsalobre [/bib_ref] [bib_ref] Novel pathogenic mutations in the glucocerebrosidase locus, Duran [/bib_ref] ; however, this method fails to detect large deletions [bib_ref] Analysis and classification of 304 mutant alleles in patients with type 1..., Koprivica [/bib_ref] [bib_ref] Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación..., Ortiz-Cabrera N V [/bib_ref] [bib_ref] Erroneous assignment of Gaucher disease genotype as a consequence of a complete..., Beutler [/bib_ref] [bib_ref] Molecular characterization of a new deletion of the GBA1 gene due to..., Cozar [/bib_ref].
GBA1 gene can also be analyzed using Next-Generation Sequencing (NGS) technologies, both as a single gene or as part of targeted gene panels, Whole exome sequencing (WES) or Whole genome sequencing (WGS). In all cases, the workflow should be optimized to avoid false positive or negative results due to misalignment of reads between the gene and the pseudogene.
Strategies to specifically analyze the GBA1 as a single gene using NGS technology have been developed [bib_ref] GBA analysis in nextgeneration era: pitfalls, challenges, and possible solutions, Zampieri [/bib_ref] [bib_ref] A large-scale full GBA1 gene screening in Parkinson's disease in the Netherlands, Den Heijer [/bib_ref] [bib_ref] False negatives in GBA1 sequencing due to polymerase dependent allelic imbalance, Den Heijer [/bib_ref]. Such NGS strategies allow the identification of single base pair variants and recombinant alleles (excluding the Recdelta55) with high specificity and sensitivity [bib_ref] GBA analysis in nextgeneration era: pitfalls, challenges, and possible solutions, Zampieri [/bib_ref] [bib_ref] False negatives in GBA1 sequencing due to polymerase dependent allelic imbalance, Den Heijer [/bib_ref]. Conversely, analysis of the GBA1 gene as part of gene panels using well designed NGS strategies that consider the presence of the pseudogene, allows only the identification of point mutations, while fail to identify both large deletions and recombinant alleles due [bib_ref] Sensitivity, advantages, limitations, and clinical utility of targeted next-generation sequencing panels for..., Málaga [/bib_ref] [bib_ref] Resolving misalignment interference for NGS-based clinical diagnostics, Lee [/bib_ref] [bib_ref] Early detection of lysosomal diseases by screening of cases of idiopathic splenomegaly..., Muñoz [/bib_ref] [bib_ref] Setup and validation of a targeted next-generation sequencing approach for the diagnosis..., Zanetti [/bib_ref] [bib_ref] Accurate molecular diagnosis of Gaucher disease using clinical exome sequencing as a..., Zampieri [/bib_ref]. However, NGS data analysis is a field in continuous and rapid evolution and new solutions to improve sensitivity and specificity are expected to be available in the near future [bib_ref] Detection of genomic rearrangements from targeted resequencing data in Parkinson's disease patients, Spataro [/bib_ref].
Indeed, the use of PacBio long-read Single Molecule Real-Time (SMRT) for GBA1 deep sequencing has recently been developed [bib_ref] Long-read single molecule real-time (SMRT) sequencing of GBA1 locus in Gaucher disease..., Drelichman [/bib_ref]. However, this technology is still not widely available in most genetic laboratories.
Multiplex ligation-probe amplification (MLPA) kits have been developed for the identification of recombinant/deleted GBA alleles. However, commercially available kits do not discriminate between L444P mutant and RecNci alleles and do not discriminate between recombination events and deletions [bib_ref] Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación..., Ortiz-Cabrera N V [/bib_ref] [bib_ref] Accurate molecular diagnosis of Gaucher disease using clinical exome sequencing as a..., Zampieri [/bib_ref] [bib_ref] MLPAbased approach for initial and simultaneous detection of GBA deletions and recombinant..., Amico [/bib_ref].
Recommendation #14: Sequencing analysis of GBA1 exons and intron exon boundaries should be performed as the primary molecular test. It should be performed using specific long template amplification of the GBA gene (avoiding the amplification of the pseudogene) followed by Sanger sequencing or NGS specifically designed to avoid reads misalignments. This strategy allows detecting point mutations and most recombinant alleles but is not suitable to detect large deletions. Recommendation #15: GBA1 could be included in gene panels analyzed by NGS. This technology allows the detection of point mutations, although false positive results have been reported. Therefore, point mutations detected by NGS methods should always be confirmed by Sanger sequencing. Standard workflows are not suitable for the detection of large deletions or recombinant alleles. Recommendation #16: Segregation of alleles by identifying variants in parents, should be determined. Recommendation #17: The presence of homozygous pathogenetic variants not confirmed in parents, as well as the absence of pathogenetic variants (in one or both allele) after sequencing should always be questioned and additional investigations should be performed. In particular, multiplex ligation-probe amplification (MLPA) and mRNA analysis should be done to identify possible undetected recombinant/deleted alleles or deep intronic pathogenetic variants, respectively. Recommendation #18: Variants should be classified following the ACMG criteria and in case of identification of VUS, pathogenicity should be investiagted by functional analysis.
Level of evidence: II and IV (retrospective cohort studies or case series with consistent results) Grade: B (Recommendation)
## Conditions with a biochemical profile suggestive of gd and no pathogenetic variants in gba1 gene
Although most cases of GD are due to mutations within the GBA1 gene, a small number of patients present mutations in the PSAP gene which encodes the GCase activator, saposin C (Sap C) [bib_ref] Mutation in the sphingolipid activator protein 2 in a patient with a..., Schnabel [/bib_ref] [bib_ref] Mutational analysis in a patient with a variant form of Gaucher disease..., Rafi [/bib_ref] [bib_ref] Activator protein deficient Gaucher's disease. A second patient with the newly identified..., Christomanou [/bib_ref] [bib_ref] Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation,..., Vaccaro [/bib_ref] [bib_ref] A rare form of Gaucher disease resulting from saposin C deficiency, Kang [/bib_ref] [bib_ref] Non-neuronopathic Gaucher disease due to saposin C deficiency, Tylki-Szymańska [/bib_ref].
Sap C is a member of a family of four small lysosomal glycoproteins (Saps A, B, C and D), all derived by proteolytic processing from a common precursor protein, prosaposin (PSAP), encoded by the PSAP gene (NM_001042465.3) located on chromosome 10 [bib_ref] Lysosomal proteolysis of prosaposin, the precursor of saposins (sphingolipid activator proteins): its..., Hiraiwa [/bib_ref] [bib_ref] Biosynthesis, processing, and targeting of sphingolipid activator protein (SAP) precursor in cultured..., Vielhaber [/bib_ref].
Sap C promotes rearrangement of lipid organization in lysosomal membranes favoring substrate accessibility to GCase. Therefore, mutations in the Sap C domain of PSAP result in the inability of GCase to degrade GlcCer, with the consequent accumulation within the lysosomes, leading to a GD like phenotype. These patients display increased chitotriosidase activity and increased levels of GlcSph. However, the in vitro GCase activity in cells results reduced or even normal since Sap C is not needed for the hydrolysis of the artificial substrate used in the diagnostic test in vitro [bib_ref] Mutational analysis in a patient with a variant form of Gaucher disease..., Rafi [/bib_ref] [bib_ref] Activator protein deficient Gaucher's disease. A second patient with the newly identified..., Christomanou [/bib_ref] [bib_ref] Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation,..., Vaccaro [/bib_ref] [bib_ref] A rare form of Gaucher disease resulting from saposin C deficiency, Kang [/bib_ref] [bib_ref] Non-neuronopathic Gaucher disease due to saposin C deficiency, Tylki-Szymańska [/bib_ref] [bib_ref] Gaucher disease due to saposin C deficiency is an inherited lysosomal disease..., Motta [/bib_ref].
## Recommendation #19:
In the absence of pathogenetic variants in the GBA1 gene in subjects with a clinical phenotype compatible with GD, increased chitotriosidase activity, increased levels of GlcSph and normal or low BGLU activity in cells, a Sap C deficiency should be suspected and the PSAP gene analyzed. Level of evidence: V (case reports) Grade: D (Option)
## Use of dbs samples for diagnosis in external laboratories
The use of dried blood spots (DBS) in the diagnosis of lysosomal storage disorders has become increasingly popular mainly due to its convenience.
As stated above, BGLU activity and GlcSph can be measured in DBS. However, results have to be interpreted with caution since BGLU testing in DBS has a very poor positive predictive value (see enzyme activity section) and although recent monocentric studies have shown encouraging results in favor of using DBS to assess
# Final conclusions
These guidelines address the laboratory workup for the diagnosis of GD type 1 and are intended to facilitate accurate and timely diagnosis regardless of demography and access to health care. Based on the gathered evidences and the recommendations above, a diagnostic algorithm has been developed as shown in [fig_ref] Figure 1: Diagnostic algorithm 1 [/fig_ref]. The group is aware that not all patients around the world have access to in-house testing and they are obliged to rely on external laboratories, sometimes commercial services, for diagnosis. In this case, dry blood spots can be used although results have to be interpreted with caution. An algorithm for diagnosis using DBS is shown in :
The interpretation of the test described in this workflow can be challenging and not always straight forward. Therefore, the group recommends that expert laboratories interpret the results in the context of the clinical description of the patient. Moreover, the group strongly recommends that the report includes a clear interpretation that reflects the conclusion of the result, possible limitations of the test, and recommendations for additional testing, where applicable. should be confirmed by multiple centers with special attention to the influence of storage and shipment conditions. 3. The potential application of plasma biomarkers to monitor disease progression and efficacy of therapeutic intervention warrants further investigation, in consultation with other IWGGD working groups. 4. Collection of more information on plasma biomarkers in other conditions in which a (partial) deficiency of GCase activity occurs: Niemann Pick type C, Action Myoclonus Renal Failure Syndrome, Saposin C deficiency. 5. Identification of biomarkers able to predict the possible neurological involvement in newly identified patients. 6. Development of new methods for accurate and cost/ effective analysis genetic testing of GBA1.
[fig] Recommendation 9: Each laboratory should establish its own Quality Management (QM) system, if possible, according to ISO15189 international standards and participate in both internal and external quality assessments. Level of evidence: V (Review, expert opinion) Grade: D (Option) Genetic testing GD is caused by biallelic pathogenic variants in the gene encoding the acid β glucocerebrosidase protein, GBA1 (GRCh37/hg19 Chromosome 1: 155,204,239 to 155,214,653). [/fig]
[fig] Figure 1: Diagnostic algorithm 1. *The presence of the 24 bp deletion has to be excluded if this is the only biomarker assessed and it results normal. **Subjects presenting suggestive GD symptoms must be reassessed even in the presence of normal BGLU in DBS of assays of various plasma biomarkers is recommended. A first step in this direction is undertaken by the IWGGD working group Biomarkers & Materials. 2. The use of DBS to assess biomarkers (e.g. GlcSph) [/fig]
[table] 1: Biomarkers of GD assisting in diagnosis A. Biomarkers described in GD: How GCase activity can be measured?C. What is the role of enzymatic activity in GD diagnosis? D. How to validate GCase assay in the laboratory? [/table]
[table] Table 2: Grade of recommendation & criteria [/table]
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COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials
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COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials
volume 18 | may 2021 | 313 Nature reviews | ClInICal OnCOlOgy P e r s P e c t i v e s 0123456789();:
As 2020 ended, we saw a glimmer of hope against the coronavirus disease 2019 (COVID-19) pandemic, with promising safety and efficacy data emerging from clinical trials of several vaccines targeting the COVID-19 causative virus, SARS-CoV-2 (refs 1-5 ). As a result, the FDA has granted emergency use authorization (EUA) to BNT162b2 and to mRNA-1273, two lipid nanoparticle-formulated, nucleoside-modified mRNA-based vaccines encoding the prefusion spike glycoprotein of SARS-CoV-2, and to Ad26.COV2.S, a replication-incompetent adenovirus type 26 (Ad26) vector vaccine encoding a authorized for use in their country of origin. Currently, more than 60 different COVID-19 vaccines are at different stages of clinical development. Limited data are available, however, on the safety, tolerability and efficacy of COVID-19 vaccines in patients with cancer, owing to the exclusion of patients with active malignancies from most of the vaccination trials [bib_ref] Commentary: SARS-CoV-2 vaccines and cancer patients, Corti [/bib_ref]. For example, among the 43,540 participants enrolled in the trial of BNT162b2, only 3.7% were reported to have cancer. Overall, only ten patients had developed severe COVID-19 at the time of reporting of initial results from this trial, one in the vaccine arm and nine in the placebo arm (whether any of these patients had cancer was not reported) [bib_ref] Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine, Polack [/bib_ref]. Thus, generating more data on the efficacy of COVID-19 vaccines in patients with cancer, especially in the setting of active cancer therapy, is a priority.
Multiple studies have revealed that patients with cancer have an increased risk of complications and mortality from COVID-19, including 30-day mortality of 30% in hospitalized patients with COVID-and cancer compared with 21% in those without cancer [bib_ref] COVID-19 and cancer: lessons from a pooled meta-analysis, Desai [/bib_ref] [bib_ref] Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study, Kuderer [/bib_ref] [bib_ref] A global effort to understand the riddles of COVID-19 and cancer, Subbiah [/bib_ref] [bib_ref] Clinical features associated with COVID-19 outcome in multiple myeloma: first results from..., Chari [/bib_ref] [bib_ref] High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal..., Barbui [/bib_ref] [bib_ref] Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an..., Sharma [/bib_ref] [bib_ref] Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in..., Richardson [/bib_ref]. Given the greater severity of the disease and higher risk of death, patients with cancer are considered a high-priority subgroup for COVID-19 vaccination. In the USA, multiple organizations, including the American Association for Cancer Research (AACR), the American Society of Clinical Oncology (ASCO) and the Association of American Cancer Institutes (AACI), have urged the Centres for Disease Control and Prevention (CDC) to prioritize patients with cancer for COVID-19 vaccination [bib_ref] Priority COVID-19 vaccination for patients with cancer while vaccine supply is limited, Ribas [/bib_ref] [bib_ref] Cancer groups urge CDC to prioritize cancer patients for COVID-19 vaccination, Ong [/bib_ref]. The European Society for Medical Oncology (ESMO), the Society for Immunotherapy of Cancer (SITC), the Spanish Medical Oncology Society (SEOM) and the National Comprehensive Cancer Network (NCCN) COVID-19 Vaccination Advisory Committee have released their preliminary recommendations supporting vaccination in all patients with cancer, including those receiving active therapy [bib_ref] The ESMO call to action on COVID-19 vaccinations and patients with cancer:..., Garassino [/bib_ref]. Exception from vaccination would apply to patients undergoing transplantation or adoptive cell therapy, for whom immunization should be delayed for at least 3 months to maximize vaccine efficacy, in line with stabilized variant of the SARS-CoV-2 spike protein 1,2 . In addition, the UK Medicines and Healthcare products Regulatory Agency has approved the ChAdOx1 nCoV-19 vaccine, comprising a recombinant, replication-deficient chimpanzee adenovirus vector also encoding the SARS-CoV-2 spike glycoprotein 5 . Encouraging preliminary safety and efficacy results have also been reported with the rAd26 and rAd5 heterologous prime-boost recombinant adenovirus vector COVID-19 vaccine developed in Russia and with the CoronaVac inactivated SARS-CoV-2 vaccine developed in China 3,4 , both of which have been COVID-19 vaccine guidance for patients with cancer participating in oncology clinical trials Abstract | Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility. the general recommendations of delaying vaccinations following such highly immunosuppressive therapies. The NCCN committee also called for the inclusion of patients with cancer in the CDC priority group for phase Ib/Ic of COVID-19 vaccine distribution, which includes essential workers (such as those involved in law enforcement, teachers and firefighters), adults ≥65 years of age and individuals 16-64 years of age with high-risk medical conditions. However, the NCCN guidelines encourage discussions between clinical trial leads and patients enrolled on their trials to prevent protocol violations or exclusions, and most of the other guidelines are silent on the language regarding patients enrolled in cancer clinical trials.
Given that the current vaccines are 'authorized' and not 'approved' in many countries, a question remains as to whether they are considered investigational. Recognition of this issue is important because the protocols of many trials include criteria prohibiting the concomitant use of other investigational agents, although usually such criteria are meant to apply to other anticancer therapies, specifically. In January 2021, the FDA provided clarification that receipt of a COVID-19 vaccine under an EUA is not considered to constitute treatment with an investigational product. Similarly, other regulatory authorities should consider providing such clarification and guidance. Furthermore, no data are available on the safety or efficacy of COVID-19 vaccines in patients enrolled on oncology clinical trials, especially of novel investigational agents; therefore, rapidly generating data in this subset of patients is crucial. Indeed, several questions remain unanswered, including the time needed for immunity to develop, the duration of immunity, the effects of different systemic treatments on immunity and the optimal time points and posology of vaccine administration in patients with cancer. Given the experience with prior vaccines, such as those against influenza 23 , no serious safety concerns are expected in patients with cancer. Moreover, the currently available vaccines do not contain functional coronavirus and are, therefore, hypothesized to have no possibility of causing an active infection, even in immunosuppressed patients.
Given the risk posed by the COVID-19 pandemic, prompt decisions need to be made regarding the use of any vaccine, including those approved and/or authorized for use against SARS-CoV-2, in patients treated with investigational agents on clinical trials.
Patients with cancer should not have to choose between enrolling on an oncology clinical trial and receiving a COVID-19 vaccine. On this background, clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently participating in oncology clinical trials or might be considering or seeking trial enrolment.
Clinical trials are integral to high-quality oncological care and are crucial for improvements in the management of cancer. During the COVID-19 pandemic, patient enrolment has decreased across oncology trials of all phases (from trials of screening and/or prevention strategies to phase I, II and III trials) [bib_ref] Association of the COVID-19 outbreak with patient willingness to enroll in cancer..., Fleury [/bib_ref] [bib_ref] Association of the coronavirus disease 2019 (COVID-19) outbreak with enrollment in cancer..., Unger [/bib_ref] , which will likely hinder scientific and medical progress. For many patients with rare diseases or specific biomarker-driven cancers, trials testing novel investigational treatments might be the best therapeutic option -or sometimes the only option -following receipt of standard-of-care therapies. Although oncology trials are often complex, with mandated protocol schedules (including laboratory tests, scans, biopsies and clinical visits) at specific time points, both the FDA and the EMA have recognized that protocol deviations might be unavoidable and protocol modifications might also be required to maximize patient safety during the COVID-19 pandemic. This timely regulatory guidance has facilitated investigators, industry partners and academic centres in working with their institutional review boards to navigate the pandemic and has made the clinical trials more patient-centric [bib_ref] COVID-19 pandemic and cancer clinical trial pandemonium: finding the silver lining, Desai [/bib_ref]. We believe that COVID-19 vaccination provides another such opportunity to focus on 'patient safety first and then protocols later' in the context of clinical trials. Depriving eligible and vulnerable patients with cancer of COVID-19 vaccination would fall below the standard of care; therefore, recruiting any patient with cancer to any trial that prevented or discouraged them from receiving a vaccine with at least EUA would be unethical. Herein, we outline COVID-19 vaccine guidance for patients participating in oncology clinical trials.
## Recommendations
## Classification of vaccines. a covid-19
vaccine that has been authorized by the appropriate regulatory authorities in the respective countries should not be considered as an investigational agent for the purposes of oncology clinical trials. An approved and/or authorized vaccine should be considered as a concomitant medication and entered as such in the electronic record. The dates of first and second vaccinations, the doses used and any adverse effects should also be recorded. This information might be helpful in the future to evaluate the effects of COVID-19 vaccination on the safety and efficacy of anticancer therapies, in particular, immunotherapies.
Patient prioritization. COVID-19 vaccines should be offered to all patients with cancer, including those participating in clinical studies. Indeed, we recommend that immunization against COVID-19 be the norm, not an exception, for patients participating in trials of cancer treatments. Moreover, eligible patients who have received COVID-19 vaccines should be accepted on all phases of clinical trials.
We further recommend that patients with cancer in general, including those enrolled on clinical trials, should be prioritized for COVID-19 vaccination. Patients participating in clinical trials often have progressive advanced-stage cancer, are undergoing active treatment and usually make several visits to clinics and hospitals for study-related procedures, which potentially increases their exposure to SARS-CoV-2 infection at multiple points. Thus, prioritization for vaccination is imperative, particularly considering that patients with cancer also seem to have an increased risk of severe COVID-19 and complications and mortality from the disease [bib_ref] COVID-19 and cancer: lessons from a pooled meta-analysis, Desai [/bib_ref] [bib_ref] Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study, Kuderer [/bib_ref] [bib_ref] A global effort to understand the riddles of COVID-19 and cancer, Subbiah [/bib_ref] [bib_ref] Clinical features associated with COVID-19 outcome in multiple myeloma: first results from..., Chari [/bib_ref] [bib_ref] High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal..., Barbui [/bib_ref] [bib_ref] Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an..., Sharma [/bib_ref] [bib_ref] Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in..., Richardson [/bib_ref]. Due consideration should also be given to other well-recognized risk factors for severe COVID-19, such as advanced age (≥65 years), comorbidities (for example, chronic pulmonary, cardiovascular or renal disease) and other sociodemographic factors (such as overcrowded housing, single-parent households and ethnicity) [bib_ref] Association of social and demographic factors With COVID-19 incidence and death rates..., Karmakar [/bib_ref] , when prioritizing patients with cancer for vaccination, with priority given to those at most risk.
In addition to patients with cancer, we also suggest that caregivers, household members and/or close contacts of these patients (adults regardless of age) should be vaccinated as early as possible based on the local guidelines for public vaccinations. This strategy will enable further reductions in risk of SARS-CoV-2 transmission from close contacts for high-risk patients with cancer.
Preference should be given to approved and/or authorized vaccines for use in patients enrolled on oncology clinical trials. In situations in which an authorized vaccine is unavailable, if a specific trial of a COVID-19 vaccine is available to patients with cancer (for example, the vaccination against COVID in cancer (VOICE) study (NCT04715438), a prospective, national, multicentre, longitudinal, multi-cohort study in patients with solid malignancies undergoing active anticancer treatment [bib_ref] COVID-19 vaccination: the VOICE for patients with cancer, Van Der Veldt [/bib_ref] , or any studies testing booster doses or revaccination schedules in immunocompromised patients that become available in the future) [bib_ref] Looking beyond COVID-19 vaccine phase 3 trials, Kim [/bib_ref] , patients who are participating in an oncology clinical trial should not be excluded from the vaccine trial. Moreover, loosening the eligibility criteria of all trials of COVID-19 vaccines to permit enrolment of patients with cancer, including those receiving investigational therapies, would be prudent.
## Timing of vaccination.
For patients currently enrolled on phase I trials, the timing of vaccination should be based on the type of anticancer treatment and the stage of the trial (dose escalation versus dose expansion) [fig_ref] Table 1 |: COVID-19 vaccine guidance for patients participating in oncology clinical trials [/fig_ref]. Due consideration should be given to any confounding variables relating to the expected adverse effects of the investigational drugs and vaccines, especially during the dose-limiting toxicity (DLT) window 32 , to avoid overlapping toxicities that might compromise the safety and tolerability of either treatment. Patients entering clinical trials, especially phase I trials, could receive the first dose of a COVID-19 vaccine while undergoing screening procedures for trial eligibility. If clinical trial sponsors have specific, mechanism-based concerns regarding the timing of vaccination relative to the investigational agents (for example, agents with cytokine-release syndrome potential or anti-CD20 antibodies), they should issue immediate guidance on vaccination of patients who enrol on the trial.
Some adverse events seen with COVID-19 vaccines might manifest similarly to those of novel anticancer agents in early phase trials, especially hypersensitivity reactions. To minimize the need to determine whether a patient is experiencing hypersensitivity to an investigational product or an adverse event related to vaccine administration, consideration should be given to the timing of vaccination based on the mechanism of action of the anticancer agents. Most hypersensitivity reactions to novel agents are observed within the first one or two doses of monoclonal antibodies or within the first 1-2 weeks after initiation of therapy with tyrosine kinase inhibitors [bib_ref] Drug hypersensitivity and anaphylaxis in cancer and chronic inflammatory diseases: the role..., Castells [/bib_ref]. This pattern might be helpful when determining whether the causality of an adverse event is related to the study treatment or the vaccine. If possible, we recommend avoiding administration of an investigational agent within 48-72 h of vaccination to minimize confusion and/or inaccurate attribution of adverse event causation.
The currently available vaccines should not be a contraindication in patients with controlled HIV infection (or other immunocompromised states) and cancer. However, such patients should be counselled regarding the lack of data on the safety and particularly the efficacy of COVID-19 vaccination, especially with novel mRNA-based vaccines, in this setting.
In general, we recommend that patients with solid tumours or haematological malignancies who are receiving cytotoxic therapies, targeted therapies, hormone therapies and/or immunotherapies on a clinical trial should be vaccinated against COVID-19 at the earliest available opportunity. The suggested vaccination schedules for such patients can vary according to the type of trial, disease and cancer treatment [fig_ref] Table 1 |: COVID-19 vaccine guidance for patients participating in oncology clinical trials [/fig_ref]. The only exception to this rule relates to patients on clinical trials involving transplantation or adoptive cell therapies: vaccine administration might need to be delayed for ≥3 months to enable these patients to regain adequate immune function, given that potential graft versus host disease and the immunosuppressive regimens used are expected to blunt immune responses to any vaccine. Other considerations in patients with haematological malignancies include the timing of vaccine administration around infusions required for various chemotherapy regimens and decreased blood counts, particularly neutropenia, lymphopenia and thrombocytopenia, according to local practices at each hospital and the treating physician's judgement in the patient's best interest.
For patients receiving cytotoxic chemotherapy, given the lack of data on the optimal timing of vaccination, we recommend COVID-19 vaccination whenever a vaccine is available [fig_ref] Table 1 |: COVID-19 vaccine guidance for patients participating in oncology clinical trials [/fig_ref]. Data from a study on the optimal timing of influenza vaccination during 3-week chemotherapy cycles indicate that antibody responses to the vaccine are similar in patients inoculated concurrently with chemotherapy administration and in those inoculated during the cytopenic period of the chemotherapy cycle [bib_ref] Optimal timing of influenza vaccination during 3-week cytotoxic chemotherapy cycles, Keam [/bib_ref]. Extrapolating from the findings of this study, we recommend that COVID-19 vaccines should be administered whenever available, until more data on optimal timing become available. This recommendation might be updated when further data on COVID-19 vaccination emerge.
According to the CDC 35 , at this time, revaccination is not recommended after immune competence is regained in persons who received one of the authorized mRNA-based COVID-19 vaccines during chemotherapy or treatment with other immunosuppressive drugs. However, recommendations on revaccination or additional doses of COVID-19 vaccines might be updated as additional information becomes available.
For patients undergoing elective surgery, the work-up time should enable COVID-19 vaccination before surgery. In the case of urgent or emergent surgery, patients can be vaccinated postoperatively, after patient recovery.
For participants in breast cancer screening trials, consideration should be given to the fact that COVID-19 vaccination can cause transient lymphadenopathy [bib_ref] Management of unilateral axillary lymphadenopathy detected on breast MRI in the era..., Edmonds [/bib_ref]. Therefore, if possible and if patient management will not be unjustifiably interrupted, screening examinations should be conducted either before the first dose of a COVID-19 vaccine or 4-6 weeks after the second dose, as recommended previously by other groups [bib_ref] Management of unilateral axillary lymphadenopathy detected on breast MRI in the era..., Edmonds [/bib_ref].
Importantly, long-term pharmacovigilance is required for all patients who receive any COVID-19 vaccine. Any emerging concerns regarding the safety or efficacy of COVID-19 vaccines should be recorded appropriately.
Clinical trial reporting. We encourage, when possible, the inclusion of the vaccination status of oncology clinical trial participants in the data record. This practice will enable accurate assessment and attribution of adverse events, which could be sub-stratified for the vaccinated and unvaccinated subgroups, wherever feasible, for further analysis. COVID-19 vaccination details (including vaccine name, batch and manufacturer, dose, date of administration and whether the right or left arm was injected) should be captured as a concomitant medication to enable better assessment of the overall effect of COVID-19 vaccination on oncology trial results.
## Additional considerations
Other reasons for delaying COVID-19 vaccination of participants in oncology clinical trials, such as recent exposure to COVID-19 or previous allergic or anaphylactic reactions to vaccine components, should be consistent with the general CDC or WHO guidelines. We hope that additional large-cohort trials and real-world data on COVID-19 vaccines with longer follow-up durations will provide timely information on the effectiveness of the vaccines in patients receiving different cancer treatments; however, the current situation requires swift action to prevent the potential harm of delaying COVID-19 vaccination for this vulnerable subgroup.
To gain a deeper understanding of patients' experiences when receiving treatment on a specific trial, the systematic integration of patient-reported outcomes and other quality-of-life assessments On vaccine availability, with timing based on mechanism of action
## Type of treatment
Surgery clinical trials Administer at discharge after recovery from post-operative complications or 1 week before surgery, whichever is most feasible Radiation oncology clinical trials On vaccine availability (the exception is total body radiation, after which vaccination might need to be delayed to provide time for immune reconstitution)
## Solid tumours
Cytotoxic chemotherapies On vaccine availability (1-2 weeks before or 1-2 weeks after drug dose, when possible, to increase the potential for the immune system to mount a response) longitudinally throughout the course of therapy is suggested when possible. This awareness of both therapy-related and cancer-related symptom burden over time while patients are on a trial will provide crucial information for the frontline clinical teams as well as patients and their families to guide decision-making and the selection of therapies that are in line with their overall goals and values. Mobilization efforts from local and state governments and increased flexibility from protocol administrators are required to bring widespread COVID-19 vaccination of patients with cancer to fruition. At the level of investigational centres, ethics committees should be more understanding in cases of protocol deviations, especially if the language in specific protocols is not clear or updated with regard to COVID-19 vaccinations. Allowances for COVID-19 vaccination should ideally be documented in the protocol. Any protocol deviations should be documented, however, considering that such deviations are generally made in the interest of patient safety.
Clinical trial sponsors have begun to roll out guidance on COVID-19 vaccination to investigators, even providing appropriate timing of when study medications should be taken (for example, at least 2 h before or after administration of the vaccine). The sponsors might also request that the electronic data capture systems be updated to reflect this vaccination and to document any associated adverse events. Importantly, major research networks such as the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP), the Experimental Therapeutics Clinical Trials Network (ETCTN) and the SWOG Cancer Research Network 40 have granted broad permission for, and indeed encouraged, COVID-19 vaccination of participants on their respective trials. Their guidance includes capturing receipt of the vaccine in the medical history, if received before trial enrolment, or as a concomitant medication if administered after enrolment. This kind of clear precedent is welcome and gives individual investigators the freedom to encourage vaccination of their trial patients without trepidation. Furthermore, nationwide coordinated research efforts, such as the NCI Serological Sciences Network for COVID-19 (SeroNet), are studying the immune response to COVID-19, with the aim of combating the pandemic by accelerating the development of treatments and vaccines.
Lastly, advocacy for patients with cancer, including those involved in clinical trials, by their caregivers, physicians and other health-care professionals is imperative to convince stakeholders to consider this group as a high priority. Guidance from the FDA, EMA, NCI and other cancer-focused organizations worldwide might also be needed. Meanwhile, all close contacts of such patients should continue to wear masks, adhere to social distancing guidelines and follow other recommendations, including avoiding unnecessary travel, in order to reduce the risk of SARS-CoV-2 infection and, thus, COVID-19. Given the need to generate data on the immunogenicity of vaccines during systemic cancer therapy, we encourage patient participation in such studies if available locally.
# Conclusions
In summary, COVID-19 vaccination, where authorized or approved, should be considered a standard of care for patients with cancer who are currently enrolled on investigational trials. Uncommon exceptions might occur when the principal investigator or treating physician considers use of the vaccine not to be safe or in the patient's best interest. Current knowledge of the safety and efficacy of the authorized COVID-19 vaccines in patients with cancer and particularly those receiving active treatment is limited, although the benefits likely outweigh the risks of vaccine-related adverse effects, considering the high risk of morbidity and mortality from COVID-19 in patients with cancer. Moreover, equitable access to cancer clinical trials and COVID-19 vaccines is imperative. Indeed, continued quality oncological care requires that patients on clinical trials be prioritized for COVID-19 vaccination, which, in and of itself, should not affect clinical trial eligibility.
[table] Table 1 |: COVID-19 vaccine guidance for patients participating in oncology clinical trials [/table]
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https://www.nature.com/articles/s41571-021-00487-z.pdf
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Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE)
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Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE)
Purpose To provide the evidence-based recommendations on the role of testosterone (T) on age-related symptoms and signs remains. Methods The Italian Society of Andrology and Sexual Medicine (SIAMS) and the and the Italian Society of Endocrinology (SIE) commissioned an expert task force to provide an updated guideline on adult-onset male hypogonadism. Derived recommendations were based on Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Results Clinical diagnosis of adult-onset hypogonadism should be based on a combination of clinical and biochemical parameters. Testosterone replacement therapy (TRT) should be offered to all symptomatic subjects with hypogonadism after the exclusion of possible contraindications. T gels and the long-acting injectable T are currently available preparations showing the best efficacy/safety profile. TRT can improve all aspects of sexual function, although its effect is limited in more complicated patients. Body composition (reducing fat mass and increasing lean mass) is improved after TRT, either in subjects with or without metabolic syndrome or type 2 diabetes. Conversely, the role of TRT in improving glycometabolic control is more conflicting. TRT can result in increasing bone mineral density, particularly at lumbar site, but no information on fracture risk is available. Limited data support the use of TRT for improving other outcomes, including mood frailty and mobility. Conclusions TRT can improve sexual function and body composition particularly in less complicated adult and in aging subjects with hypogonadism. When hypogonadism is adequately diagnosed, T appropriately prescribed and subjects correctly followed up, no short-term increased risk of adverse events is observed. Longer and larger studies are advisable to better clarify TRT long-term efficacy/safety profile.
# Introduction
During the last 2 decades, there was a growing awareness concerning male hypogonadism and its potential treatment. To the classical forms of hypogonadism, the description of an "age-associated testosterone decline", supported by several epidemiological studies [bib_ref] Sex hormones and age: a cross-sectional study of testosterone and estradiol and..., Ferrini [/bib_ref] [bib_ref] Normal, bound and nonbound testosterone levels in normally ageing men: results from..., Mohr [/bib_ref] [bib_ref] Longitudinal effects of aging on serum total and free testosterone levels in..., Harman [/bib_ref] [bib_ref] Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and..., Wu [/bib_ref] , widely broadened the number of potentially treatable men. To what extent the decline in testosterone (T) concentrations observed in the aging male contributes to age-related morbidities and symptoms remains under scrutiny [bib_ref] Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or merely an epiphenomenon..., Corona [/bib_ref]. Interestingly, the sales of T-containing medications dramatically increased worldwide [bib_ref] expanding the spectrum of prescription drug misuse, Handelsman [/bib_ref]. While the global trend reflected an increased awareness toward male hypogonadism, often an underdiagnosed and undertreated condition with a worldwide evenly distributed prevalence in North America reflected the effect of direct-to-consumer advertising (DTCPA). T treatment was inappropriately promoted as a fountain of youth, and exposure to televised DTCPA was associated with greater T testing, new initiation of therapy and, especially, initiation of therapy without prior T testing [bib_ref] Association between direct-to-consumer advertising and testosterone testing and initiation in the United..., Layton [/bib_ref]. To halt T overuse, the US Food and Drug Administration (FDA) cautioned that the benefits of T treatment were not clearly established when T concentrations were low due to aging. The FDA warned that T replacement therapy (TRT) should be considered only for men with "classical hypogonadism", i.e. due to primary or secondary T deficiency resulting from known problems within the testis, pituitary, or hypothalamus. Later on, this concept was partially incorporated into the clinical practice guidelines of the US Endocrine Societyas well as in the Australian one [bib_ref] Endocrine society of Australia position statement on male hypogonadism (part 1): assessment..., Yeap [/bib_ref] advocating a theoretical dichotomic distinction between organic (classic) and functional hypogonadism, the latter including the age-associated T deficiency.
In Southern Europe, however, the picture is different and DTCPA more often prohibited. The first Italian guidelines covering the issue of male hypogonadism, including ageassociated deficiency, were issued in 2015 by the Italian Society of Endocrinology [bib_ref] Outcomes of androgen replacement therapy in adult male hypogonadism: recommendations from the..., Isidori [/bib_ref]. Important multicenter trials have been published since then, disclosing novel data on the effectiveness of TRT on various outcomes. Considering the different background between the European and North American situation, aim of these guidelines is to provide an evidence-based updated support to clinician operating on male hypogonadism on behalf of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE).
# Methods
The SIAMS and SIE are large national multidisciplinary non-profit scientific societies leading research in this field. The SIAMS and SIE have commissioned an expert task force to provide an updated guideline on male hypogonadism. Following scrutiny and discussion of the best evidence from published literature available in PubMed, the Authors generated a series of consensus recommendations according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [bib_ref] A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in..., Swiglo [/bib_ref]. The GRADE system allows to rate the quality of evidence and the strength of recommendations and to enhance the value of the clinical advices here provided [bib_ref] A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in..., Swiglo [/bib_ref] with a consistent language and graphical descriptions for standardizing the grading of both the strength of recommendation and the quality of evidence [bib_ref] A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in..., Swiglo [/bib_ref]. Concerning the strength of recommendation, the number 1 indicates a strong recommendation and is associated with the terminology "we recommend"; the number 2 denotes a weak recommendation and is associated with the wording "we suggest". The four levels grading of the quality of evidence employs the following graphical descriptions: ØOOO denotes "very low-quality evidence", ØØOO "low quality", ØØØO "moderate quality", and ØØØØ "high quality".
According to SIAMS rulings, these Guidelines have been arranged by a team of experts on the topic coordinated by the senior author and two members of the SIAMS Guideline Committee, then sent to the SIAMS and SIE Executive Committee and to the Directors of all SIAMS Excellence Centers for revisions and/or approval. Guidelines have then been announced by mail and published for two weeks on the SIAMS and SIE Society's website, siams.info, so that all SIAMS Members could provide further comments and suggest additional minor revisions. Following this last step, the present manuscript has been submitted to the Journal of Endocrinological Investigation for international peer reviewing.
## Definitions
Hypogonadism refers to a clinical and biochemical syndrome characterized by the inability of the testes to produce physiological concentrations of T and/or number of normal sperm cells [bib_ref] Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline, Bhasin [/bib_ref] [bib_ref] European association of urology guidelines on sexual and reproductive health-2021 update: male..., Salonia [/bib_ref] [bib_ref] Critical evaluation of different available guidelines for late-onset hypogonadism, Giagulli [/bib_ref] [bib_ref] Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men, Lunenfeld [/bib_ref].
Male hypogonadism can be due to a testicular dysfunction (primary hypogonadism), a pituitary/hypothalamic failure (secondary hypogonadism) or a combination of both (mixed hypogonadism) [bib_ref] Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline, Bhasin [/bib_ref] [bib_ref] European association of urology guidelines on sexual and reproductive health-2021 update: male..., Salonia [/bib_ref] [bib_ref] Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men, Lunenfeld [/bib_ref]. Some classifications also consider the onset of symptoms (e.g., late-onset hypogonadism-LOH) or the potential reversibility of the condition. In this respect, "organic hypogonadism" refers to an irreversible form of hypogonadism caused by congenital or acquired (destructive or structural) impairment occurring at any level of the hypothalamic-pituitary-testis axis [bib_ref] A perspective on middle-aged and older men with functional hypogonadism: focus on..., Grossmann [/bib_ref] [bib_ref] European academy of andrology (EAA) guidelines on investigation, treatment and monitoring of..., Corona [/bib_ref] [bib_ref] Treatment of functional hypogonadism besides pharmacological substitution, Corona [/bib_ref] , while "functional hypogonadism" refers to a potentially reversible impairment of the hypothalamic-pituitary-testis feedback loop. Functional hypogonadism more often occurs in middle aged or older men (> 40-50 years), is associated to comorbid illnesses (e.g. poor health or obesity), and is associated with a less marked lowering of T concentrations [bib_ref] A perspective on middle-aged and older men with functional hypogonadism: focus on..., Grossmann [/bib_ref] [bib_ref] European academy of andrology (EAA) guidelines on investigation, treatment and monitoring of..., Corona [/bib_ref] [bib_ref] Treatment of functional hypogonadism besides pharmacological substitution, Corona [/bib_ref]. The latter classification is not universally accepted and still a matter of vivid debate.
## Clinical presentation
Signs and symptoms of hypogonadism vary according to the age of onset, etiology and severity of T reduction [bib_ref] Paediatric and adult-onset male hypogonadism, Salonia [/bib_ref] [bib_ref] Which patients with sexual dysfunction are suitable for testosterone replacement therapy?, Morelli [/bib_ref]. In adults, the predominant symptoms include sexual dysfunctions (e.g., erectile dysfunction, decreased libido, reduced nocturnal/morning erections), fatigue, impaired concentration, sweating, low wellbeing and depressive mood [bib_ref] Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline, Bhasin [/bib_ref] [bib_ref] European association of urology guidelines on sexual and reproductive health-2021 update: male..., Salonia [/bib_ref] [bib_ref] Paediatric and adult-onset male hypogonadism, Salonia [/bib_ref] [bib_ref] Which patients with sexual dysfunction are suitable for testosterone replacement therapy?, Morelli [/bib_ref]. Increased body fat, decreased muscle mass and body hair, gynecomastia and reduced testicular volume are common findings at physical examination. Hypogonadism is also associated with anemia, lower prostatic-specific antigen (PSA) concentrations for age, and reduced bone mineral density [bib_ref] Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline, Bhasin [/bib_ref] [bib_ref] European association of urology guidelines on sexual and reproductive health-2021 update: male..., Salonia [/bib_ref] [bib_ref] Paediatric and adult-onset male hypogonadism, Salonia [/bib_ref] [bib_ref] Which patients with sexual dysfunction are suitable for testosterone replacement therapy?, Morelli [/bib_ref] [fig_ref] Figure 1: Symptoms and signs frequently associated with adult-onset hypogonadism documented when T concentrations... [/fig_ref].
## Diagnosis
We recommend measuring total testosterone (tT) and luteinizing hormone (LH) in all men with clinical manifestations consistent with hypogonadism and to adopt a threshold of ≤ 12.0 nmol/L to define low total testosterone (1ØØØO).
We suggest measuring sex hormone-binding globulin (SHBG) during diagnostic workup to calculate free testosterone in all men with clinical manifestations consistent with hypogonadism and to adopt a threshold < 220 pmol/L to define low calculated low free testosterone (fT) .
A value of LH ≥ 9.4 IU/L, in the presence of low total or calculated free testosterone, suggests primary hypogonadism. For LH concentrations < 9.4 IU/L, measuring follicular stimulating hormone (FSH) is helpful in the differential diagnosis between primary and secondary hypogonadism (2ØOOO).
We suggest a diagnosis of compensated hypogonadism in presence of LH ≥ 9.4 IU/l and normal testosterone or calculated free testosterone concentrations (Expert Opinion).
## Evidence
The diagnosis of hypogonadism relies on the concomitant presence of low T concentrations and clinical symptoms and signs of T deficiency [bib_ref] Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline, Bhasin [/bib_ref] [bib_ref] European association of urology guidelines on sexual and reproductive health-2021 update: male..., Salonia [/bib_ref] [bib_ref] Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men, Lunenfeld [/bib_ref] [bib_ref] Paediatric and adult-onset male hypogonadism, Salonia [/bib_ref] [bib_ref] Which patients with sexual dysfunction are suitable for testosterone replacement therapy?, Morelli [/bib_ref] [bib_ref] Identification of late-onset hypogonadism in middleaged and elderly men, Wu [/bib_ref]. Sexual symptoms (erectile dysfunction, low libido, reduced nocturnal erections) are the most frequently complained in adult men with reduced T concentrations [bib_ref] Identification of late-onset hypogonadism in middleaged and elderly men, Wu [/bib_ref] [bib_ref] How to define hypogonadism? Results from a population of men consulting for..., Rastrelli [/bib_ref].
The diagnosis requires the detection of a low T on two separate occasions with blood taken in the morning in standardized conditions, i.e., before 10:00 am and fasting. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is considered the gold standard for T measurement; however. good-quality immunoassays still provide reliable results in the clinical settings [bib_ref] Mass spectrometry and immunoassay: how to measure steroid hormones today and tomorrow, Taylor [/bib_ref]. Conversely, the available immunoassays cannot guarantee accurate values of fT. Hence, fT evaluation by immunoassay is discouraged [bib_ref] Toward excellence in testosterone testing: a consensus statement, Rosner [/bib_ref].
To date, there is no agreement on what should be the T threshold value defining hypogonadism or the lower limit of normal for T distribution in the population, whose values (harmonized to the 2.5th percentile) ranges from 264 ng/ ml (9.2 nmol/L) to 348 ng/ml (12 nmol/L), according to large cohort studies on healthy, non-obese, young adult males [bib_ref] Harmonized reference ranges for circulating testosterone levels in men of four cohort..., Travison [/bib_ref]. However, different thresholds, ranging from 220 (7.6 nmol/L) to 350 ng/dl (12.1 nmol/L), have also been proposed [bib_ref] Critical evaluation of different available guidelines for late-onset hypogonadism, Giagulli [/bib_ref]. Data derived from available meta-analyses suggest that TRT is without effects in subjects with baseline T concentrations > 12 nmol/L (3.5 ng/mL) [bib_ref] Paediatric and adult-onset male hypogonadism, Salonia [/bib_ref] [bib_ref] Testosterone therapy: what we have learned from trials, Corona [/bib_ref]. Since some beneficial effects on various outcomes have been [bib_ref] Paediatric and adult-onset male hypogonadism, Salonia [/bib_ref] [bib_ref] Testosterone therapy: what we have learned from trials, Corona [/bib_ref] , the panel reached consensus on adopting the 12 nmol/L as a threshold for considering TRT in symptomatic hypogonadal men.
The EMAS study showed that fT improved the possibility to correctly identify LOH. According to that study, reduced fT (< 220 pmol/L) increased the odds ratio for hypogonadism as compared with the total T level alone, especially for thresholds between 8.0 and 11 nmol per liter [bib_ref] Identification of late-onset hypogonadism in middleaged and elderly men, Wu [/bib_ref] [bib_ref] Low free testosterone is associated with hypogonadal signs and symptoms in men..., Antonio [/bib_ref]. Similar data have been observed in the longitudinal evaluation of the same study [bib_ref] Symptomatic androgen deficiency develops only when both total and free testosterone decline..., Rastrelli [/bib_ref].
fT can be determined after physical separation from the protein-bound forms, which is achieved through equilibrium dialysis or ultracentrifugation. Equilibrium dialysis is the most accurate method [bib_ref] Reassessing free-testosterone calculation by liquid chromatography-tandem mass spectrometry direct equilibrium dialysis, Fiers [/bib_ref]. However, the latter is expensive, time-consuming, and unfeasible in a clinical setting. Several SHBG and albumin level-based calculations have been proposed to estimate fT (cfT). The Vermeulen method [bib_ref] A critical evaluation of simple methods for the estimation of free testosterone..., Vermeulen [/bib_ref] is still the most accurate, albeit slightly overestimating fT value [bib_ref] Reassessing free-testosterone calculation by liquid chromatography-tandem mass spectrometry direct equilibrium dialysis, Fiers [/bib_ref].
The classification into primary vs. secondary hypogonadism has important clinical and therapeutic implications [bib_ref] Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline, Bhasin [/bib_ref] [bib_ref] European association of urology guidelines on sexual and reproductive health-2021 update: male..., Salonia [/bib_ref]. According to the baseline data of European Male Aging Study (EMAS), LH concentrations ≥ 9.4 IU/l define primary hypogonadism, whereas low or lownormal LH concentrations, in the presence of reduced T concentrations, define secondary hypogonadism. LH concentrations failing to rise when T is low, suggest they are inappropriately normal . When LH concentrations are close to the 9.4 IU/l threshold value, FSH determination, a marker of Sertoli function [33], may help to identify primary testicular failure, despite there is no consensus on a specific FSH threshold value [bib_ref] Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline, Bhasin [/bib_ref] [bib_ref] European association of urology guidelines on sexual and reproductive health-2021 update: male..., Salonia [/bib_ref].
Conversely, a suspect of organic secondary hypogonadism requires additional investigations including magnetic resonance imaging (MRI) scanning of the pituitaryhypothalamus, iron saturation as well as prolactin and other anterior pituitary function. To adopt cost-effective strategy, the aforementioned examinations are indicated when a greater suspicion is driven by specific features including-but not limited to-pituitary mass effects symptoms, visual disturbances, headache or significant hyperprolactinemia or severely reduced T concentrations (i.e. < 6 nmol/L or < 175 ng/dL) are detected ([34-36]; see also .
According to EMAS data, LOH is more frequently characterized by a secondary or mixed, rather than primary or 'compensated' hypogonadism . The EMAS consortium proposed to categorize men with a 'compensated hypogonadism' those having normal T and elevated LH (≥ 9.4 IU/L) . These subjects report mainly physical symptoms, and they had 16-fold increased risk to progress to genuine primary hypogonadism over time, when compared to eugonadal individuals . For this reason, as for thyroid
## Remarks
Clinical manifestations of hypogonadism can occur at different T thresholds and, owing to inter-individual variability, some patients may experience symptoms having serum T in the range of, rather than at, the punctual, threshold values [bib_ref] Identification of late-onset hypogonadism in middleaged and elderly men, Wu [/bib_ref]. For this reason, information coming from LH, SHBG and cfT is much needed.
## Trt options
We recommend starting TRT in all symptomatic hypogonadal men, after contraindications are excluded, in whom a reversal of the condition cannot be expected in a reasonable time-frame (1 ØØOO). We suggest using testosterone gels in older hypogonadal men, in particular in case of potentially reversible conditions (Expert Opinion).
We suggest using long-acting injectable T preparations to treat younger hypogonadal men, in particular in case of irreversible conditions (Expert Opinion).
## Evidence
T delivered at any age with several preparations, including oral, parental and transdermal T formulations [fig_ref] Table 2: Testosterone preparations for hypogonadism treatment available in the Italian market Preparations in... [/fig_ref] , once patients are adequately informed on the advantages and disadvantages of TRT and available formulations. Absolute contraindications should be ruled out and the final decision should be made balancing the clinical situation, available formulations and patient preferences.
Compared to primary hypogonadism, LOH can be a reversible condition associated with co-morbidities and medications interfering with T production or activity. Lifestyle modifications and weight loss should be strongly encouraged in all overweight and obese men with hypogonadism since able to increase T levels per se [bib_ref] Treatment of functional hypogonadism besides pharmacological substitution, Corona [/bib_ref]. Similarly, when possible, interfering drugs should be withdrawn .
Old oral T undecanoate formulations, although still available in Europe and in Italy are no longer recommended, due to the poor bioavailability [42]. The US FDA approved a new formulation of oral T undecanoate incorporating a liquid-filled hard capsule drug delivery system improving oral availability (https:// www. fda. gov/ media/ 110187/ downl oad). However, the latter compound is not yet available in several European countries. Very short-or short-acting parental T formulations such as propionate, cypionate and enanthate have been associated with wider fluctuations of T concentrations, often resulting in patient discomfort and more adverse effects, such as polycythemia . At present time, long-acting injectable T undecanoate and T gels appear the most suitable formulations to restore serum T concentrations in the normal range with good safety profile . The implantation of T pellets represents the longest available T formulations lasting from 4 to 7 months. Implants have a good safety profile, but the procedure is invasive, limiting its widespread use . In addition, the latter, like the trans-nasal and trans-buccal formulations, are not available in Italy. Although face-to-face comparisons among different T formulation are lacking, T gels should be preferred in older subjects with a higher risk profile or when a potential reversible condition is suggested. The T gel formulations may also better mimic the circadian variation in T secretion, higher in the morning and lower at bedtime [42]. Conversely, when hypogonadism is irreversible, especially in younger patients, long-acting parental injectable formulation should be considered, as the first option. Accordingly, the daily application of rub-on gel is often considered a time-consuming procedure, reinforcing the suffering from a chronic condition, with possible consequences on long-term compliance. In contrast, long-lasting injectable T preparations, requiring between three to five deliveries per year, can relieve the patient from being remembered daily to suffer from a chronic, irreversible condition [43].
## Remarks
Data on the role of TRT in patients with compensated hypogonadism are lacking. This condition represents only a preclinical form of an overt hypogonadism, which might deserve an adequate follow-up. TRT should be started only when overt hypogonadism occurs. Anti-estrogens or aromatase inhibitors have been frequently used for the treatment of secondary hypogonadism, especially in patients with obesity or with metabolic derangements . However, up to now, the available data are limited and more studies are advisable to better clarify the use of these compounds in patients with LOH.
## Contraindications
## Prostate and breast contraindications
We recommend against starting TRT in patients with active breast and prostate cancers (Good clinical practice).
We suggest not considering a treated low-risk prostate cancer as an absolute contraindication to TRT (2, ØOOO).
We suggest not considering a mild-to-moderate lower urinary tract symptoms (LUTS) as absolute contraindication to TRT (2, ØØØO).
## Evidence
Prostate cancer (PC) growth and development occur in a T-sensitive manner . As a result, hormonal castration is included among the available therapeutic options Similarly, patients with a suspicion of PC (e.g. increased/ raising PSA concentrations and/or relevant findings at digital rectal examination) deserve further evaluation before commencing TRT. Some meta-analyses reported a very low risk of PC recurrence in patients on TRT after local therapy completion (radical prostatectomy, external beam radiation therapy, brachytherapy, cryotherapy) . However, it should be recognized that the available data are insufficient to address this issue, due to the high heterogeneity and limited follow-up. Hence, risks and benefits of starting TRT in symptomatic hypogonadal men with a treated low-risk PC should be extensively discussed and tailored to the individual condition.
Male breast cancer (MBC) is a rare tumor. Even in men, breast cancer can be hormone sensitive. Considering that breast cancer tissue expresses high levels of P450 aromatase , it is conceivable that T administration to an otherwise hypogonadal men with a history of treated mammary cancer could increase the risk of recurrence, although evidence on this topic are very limited [bib_ref] Testosterone therapy and risk of breast cancer development: a systematic review, Ray [/bib_ref].
The effects of TRT on benign prostatic hyperplasia (BPH) and low LUTS are a matter of debate. Although some concerns have been raised in patients with BPH-LUTS on TRT, a meta-analysis of 14 RCTs (2029 participants, mean follow-up 34.4 months) reported that TRT does not change the International Prostatic Symptoms Score (IPSS) in patients with LOH [bib_ref] Effects of testosterone replacement therapy on lower urinary tract symptoms: a systematic..., Kohn [/bib_ref]. Similarly, another meta-analysis on RCTs (1779 patients) reported no effect of TRT on LUTS [bib_ref] The efficacy and adverse events of testosterone replacement therapy in hypogonadal men:..., Ponce [/bib_ref]. A single study carried out in 52 patients with hypogonadism, mild BPH and LUTS showed an improvement of IPSS, maximum flow rate, and voiding volume and no change in post-voiding residual volume after 12 months compared with an untreated control group [bib_ref] Androgen replacement therapy contributes to improving lower urinary tract symptoms in patients..., Shigehara [/bib_ref]. It is important to note that these data refer to patients with mild-to-moderate LUTS since patients with severe LUTS (IPSS > 19) were systematically excluded from RCTs [bib_ref] Testosterone therapy: what we have learned from trials, Corona [/bib_ref].
## Values
The evidence places a high value on the unsafe use of TRT in patients with active breast and prostate cancers. The evidence against considering mild-to-moderate LUTS as an absolute contraindication for TRT in patients with hypogonadism is of moderate quality.
## Remarks
Limited evidence is available on the effects of TRT in patients with severe LUTS (IPSS > 19), mainly because they are not included in RCTs. Moreover, BPH has not been clearly specified as an inclusion criterion in meta-analytical studies exploring the effects of TRT on LUTS [bib_ref] Effects of testosterone replacement therapy on lower urinary tract symptoms: a systematic..., Kohn [/bib_ref] [bib_ref] The efficacy and adverse events of testosterone replacement therapy in hypogonadal men:..., Ponce [/bib_ref] [bib_ref] Testosterone and benign prostatic hyperplasia, Rastrelli [/bib_ref].
## Cardiovascular contraindications
We suggest not considering mild-to-moderate heart failure as an absolute contraindication for TRT .
We suggest not prescribing TRT to patients with a recent major adverse cardiovascular event .
We suggest considering the global cardiovascular risk and associated morbidities, including hematocrit level, before prescribing TRT .
We suggest collecting a detailed family, personal and clinical history of venous thromboembolism before prescribing TRT (2, ØOOO).
## Evidence
In prospective RCTs, analysis of the effects of TRT in patients with mild-to-moderate heart failure (HF) and reduced ejection fraction (rEF) including classes New York Heart Association (NYHA) II and III and left ventricular ejection fraction (LVEF) < 40%,-showed no [bib_ref] Testosterone supplementation in patients with chronic heart failure: a meta-analysis of randomized..., Tao [/bib_ref] [bib_ref] Testosterone replacement therapy in deficient patients with chronic heart failure: a randomized..., Navarro-Peñalver [/bib_ref] or positive effects [bib_ref] Beneficial effects of testosterone therapy on functional capacity, cardiovascular parameters, and quality..., Mirdamadi [/bib_ref] on heart function and no TRT-related major events [bib_ref] Testosterone replacement therapy in deficient patients with chronic heart failure: a randomized..., Navarro-Peñalver [/bib_ref] [bib_ref] Beneficial effects of testosterone therapy on functional capacity, cardiovascular parameters, and quality..., Mirdamadi [/bib_ref] [bib_ref] Survival and cardiovascular events in men treated with testosterone replacement therapy: an..., Wallis [/bib_ref] [bib_ref] Effect of exercise training and testosterone replacement on skeletal muscle wasting in..., Santos [/bib_ref] [bib_ref] Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure..., Stout [/bib_ref]. Accordingly, a meta-analysis of RCTs including 198 patients with heart failure (LVEF < 40%, NHYA II and III) with a duration up to 52 weeks described a significant amelioration of the six-minute-walking test and no adverse cardiovascular events [bib_ref] Testosterone supplementation in heart failure: a meta-analysis, Toma [/bib_ref]. Conversely, no data are available on the effects of TRT in patients with severe HF and rEF (class NYHA IV), nor in those with recent major adverse cardiovascular events (MACE).
The association between TRT and cardiovascular (CV) risk remains one of the most conflicting issues of the topic. Limited data, mainly derived from pharmaco-epidemiological studies published in the last 10 years, have suggested a possible increased risk of CV mortality and morbidity during TRT, especially in aging and complicated patients (see above; [bib_ref] Late-onset hypogonadism: reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement..., Sesti [/bib_ref] [bib_ref] Testosterone therapy and cardiovascular risk: a critical analysis of studies reporting increased..., Khera [/bib_ref].
However, it is important to recognize that several doubleblind, placebo-controlled randomized clinical trials (RCTs) have shown that T can delay time to ischemia in patients with coronary artery disease and stable angina followed up from four weeks to 12 months (see for review [bib_ref] Late-onset hypogonadism: reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement..., Sesti [/bib_ref]. In addition, a meta-analysis including 37 observational studies and 43,041 subjects, showed that reduced T concentrations at baseline was associated with an increased CV mortality and morbidity [bib_ref] Endogenous testosterone levels and cardiovascular risk: meta-analysis of observational studies, Corona [/bib_ref]. Data were confirmed when only population-based studies were considered [bib_ref] Endogenous testosterone levels and cardiovascular risk: meta-analysis of observational studies, Corona [/bib_ref]. Similarly, a large epidemiological study including 154,965 men from United Kingdom (UK) Biobank showed that tT and fT concentrations were inversely associated with all-cause and cancer mortality [bib_ref] Sex-specific associations of circulating testosterone levels with all-cause and cause-specific mortality, Wang [/bib_ref]. In line with these data, the largest meta-analysis published so far on CV effect of TRT, including 15 pharmaco-epidemiological and 93 RCTs, documented that TRT reduces overall mortality and CV morbidity in pharmaco-epidemiological studies and had no clear effect, either beneficial or detrimental, on the incidence of CV events when RCTs were considered [bib_ref] Testosterone and cardiovascular risk: metaanalysis of interventional studies, Corona [/bib_ref]. The latter study also documented that an increased risk of CV diseases was observed in RCTs when T preparations were prescribed at dosages above those normally recommended, or when frail men were considered [bib_ref] Testosterone and cardiovascular risk: metaanalysis of interventional studies, Corona [/bib_ref]. In line wih this evidence a more recent individual patient and aggregate data meta-analysis, including 35 primary studies (5601 participants, mean age 65 years) found no evidence that TRT increased shortterm to medium-term CV risks in men with hypogonadism [bib_ref] Adverse cardiovascular events and mortality in men during testosterone treatment: an individual..., Hudson [/bib_ref]. Accordingly, the conclusion of the European Medicine Agency (EMA) did not align with the FDA opinion and stated the safety of TRT on the cardiovascular profile.
Data mainly derived from subjects with an undiagnosed family history of thrombophilia-hypofibrinolysis have emphasized a possible increased risk of venous thromboembolism (VTE) in men under TRT [bib_ref] Testosterone treatment and cardiovascular and venous thromboembolism risk: what is "new, Corona [/bib_ref]. In addition, a Mendelian randomized study on 3,225 men of European ancestry, 392,038 white British men and women from the UK Biobank, and 171,875 participants of about 77% European descent, reported that endogenous T, genetically predicted by variants in the JMJD1C gene region, was positively associated with VTE in men [bib_ref] Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction:..., Luo [/bib_ref]. However, the most updated meta-analysis, including 13 RCTs and enrolling 5050 subjects with hypogonadism on TRT, does not support the association between VTE and TRT [bib_ref] Testosterone replacement therapy and the risk of venous thromboembolism: a systematic review..., Ayele [/bib_ref].
## Values
Evidence on the safety of TRT on the cardiovascular profile is of moderate quality and place a high value when TRT is given to restore physiological concentrations. An accurate family history evaluation to rule out thrombophilia-hypofibrinolysis is crucial before initiating TRT.
## Remarks
Available data on CV risk of TRT are mainly derived from studies with non-CV primary endpoints and whose design was inadequate to exclude such a risk (limited duration of exposure and insufficient numbers of participants). An industry-supported multicenter RCT is underway to better clarify the CV risk of TRT (clinicaltrials.gov: NCT03518034).
## Other contraindications
We recommend against TRT in men desiring fatherhood in the near future (1, ØØØØ).
We suggest not considering a treated obstructive sleep apnea syndrome (OSAS) as an absolute contraindication for testosterone replacement therapy .
## Evidence
Male hormonal contraceptive trials have clearly shown that T administration suppresses sperm production and sperm cell concentration to various degrees and in 100% of subjects within 24 months [bib_ref] Update on novel hormonal and nonhormonal male contraceptive development, Long [/bib_ref]. The recovery period from T-induced spermatogenesis suppression is variable, being reported longer when it is consequence of anabolic-androgenic steroids (AAS) abuse [bib_ref] Consequences of anabolic-androgenic steroid abuse in males; sexual and reproductive perspective, Corona [/bib_ref]. Hence, TRT is contraindicated in all men who desire fatherhood. Specific SIAMS recommendations on this topic were provided elsewhere [bib_ref] Management of male factor infertility: position statement from the Italian society of..., Ferlin [/bib_ref].
The impact of TRT on respiratory parameters in subjects with hypogonadism with OSAS, studied in RCTs, seems to be transient and time-dependent. TRT can worsen saturation index and nocturnal hypoxemia (sleep time with oxygen saturation < 90%) after seven weeks [bib_ref] The effects of testosterone on ventilatory responses in men with obstructive sleep..., Killick [/bib_ref] [bib_ref] Effects of testosterone therapy on sleep and breathing in obese men with..., Hoyos [/bib_ref] , but the effects are neutral after 12-18 weeks [bib_ref] The effects of testosterone on ventilatory responses in men with obstructive sleep..., Killick [/bib_ref] [bib_ref] Effects of testosterone therapy on sleep and breathing in obese men with..., Hoyos [/bib_ref] [bib_ref] Increased sexual desire with exogenous testosterone administration in men with obstructive sleep..., Melehan [/bib_ref] , and eventually resulted in a significant improvement of sleep disturbances after 12 months [bib_ref] Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone..., Shigehara [/bib_ref]. Taken together these data suggest that short-term, high-dose TRT may worsen OSAS. However, these adverse effects seem to have disappeared with time, rather than worsen [bib_ref] Obstructive sleep apnea and testosterone therapy, Payne [/bib_ref].
## Remarks
The available evidence regarding the role of TRT in men with OSAS is poor. In addition, the possible role played by obesity in these patients remains unclear.
## Outcomes
## Sexual function
We recommend using TRT in subjects with hypogonadism with low sexual desire and/or erectile dysfunction (ED) (1 ØØØØ).
Since ED is a multifactorial disorder, we suggest promptly considering combination therapies, in subjects with hypogonadism, whenever needed to fully address the condition (2 ØØØO).
## Evidence
As previously reported, sexual dysfunctions are considered a hallmark of T deficiency [bib_ref] Identification of late-onset hypogonadism in middleaged and elderly men, Wu [/bib_ref] [bib_ref] How to define hypogonadism? Results from a population of men consulting for..., Rastrelli [/bib_ref] [bib_ref] Androgens and male sexual function, Corona [/bib_ref]. Data derived from available meta-analyses documented that TRT can significantly improve all aspects of sexual function, being the magnitude of the outcomes more evident when sexual desire and erectile function were considered [bib_ref] The efficacy and adverse events of testosterone replacement therapy in hypogonadal men:..., Ponce [/bib_ref] [bib_ref] Effects of testosterone on sexual function in men: results of a meta-analysis, Isidori [/bib_ref] [bib_ref] Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis..., Boloña [/bib_ref] [bib_ref] Testosterone supplementation and sexual function: a meta-analysis study, Corona [/bib_ref] [bib_ref] Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis, Elliott [/bib_ref] [bib_ref] Testosterone therapy for sexual dysfunction in men with type 2 diabetes: a..., Algeffari [/bib_ref] [bib_ref] Do testosterone supplements enhance response to phosphodiesterase 5 inhibitors in men with..., Zhu [/bib_ref] ; [fig_ref] Table 3: Summary of testosterone replacement therapy [/fig_ref] and Supplementary. The same studies [bib_ref] The efficacy and adverse events of testosterone replacement therapy in hypogonadal men:..., Ponce [/bib_ref] [bib_ref] Effects of testosterone on sexual function in men: results of a meta-analysis, Isidori [/bib_ref] [bib_ref] Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis..., Boloña [/bib_ref] [bib_ref] Testosterone supplementation and sexual function: a meta-analysis study, Corona [/bib_ref] [bib_ref] Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis, Elliott [/bib_ref] [bib_ref] Testosterone therapy for sexual dysfunction in men with type 2 diabetes: a..., Algeffari [/bib_ref] [bib_ref] Do testosterone supplements enhance response to phosphodiesterase 5 inhibitors in men with..., Zhu [/bib_ref] also excluded beneficial effects of TRT when the mean T of the enrolled subjects exceeded 12 nmol/L. The first metaanalysis of studies reporting International Index of Erectile Function as main outcome suggested that TRT alone is only able to improve mild ED [bib_ref] Meta-analysis of results of testosterone therapy on sexual function based on international..., Corona [/bib_ref]. Similar results were reported by a comparable study [bib_ref] Testosterone therapy for late-onset hypogonadism improves erectile function: a systematic review and..., Taniguchi [/bib_ref]. The effect, small, is even attenuated by metabolic impairment, such in obesity and diabetes, most probably because of underlying neuro-vascular alterations [bib_ref] Meta-analysis of results of testosterone therapy on sexual function based on international..., Corona [/bib_ref]. Accordingly, lifestyle modifications and reduction of CV risk is advocated to improve ED [bib_ref] Health-related lifestyle factors and sexual dysfunction: a meta-analysis of population-based research, Allen [/bib_ref] [bib_ref] Erectile dysfunction and cardiovascular risk: a review of current findings, Corona [/bib_ref]. In subjects with hypogonadism with comorbid ED, T should be given prior to phosphodiesterase-5 inhibitors (PDE5i) but if it turns out insufficient to restore sexual function in comorbid vascular patients the add-on of PDE5i should be considered without delay. In this respect, the first meta-analysis of the very few studies on the combination of PDE5i and TRT (mixed enrollment) failed to reveal additive effects [bib_ref] Testosterone supplementation and sexual function: a meta-analysis study, Corona [/bib_ref]. The re-analysis of the latter data, however, documented that the combination therapy (TRT and PDE5i) can produce better outcome in more complicated subjects such as those with type 2 diabetes mellitus [bib_ref] Androgens and male sexual function, Corona [/bib_ref]. A further meta-analysis including eight studies and 913 patients concluded that combination therapy (TTR plus PDE5-i) is superior to PDE5i monotherapy in restoring erectile function [bib_ref] Do testosterone supplements enhance response to phosphodiesterase 5 inhibitors in men with..., Zhu [/bib_ref]. However, the analysis included also non-placebo-controlled RCTs and paper not published in English language, limiting its generalizability.
## Values
We place a high value for TRT in improving low sexual desire and erectile function in subjects with hypogonadism (tT < 12 nmol/L). We place a lower value on the less consistent effects of TRT on other sexual problems including ejaculatory dysfunctions.
## Remarks
At present, the place and timing of combination therapy T plus PDE5i in the management of ED remains unclear, requiring an individually tailored approach. The efficacy of the combined use of TRT and intracavernosal injection of prostaglandin E1 (PGE-1) and/ other drugs is lacking.
## Bone
## We recommend trt to improve bone mineral density and prevent bone loss in subjects with hypogonadism (1 øøøo).
We recommend against TRT as monotherapy to prevent bone fracture in subjects with hypogonadism with high fracture risk (1 ØØOO).
## Evidence
T is essential for skeletal development during puberty and bone health maintenance (mass and strength) throughout adult life, by promoting periosteal apposition and endocortical bone resorption, and by slowing bone remodeling rate [bib_ref] Estrogens and androgens in skeletal physiology and pathophysiology, Almeida [/bib_ref]. Hypogonadism, both in the young men and in aging, is associated with lower bone mineral density (BMD) and represents a major cause of osteoporosis [bib_ref] Testicular function and bone metabolism-beyond testosterone, Ferlin [/bib_ref] [bib_ref] Management of endocrine disease: male osteoporosis: diagnosis and management -should the treatment..., Porcelli [/bib_ref]. TRT can improve BMD, particularly at the vertebral level and when T concentrations are very low [fig_ref] Table 2: Testosterone preparations for hypogonadism treatment available in the Italian market Preparations in... [/fig_ref] ; [bib_ref] Effects of testosterone on body composition, bone metabolism and serum lipid profile..., Isidori [/bib_ref] [bib_ref] Testosterone use in men and its effects on bone health. A systematic..., Tracz [/bib_ref] [bib_ref] Testosterone replacement therapy has limited effect on increasing bone mass density in..., Junjie [/bib_ref] [bib_ref] The effects of testosterone on bone health in males with testosterone deficiency:..., Zhang [/bib_ref] [bib_ref] Testosterone supplementation and bone parameters: a systematic review and meta-analysis study, Corona [/bib_ref]. The effect is more evident in younger men with organic hypogonadism, as a meta-analysis showed in men with Klinefelter syndrome [bib_ref] Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and..., Pizzocaro [/bib_ref]. The Bone Trial of the Testosterone Trials (T-Trials), showed that T treatment for one year in older men with low T significantly increased volumetric BMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip [bib_ref] Effect of testosterone treatment on volumetric bone density and strength in older..., Snyder [/bib_ref]. Similarly, the T4 Bone trial, a sub-study of the larger Testosterone for Diabetes Mellitus (T4DM), confirmed that
## Values
Hypogonadism should always be considered during the clinical workup of male osteoporosis and, similarly, subjects with hypogonadism should be assessed for bone health [bib_ref] EAA clinical guideline on management of bone health in the andrological outpatient..., Rochira [/bib_ref]. There is growing evidence on the effects of TRT on BMD, although trials exploring its beneficial effect on osteoporosis are lacking. TRT is particularly recommended in young adult subjects with hypogonadism to prevent bone loss and help acquiring peak bone mass [bib_ref] EAA clinical guideline on management of bone health in the andrological outpatient..., Rochira [/bib_ref]. In the other groups of patients, mainly older men with LOH, the benefits and risks of TRT should be accurately discussed with the patients.
To date, TRT cannot be recommended as monotherapy and should be associated with antiresorptive drugs when fracture risk is high [bib_ref] EAA clinical guideline on management of bone health in the andrological outpatient..., Rochira [/bib_ref] [bib_ref] Osteoporosis in men: an endocrine society clinical practice guideline, Watts [/bib_ref]. In general, we recommend following the European Academy of Andrology clinical guidelines on management of bone health in the andrological outpatient clinic [bib_ref] EAA clinical guideline on management of bone health in the andrological outpatient..., Rochira [/bib_ref].
## Remarks
The effect of TRT alone on bone health in subjects with hypogonadism is still not completely defined [bib_ref] Management of endocrine disease: male osteoporosis: diagnosis and management -should the treatment..., Porcelli [/bib_ref] [bib_ref] EAA clinical guideline on management of bone health in the andrological outpatient..., Rochira [/bib_ref] , specifically, no studies with fractures as primary endpoint are yet available. The combined treatment of TRT with drugs approved for the treatment of osteoporosis has not been investigated. To what extent the effects on TRT on bone density are a direct on bone metabolism, or rather an indirect effect through skeletal muscle is still unclear.
## Mood
We recommend against TRT as monotherapy for improving major depressive symptoms in subjects with hypogonadism (1 ØØOO).
## Evidence
Observational studies found depressive symptoms, including major depressive disorder, and hypogonadism associated [bib_ref] Identification of late-onset hypogonadism in middleaged and elderly men, Wu [/bib_ref] [bib_ref] How to define hypogonadism? Results from a population of men consulting for..., Rastrelli [/bib_ref] [bib_ref] Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo study, Barrett-Connor [/bib_ref] [bib_ref] Plasma testosterone and the course of major depressive disorder in older men..., Giltay [/bib_ref] [bib_ref] Calculated bioavailable testosterone levels and depression in middle-aged men, Mcintyre [/bib_ref] [bib_ref] High rates of depression and depressive symptoms among men referred for borderline..., Westley [/bib_ref]. A nine-year follow-up study found the risk of depression nearly double in men with low T at baseline [bib_ref] Prospective longitudinal study of testosterone and incident depression in older men: the..., Ford [/bib_ref] , confirming previous results of an increased incidence of depression in men with low T concentrations during two-year observation [bib_ref] Increased incidence of diagnosed depressive illness in hypogonadal older men, Shores [/bib_ref]. However, very few placebo-controlled RCTs investigated the role of TRT on depressive symptoms as primary outcome. Overall, they found TRT beneficial, with effect size larger among those subjects with milder symptoms than those who met criteria for major depressive disorder [bib_ref] Low serum testosterone in outpatient psychiatry clinics: addressing challenges to the screening..., Smith [/bib_ref]. Data from the Vitality Testosterone Trial [bib_ref] Effects of testosterone treatment in older men, Snyder [/bib_ref] showed that TRT in subjects with hypogonadism, who self-reported low vitality and fatigue scores, slightly improved mood and depressive symptoms. A systematic review of six RCTs confirmed that TRT can reduce depressive symptoms in patients with mild depression and in the presence of hypogonadism but not in those with major depressive disorders [fig_ref] Table 3: Summary of testosterone replacement therapy [/fig_ref] ; [bib_ref] Systematic review of the impact of testosterone replacement therapy on depression in..., Vartolomei [/bib_ref] [bib_ref] Testosterone and depression: systematic review and meta-analysis, Zarrouf [/bib_ref] [bib_ref] Impact of exogenous testosterone on mood: a systematic review and meta-analysis of..., Amanatkar [/bib_ref] [bib_ref] Association of testosterone treatment with alleviation of depressive symptoms in men: a..., Walther [/bib_ref].
## Values
Although TRT may produce marginal improvement in mood and depressive symptoms in subjects with hypogonadism, we place a high value on the recommendation not to offer TRT with the sole purpose of improving these symptoms.
Established anti-depressive treatments should be considered in combination to TRT in all hypogonadal subjects with hypogonadism with major depression.
## Remarks
Depressive mood and other non-specific symptoms of hypogonadism are indistinguishable from true psychiatric conditions related to mood and major depressive disorders [bib_ref] Low serum testosterone in outpatient psychiatry clinics: addressing challenges to the screening..., Smith [/bib_ref]. Low T can impact on mood in patients with hypogonadaltype depressive conditions [bib_ref] Testosterone treatment of depressive disorders in men: too much smoke, not enough..., Bhasin [/bib_ref]. However, the benefit of restoring T concentrations for depressive symptoms and for treatment of major depressive disorder is more controversial. Similarly, it is unclear whether low T is related to the development of major depressive disorders. Studies on the combination of TRT with established anti-depressive therapies have not been performed.
## Cognition
We recommend against testosterone replacement therapy in subjects with hypogonadism to specifically improve cognitive function (1 ØØØØ).
## Evidence
Some studies suggest that T deficiency might be involved in the pathogenesis of both age-related and Alzheimer disease (AD)-related cognitive impairment [bib_ref] Testosterone deficiency and risk of cognitive disorders in aging males, Corona [/bib_ref] [bib_ref] Endogenous sex hormones, cognitive decline, and future dementia in old men, Geerlings [/bib_ref]. A meta-analysis including 27 studies and 18 599 subjects concluded that low T can predict all-cause dementia or AD [bib_ref] Testosterone and cognitive impairment or dementia in middle-aged or aging males: causation..., Zhang [/bib_ref]. However, that latter study used a fixed model for the analysis which strongly limits the results obtained [bib_ref] Testosterone and cognitive impairment or dementia in middle-aged or aging males: causation..., Zhang [/bib_ref]. The association between LOH and cognitive decline are partially supported by studies on patients undergoing androgen deprivation therapy (ADT), in whom a worse performance in visuomotor tasks, but not in visuospatial tasks not comprising motor components, has been observed when compared to baseline concentrations or to controls [bib_ref] Cognitive functioning in men receiving androgen deprivation therapy for prostate cancer: a..., Mcginty [/bib_ref]. However, the available meta-analyses failed to document a beneficial effect of TRT in improving cognitive function of ageing men [bib_ref] Testosterone deficiency and risk of cognitive disorders in aging males, Corona [/bib_ref] [bib_ref] Testosterone supplementation and cognitive functioning in men-a systematic review and meta-analysis, Buskbjerg [/bib_ref] [bib_ref] Effects of testosterone supplementation on separate cognitive domains in cognitively healthy older..., Tan [/bib_ref] ; [fig_ref] Table 3: Summary of testosterone replacement therapy [/fig_ref]. A first metaanalysis of 14 RCTs and 1406 patients without definite cognitive impairment, reported a small, albeit significant, improvement in psychomotor speed and executive function in TRT compared to placebo group [bib_ref] Effects of testosterone supplementation on separate cognitive domains in cognitively healthy older..., Tan [/bib_ref] ; but no effects on various cognitive domains were observed in two other larger meta-analyses, even in the subgroup of subjects with hypogonadism only [bib_ref] Testosterone deficiency and risk of cognitive disorders in aging males, Corona [/bib_ref] [bib_ref] Testosterone supplementation and cognitive functioning in men-a systematic review and meta-analysis, Buskbjerg [/bib_ref].
## Remarks
It should be emphasized that the majority of available RCTs and meta-analyses included mixed eugonadal/hypogonadal populations. Only few studies dedicated to subjects with hypogonadism are available, overall reporting no effect of TRT on cognitive function. The current evidence does not allow to draw specific recommendations on the role of TRT on cognitive function in subjects with hypogonadism.
## Frailty and mobility
We recommend against prescribing testosterone replacement therapy to improve muscle strength, with a clinically meaningful aim, in frailty of subjects with hypogonadism (1 ØØØ0).
## Evidence
Observational studies repeatedly reported an association between low T and frailty [bib_ref] Circulating biomarkers characterizing physical frailty: CRP, hemoglobin, albumin, 25OHD and free testosterone..., Mailliez [/bib_ref] [bib_ref] Frailty and the endocrine system, Clegg [/bib_ref]. In line with these a meta-analysis including 7 cross-sectional studies and 4 cohort studies showed either reduced tT or fT concentrations were related to an increased risk of frailty in men but not in women [bib_ref] Frailty and testosterone level in older adults: a systematic review and meta-analysis, Peng [/bib_ref]. Impairment of mobility and balance, common features in frail individuals, has been frequently found associated with low T concentrations [bib_ref] Increased risk of falls and increased bone resorption in elderly men with..., Szulc [/bib_ref]. Accordingly, patients with LOH display an increased risk of falls and functional disabilities [bib_ref] Androgen treatment and muscle strength in elderly men: a meta-analysis, Ottenbacher [/bib_ref]. Despite this evidence, the role of TRT in frail patients with low T remains controversial [bib_ref] Muscular responses to testosterone replacement vary by administration route: a systematic review..., Skinner [/bib_ref] [bib_ref] Effect of testosterone supplementation on sarcopenic components in middle-aged and elderly men:..., Parahiba [/bib_ref] [bib_ref] Effects of transdermal testosterone on bone and muscle in older men with..., Kenny [/bib_ref].
In fact, although TRT was shown to reverse sarcopenia in aging men with LOH [bib_ref] Effect of testosterone treatment on body composition and muscle strength in men..., Snyder [/bib_ref] [bib_ref] Testosterone treatment in elderly men with subnormal testosterone levels improves body composition..., Svartberg [/bib_ref] [bib_ref] Effect of testosterone replacement on measures of mobility in older men with..., Bhasin [/bib_ref] , data derived from available meta-analyses failed to confirm a meaningful improvement of muscle strength and mobility [fig_ref] Table 3: Summary of testosterone replacement therapy [/fig_ref] ; [bib_ref] Effects of testosterone on body composition, bone metabolism and serum lipid profile..., Isidori [/bib_ref] [bib_ref] Androgen treatment and muscle strength in elderly men: a meta-analysis, Ottenbacher [/bib_ref] [bib_ref] Muscular responses to testosterone replacement vary by administration route: a systematic review..., Skinner [/bib_ref] [bib_ref] Effect of testosterone supplementation on sarcopenic components in middle-aged and elderly men:..., Parahiba [/bib_ref]. Data derived from TTrials demonstrated that TRT significantly improved the six minutes walking distance test in the overall cohort and in patients without baseline mobility limitations, but not in patients affected by mobility limitations at baseline (primary outcome). In addition, although TRT was able to significantly improve the parameter of self-reported physical function, the evaluation at the six minutes walking test failed to demonstrate an objective improvement among patients with functional limitation at enrollment [bib_ref] Effect of testosterone replacement on measures of mobility in older men with..., Bhasin [/bib_ref].
## Remarks
The majority of RCTs do not support a beneficial effect of TRT on physical function of frail men; however, some improvement in frailer patients, improvement in body composition and sarcopenia have been consistently reported in aging subjects with hypogonadism. Therefore, a beneficial impact of TRT on these outcomes in frail men cannot be completely ruled out.
## Body composition and metabolic parameters
## We recommend trt to improve body composition (reducing fat mass and increasing lean mass) in subjects with hypogonadism with or without metabolic syndrome (mets) or type 2 diabetes (t2dm) (1 øøøo).
We suggest TRT to improve fasting and post-load glycemic control in subjects with hypogonadism with MetS or prediabetic conditions to reduce the risk of developing T2DM (2 ØØOO).
We suggest not considering TRT to control dyslipidemia or to improve glycated hemoglobin in patients with or without T2DM (2 ØØOO).
We suggest TRT to reduce waist circumference in subjects with hypogonadism with MetS (2 ØOOO).
## Evidence
The beneficial effects of T on body composition are well studied. Several RCTs have proven that T can reduce fat mass. In detail, TRT has been demonstrated to reduce both visceral [bib_ref] Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal..., Allan [/bib_ref] [bib_ref] Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men..., Aversa [/bib_ref] and subcutaneous fat mass [bib_ref] Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone..., Dhindsa [/bib_ref] in subjects with hypogonadism with or without MetS and T2DM. Some double-blind, placebo-controlled studies have shown that TRT can reduce waist circumference and increase lean mass [bib_ref] Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men..., Aversa [/bib_ref] [bib_ref] Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone..., Dhindsa [/bib_ref] [bib_ref] Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia..., Kapoor [/bib_ref] [bib_ref] Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation..., Kalinchenko [/bib_ref]. These findings mirror meta-analytic studies [bib_ref] Effects of testosterone on body composition, bone metabolism and serum lipid profile..., Isidori [/bib_ref] [bib_ref] Therapy of endocrine disease: testosterone supplementation and body composition: results from a..., Corona [/bib_ref] and were confirmed by the T4DM trial, where two years of TRT reduced waist circumference (-2.1 cm), total fat mass (-2.7 kg), and abdominal fat mass (-2.3%), while increasing total muscle mass (+ 1.7 kg), over life-style interventions and placebo [bib_ref] Testosterone treatment to prevent or revert type 2 diabetes in men enrolled..., Wittert [/bib_ref].
There is a well-known relation between low endogenous serum T concentrations and risk of T2DM in observational studies, however data from RTCs are more controversial. Some RCT found TRT positively affecting glycemic control in subjects with MetS and/or T2DM. In the Burntwood Lichfield Atherstone Sutton Tamworth (BLAST) study, 199 men with T2DM were enrolled to study TRT's effects on glycated hemoglobin (HbA1c). A significant improvement of HbA1c concentrations was achieved after 30 weeks of long-acting injectable T undecanoate administration [bib_ref] Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2..., Hackett [/bib_ref]. However, in the TIMES-2 trial, a larger study on 220 patients with T2DM or MetS treated for six months with 1% T gel or placebo, no significant difference in HbA1c concentrations was found between groups [bib_ref] Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome..., Jones [/bib_ref]. Similar results were obtained in other double-blind, placebo-controlled studies [bib_ref] Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone..., Dhindsa [/bib_ref] [bib_ref] Effect of testosterone treatment on glucose metabolism in men with type 2..., Gianatti [/bib_ref] [bib_ref] Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus, Gopal [/bib_ref]. The T4DM, the largest (1007 men) RTC, demonstrated that T is able to prevent T2DM, over an intensive lifestyle program, to an extent greater than seen for metformin in the Diabetes Prevention Program. The T4DM trial found a significant TRT-related reduction in fasting glucose and an approximately 40% lowering of the relative risk to have a 2-h glucose on oral glucose tolerance test (OGTT) ≥ 11.1 mmol/L after two years of TRT over lifestyle interventions; however, as previous studies, they found no significant effect on Hb1Ac concentrations advocating the discrepancy-when compared the impressive changes in glucose concentrations-due to a TRT-related change in red blood cell turnover that hampers the possibility to detect Hb1Ac improvements by measuring its circulating concentrations [bib_ref] Testosterone treatment to prevent or revert type 2 diabetes in men enrolled..., Wittert [/bib_ref].
Results of clinical studies on the effect of T on circulating lipids are contrasting. In some RCTs including subjects with hypogonadism, with or without MetS and T2DM, a reduction of total cholesterol and low-density lipoprotein cholesterol [bib_ref] Effect of testosterone treatment on glucose metabolism in men with type 2..., Gianatti [/bib_ref] [bib_ref] The effect of testosterone on cardiovascular biomarkers in the testosterone trials, Mohler Er 3rd [/bib_ref] [bib_ref] Adverse events associated with testosterone administration, Basaria [/bib_ref] was observed in the TRT group. In contrast, other studies reported no change in lipid parameters [bib_ref] Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone..., Dhindsa [/bib_ref] [bib_ref] Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation..., Kalinchenko [/bib_ref] [bib_ref] Treatment of hypogonadism with testosterone in patients with type 2 diabetes mellitus, Gopal [/bib_ref] [bib_ref] Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in..., Basaria [/bib_ref]. Moreover, T seems to have an unfavorable effect on highdensity lipoprotein cholesterol concentrations [bib_ref] Testosterone treatment to prevent or revert type 2 diabetes in men enrolled..., Wittert [/bib_ref] [bib_ref] Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome..., Jones [/bib_ref] [bib_ref] The effect of testosterone on cardiovascular biomarkers in the testosterone trials, Mohler Er 3rd [/bib_ref] [bib_ref] Adverse events associated with testosterone administration, Basaria [/bib_ref]. Unfortunately, the T4DM did not analyzed lipid concentration changes because of budget constraints [bib_ref] Testosterone treatment to prevent or revert type 2 diabetes in men enrolled..., Wittert [/bib_ref]. A comparison of available meta-analysis is reported in Supplementary Tables 6-8 [bib_ref] Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or merely an epiphenomenon..., Corona [/bib_ref] [bib_ref] Effects of testosterone on body composition, bone metabolism and serum lipid profile..., Isidori [/bib_ref] [bib_ref] Testosterone replacement therapy has limited effect on increasing bone mass density in..., Junjie [/bib_ref] [bib_ref] Therapy of endocrine disease: testosterone supplementation and body composition: results from a..., Corona [/bib_ref] [bib_ref] Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis, Whitsel [/bib_ref] [bib_ref] Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of..., Haddad [/bib_ref] [bib_ref] Clinical review 1: adverse effects of testosterone therapy in adult men: a..., Fernández-Balsells [/bib_ref] [bib_ref] Effects of testosterone on lean mass gain in elderly men: systematic review..., Neto [/bib_ref] [bib_ref] Efficacy and safety of testosterone replacement therapy in men with hypogonadism: a..., Guo [/bib_ref] [bib_ref] Type 2 diabetes mellitus and testosterone: a metaanalysis study, Corona [/bib_ref] [bib_ref] Diagnosis and treatment of late-onset hypogonadism: systematic review and metaanalysis of TRT..., Corona [/bib_ref] [bib_ref] Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2..., Cai [/bib_ref] [bib_ref] The role of testosterone treatment in patients with metabolic disorders, Corona [/bib_ref] [bib_ref] Testosterone and metabolic syndrome: a metaanalysis study, Corona [/bib_ref] [bib_ref] Effects of testosterone supplement treatment in hypogonadal adult males with T2DM: a..., Zhang [/bib_ref].
## Value
Although it is unequivocally the effect of TRT in improving body compositions, we place a great value in implementing lifestyle changes needed to control and reduce obesity prior to considering TRT. In those subjects failing to restore normal T concentrations after life style interventions, TRT can prevent the development of T2DM and improve body composition. Dyslipidemia seems not adequately targeted by TRT, suggesting that additional pharmacological interventions might be needed to restore normal lipid concentrations.
## Remarks
Hyperinsulinemia, T2DM and MetS are associated with reduced SHBG concentrations; therefore, in the affected subjects, it is recommended to calculate cFT to avoid unnecessary TRT (see . The encouraging data on TRT on diabetes mellitus prevention are limited to a 2-year observation in subjects with borderline hypogonadism who underwent a concomitant lifestyle program, whether the same findings can be expected in all subjects with hypogonadism remains to be established and balanced with longterm safety profile.
## Chronic diseases (hiv end-stage renal disease, bowel inflammatory diseases, chronic pulmonary diseases)
## We suggest not considering trt in subjects with hypogonadism with chronic diseases (such as human immunodeficiency virus infection (hiv), chronic obstructive pulmonary diseases (copd), end-stage renal disease (esrd), and bowel inflammatory diseases) to improve disease outcomes (2 øøoo).
## Evidence and remarks
Many chronic diseases, such as HIV infection/AIDS, COPD, ESRD, and bowel inflammatory diseases, have been associated with hypogonadism [bib_ref] Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or merely an epiphenomenon..., Corona [/bib_ref] [bib_ref] A perspective on middle-aged and older men with functional hypogonadism: focus on..., Grossmann [/bib_ref] [bib_ref] Testosterone therapy in men with Crohn's disease improves the clinical course of..., Nasser [/bib_ref] [bib_ref] The prevalence of hypogonadism and the effectiveness of androgen administration on body..., Santi [/bib_ref]. Data suggest that lean mass may improve in HIV men receiving TRT [bib_ref] Diagnosis and treatment of late-onset hypogonadism: systematic review and metaanalysis of TRT..., Corona [/bib_ref] [bib_ref] The prevalence of hypogonadism and the effectiveness of androgen administration on body..., Santi [/bib_ref] [bib_ref] Effects of Testosterone supplementation on body composition in HIV patients: a meta-analysis..., Zhou [/bib_ref] and COPD patients [bib_ref] Diagnosis and treatment of late-onset hypogonadism: systematic review and metaanalysis of TRT..., Corona [/bib_ref] [bib_ref] Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease..., Atlantis [/bib_ref]. However, evidence from RCT is too weak to indicate that TRT may beneficial in this subset of patients and improve their morbidity and mortality. Similar considerations can be drawn for coronavirus disease 19 (COVID-19) infection [bib_ref] Diabetes is most important cause for mortality in COVID-19 hospitalized patients: systematic..., Corona [/bib_ref] [bib_ref] SARS-CoV-2, testosterone and frailty in males (PROTEGGIMI): a multidimensional research project, Salonia [/bib_ref] [bib_ref] Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients, Rastrelli [/bib_ref] [bib_ref] Sex disparities in COVID-19 severity and outcome: are men weaker or women..., Pivonello [/bib_ref] [bib_ref] Andrological effects of SARS-Cov-2 infection: a systematic review and meta-analysis, Corona [/bib_ref] [bib_ref] Low testosterone predicts hypoxemic respiratory insufficiency and mortality in patients with COVID-19..., Vena [/bib_ref] [bib_ref] Addressing male sexual and reproductive health in the wake of COVID-19 outbreak, Sansone [/bib_ref]. For this reason, the task force agreed that are the specific outcomes, as detailed in the previous recommendations, to drive decisions and TRT should be individualized based on the signs and symptoms and severity of hypogonadism.
## Monitoring
We recommend evaluating clinical outcomes, including biochemical parameters (hematocrit, PSA and testosterone) every 3/6 months during the first year and at least annually thereafter .
We suggest further evaluation, if there is: (a) confirmed PSA > 4 ng/mL at any time and (b) detection of a prostatic abnormality on digito-rectal examinations (DRE) or a substantial worsening of LUTS (2 ØOOO).
## Evidence
Sexual problems are among the commonest issues complained by subjects with hypogonadism. Data derived from TTrials and meta-analysis have shown that sexual function can be significantly improved after three month of therapy [bib_ref] Meta-analysis of results of testosterone therapy on sexual function based on international..., Corona [/bib_ref] [bib_ref] Testosterone treatment in older men, Snyder [/bib_ref]. Hence, three months appear a reasonable time to check, for the first time, TRT outcomes. Given the wellknown stimulatory effects of T on erythropoiesis [bib_ref] Erythrocytosis following testosterone therapy, Ohlander [/bib_ref] , and its potential effects on the prostate [bib_ref] Testosterone and benign prostatic hyperplasia, Rastrelli [/bib_ref] , the PSA and hematocrit (HCT) evaluation should be mandatory considered before and early checked during TRT. The optimal target concentrations for circulating T upon TRT have not been completely clarified. TTrials showed that maintaining the serum T concentration within the normal range for young men (280-873 ng/dL or 9.6-30 nmol/l; [bib_ref] Testosterone treatment in older men, Snyder [/bib_ref] resulted in a good benefit/risk ratio. However, lower or higher concentrations should be tailored according to individual comorbidities, specific symptoms and HCT levels. In fact, although the data are still not completely clarified, there is a general consensus that a HCT level higher than 54% require phlebotomy, along with TRT withdrawal, to reduce the risk of cardio-vascular complications [bib_ref] Critical evaluation of different available guidelines for late-onset hypogonadism, Giagulli [/bib_ref]. However, particularly in the presence of specific conditions, as COPD or OSAS, HCT levels between 48 and 51% should be carefully considered, and handled on an individual basis, before and during TRT [bib_ref] European academy of andrology (EAA) guidelines on investigation, treatment and monitoring of..., Corona [/bib_ref].
Considering the strong association between LOH and metabolic disturbances, baseline and, at least, annually glycometabolic profile evaluations are suggested. Similarly, bone density scan may be also considered at baseline and 18 to 24 months following TRT, particularly in those subjects with more severe hypogonadism [bib_ref] EAA clinical guideline on management of bone health in the andrological outpatient..., Rochira [/bib_ref].
Overall, complete and andrological clinical evaluation is mandatory before and during TRT patient evaluation. DRE must be performed at any time to rule-out the presence of prostate abnormalities.
## Remarks
The correct timing for T concentration evaluation should be managed according to the type of T preparation used (see [fig_ref] Table 2: Testosterone preparations for hypogonadism treatment available in the Italian market Preparations in... [/fig_ref]. SHBG evaluation and fT calculation should be considered for a better estimation of circulating T levels. Although PSA value above 4 ng/mL still represents a well accepted threshold for further prostate evaluation, it should be recognized that the latter varies according to several other parameters [bib_ref] EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. Part 1: screening, diagnosis, and local..., Mottet [/bib_ref]. In particular, the risk of PC is increased in African descent and in those with a first-degree relative with diagnosed PC or previously positive prostate biopsy, and in those with baseline PSA concentrations > 1 ng/mL at age 40 years or > 2 ng/mL at age 60 years [bib_ref] EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. Part 1: screening, diagnosis, and local..., Mottet [/bib_ref]. Hence, those subjects deserve particular attention during TRT. The PSA velocity, previously considered a marker for TRT withdrawn and prostate biopsy, has been criticized [bib_ref] Association of prostate-specific antigen velocity with clinical progression among African American and..., Nelson [/bib_ref] [bib_ref] Effect of testosterone administration to men with prostate cancer is unpredictable: a..., Morales [/bib_ref]. Accordingly, the European Association of Urology guidelines suggest that PSA density (PSAD) with a Prostate Imaging Reporting and Data System (PI-RADS) score (≥ 3) might help in decision for further evaluations [bib_ref] EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. Part 1: screening, diagnosis, and local..., Mottet [/bib_ref].
# Conclusions
Whereas the development of male hypogonadism during fetal and pre-pubertal condition can profoundly affect sexual development and the appearance of sexual secondary characteristics, the underlying pathogenetic mechanisms, and the clinical significance of adult-and late-onset hypogonadism are still not completely clarified. Sexual impairment is the main condition tightly related to the development hypogonadism in adult or aging men. Conversely, the role played by age-associated low T in the characterization of several other symptoms including mood discrepancies, frailty and cognitive impairment is more conflicting. Similarly, metabolic derangements such as obesity T2DM and MetS are frequently associated with low T in aging men. In the latter cases, emerging evidence suggests that TRT can positively influence body composition and metabolic profile in less complicated subjects. Conversely, the role of T substitution in older frailty and more complicated subjects is still contradictory. Available data do not support a role of TRT in increasing CV risk when subjects with hypogonadism are correctly diagnosed, T appropriately prescribed and subjects adequately followed up during the treatment. However, it should be important to recognize that the duration of existing studies is too limited (up to three years) to draw any final conclusions. Hence, further and longer studies are strongly advisable the better clarify the long-term benefit/ratio of TRT in adult and aging men with hypogonadism.
## Supplementary information
The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s40618-022-01859-7.
Acknowledgements The authors would like to thanks Marco Zavattaro and Rossella Cannarella for their helpful collaboration during manuscript preparation.
# Declarations
## Conflict of interest no conflict of interest was reported by any of the authors.
Ethical approval This article does not contain any study with human participants or animals performed by any of the authors.
[fig] Figure 1: Symptoms and signs frequently associated with adult-onset hypogonadism documented when T concentrations are below 12 nmol/l [/fig]
[table] Table 2: Testosterone preparations for hypogonadism treatment available in the Italian market Preparations in bold are supported by the national health service. Nebid is supported only in a limited number of Italian regions including Friuli Venezia-Giulia, Emilia Romagna, Toscana, Marche, Puglia for advanced and metastatic PC [46]. This justifies the absolute contraindication of TRT in patients with PC. [/table]
[table] Table 3: Summary of testosterone replacement therapy (TRT) outcomes ⊕ ⊕ ⊕ = strong effect. ↑ = positive effect ↓ = negative effect ↔ = neutral effect. NA = not available; PDE5i, phosphodiesterase type 5 inhibitors [/table]
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Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines
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Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines
Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.@ERSpublications Practical guidelines for idiopathic pulmonary fibrosis are now available
# Introduction
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative, irreversible disease of unknown cause. The evolution of IPF is usually progressive, primarily occurring from 60 years of age and is limited to the lungs. It is the most frequent type of chronic idiopathic interstitial pneumonia in adults.
Once considered an orphan disease because no specific treatment with proven efficacy was available, IPF is a rare disease with an estimated prevalence in the USA of between 14 and 28 cases per 100 000 population [bib_ref] Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature, Nalysnyk [/bib_ref].
The annual estimated incidence in the USA is between 6.8 and 8.8 cases per 100 000 population [bib_ref] Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature, Nalysnyk [/bib_ref]. No estimate of the epidemiology of IPF has been published for France.
In France, one national reference centre and nine regional competence centres for rare lung diseases have been endorsed to organise the diagnosis and management of IPF within the general framework of two national plans for rare diseases .
Since the publication of international guidelines for the diagnosis and management of IPF in 2011 [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref] , new data have been published regarding, in particular, the efficacy and tolerance of several new treatments proposed to modify the evolution of the disease or alleviate symptoms. The current aim, coordinated by the reference and competence centres, is to provide pulmonologists with a synopsis of the currently available data and to define as clearly as possible, using terms adapted to real-life daily practice, the modalities of diagnosis and patient-centred management of IPF [bib_ref] Patient-centred management in idiopathic pulmonary fibrosis: similar themes in three communication models, Wuyts [/bib_ref].
The present document is an English version of the executive summary and outlines the main conclusions of the French guidelines for the diagnosis and management of IPF.
## Missions of the committees
This article was written by French IPF specialists as a practical overview of the international recommendations for the diagnosis and management of IPF published in 2011 [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref] , in combination with a critical review of the literature published in this field since 2011, including therapeutic trials. This article was produced by a Coordination committee, a Writing committee and a Reviewing committee.
The committees adopted rules that were applicable to the development of good clinical practice based on the method issued by the Haute Autorité de Santé.
## Coordination committee
The Coordination committee submitted the process and validation protocol to the Société de Pneumologie de Langue Française (SPLF), conducted a systematic review of the literature, prepared a first draft of the document intended for the Writing committee, organised the process and validation protocol and monitored its application, and submitted the recommendations validated by the Writing committee and the Reviewing committee to the SPLF.
## Writing committee
The Writing committee assessed the first version of the document prepared by the Coordination committee. Using a three-point scale (I agree, I hesitate or I do not agree) they identified the points to be reviewed, made suggestions about the form and contents of the document, and validated the document to be submitted to the Reviewing committee.
## Reviewing committee
The Reviewing committee comprised three pulmonologists working in a university hospital (excluding the competence centres), three pulmonologists working in a general hospital, three pulmonologists working in private practice, two radiologists with expertise in interstitial lung disease (ILD), and two pathologists who were specialised in thoracic pathology. The committee assessed all the themes and the corresponding recommendations using a scale ranging from 1 (total disagreement) to 9 (total agreement). The vote was conducted electronically and the results were anonymised before analysis. All recommendations submitted to the scrutiny of the Reviewing committee had been approved first by at least 80% of the Writing committee members. The rating of each statement was based on the synthesis of data published in the literature (which was provided together with the questionnaire) and the experience of the reader in the corresponding field. The members of the Reviewing committee could only answer questions for which they felt competent.
## Guidelines development process
The development of the recommendations comprised the following steps. 1) Critical review of the literature published since 2010 in the field of IPF by the Coordination committee. 2) First version written by the Coordination committee. 3) Review of the first version by the Writing committee. 4) Production of a revised version by the Coordination committee. 5) Review and votes by the Writing committee. 6) Rewriting of issues generating an insufficient consensus level by the Coordination committee. 7) Review and votes by the Reviewing committee. 8) Production of a revised version by the Coordination committee. 9) Review by the SPLF Scientific Council. 10) Production of a revised version by the Coordination committee. 11) Submission of the manuscript.
The SPLF Scientific Council gave advice on the relevance, writing and applicability of the recommendations. In order to be validated, recommendations had to be approved by at least 90% of the Reviewing committee members.
The recommendations were formulated as follows. 1) ''It is recommended'' means that the option described is relevant in the majority of patients (e.g. treatment with established efficacy). 2) ''It is proposed'' means that the option described may be relevant in some patients (e.g. treatment with highly probable efficacy). 3) ''It is possible'' means that the option described may be relevant in some patients but that available data do not allow a stronger recommendation (e.g. treatment with uncertain efficacy). 4) ''It is not recommended'' means that the option described is not relevant in the majority of patients (e.g. treatment shown to be inefficient). 5) ''It is recommended not to'' means that the option described should be avoided (e.g. treatment with harmful effects).
The SPLF Scientific Council approved the methods used to develop these recommendations on January 10, 2013, and approved the written recommendations on June 12, 2013. The recommendations were published in December 2013. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.
## Diagnosis of ipf
IPF is a fibroproliferative disease of unknown cause, associated with the histopathological and/or highresolution computed tomography (HRCT) pattern of usual interstitial pneumonia (UIP) [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref]. The presence of a radiological and/or histological UIP pattern is required to establish the diagnosis of IPF. In patients not subjected to video-assisted surgical lung biopsy (SLB), the diagnosis may be made when an ILD is present (with neither extrapulmonary manifestations nor aetiological context) if HRCT shows a (definite) UIP pattern . In patients subjected to video-assisted SLB, the diagnosis is established in the presence of specific combinations of HRCT and SLB aspects showing a UIP pattern [fig_ref] TABLE 2: Diagnosis of idiopathic pulmonary fibrosis [/fig_ref]. In all cases, exclusion of other known causes of ILD (in particular those linked to the environment, notably occupational exposure, drug toxicity or systemic disease) is required to establish the diagnosis of IPF.
IPF primarily occurs between 60 and 70 years of age, and is slightly more predominant in males [bib_ref] Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK, Gribbin [/bib_ref] [bib_ref] What causes cryptogenic fibrosing alveolitis? A case-control study of environmental exposure to..., Scott [/bib_ref] [bib_ref] Pulmonary fibrosis deaths in the United States, 1979-1991. An analysis of multiple-cause..., Mannino [/bib_ref] [bib_ref] High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis, Raghu [/bib_ref]. There are no specific clinical signs of IPF, which explains why the diagnosis is often established (too) late. The initial clinical presentation consists of progressive exertional dyspnoea combined with dry cough; bibasilar inspiratory crackles (velcro crackles) are constant and appear early in the disease [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref] [bib_ref] Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy..., Douglas [/bib_ref] [bib_ref] Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model, King [/bib_ref] [bib_ref] Velcro crackles: the key for early diagnosis of idiopathic pulmonary fibrosis?, Cottin [/bib_ref] [bib_ref] Fundamentals of lung auscultation, Bohadana [/bib_ref]. Finger clubbing is present in ,50% of cases. Weight loss and alteration of the general status are uncommon. Cyanosis and signs of right ventricular failure only occur in the advanced stages with respiratory insufficiency. The disease progresses towards chronic restrictive respiratory failure and death. Precapillary pulmonary hypertension is often present in advanced stages, in particular if emphysema is associated with IPF.
Question 1: What main causes of diffuse interstitial pneumonia should be clinically investigated in patients considered to potentially have IPF?
## Recommendation
It is recommended that a cause of ILD, including exposure to pharmaceutical agents, an inhaled organic antigen or mineral particles, or connective tissue disease and cancer, be clinically investigated in patients for whom a diagnosis of IPF is considered.
## Comment
The diagnosis of IPF requires the exclusion of other forms of ILD, including interstitial pneumonias either 1) with an identified cause: hypersensitivity pneumonitis due to inhalation of organic antigen(s), toxicity of pharmaceutical agents, pneumoconiosis caused by a mineral agent (silica and asbestos among others), primary or secondary cancer, or traumatic or haemodynamic pulmonary oedema; or 2) with no identified cause but occurring in a specific context of connective tissue disease (especially rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis), sarcoidosis, a well-defined infiltrative lung disease such as lymphangioleiomyomatosis, pulmonary Langerhans' cell granulomatosis or idiopathic chronic eosinophilic pneumonia, or any other well identified ILD.
Question 2: What biological work-up should be performed in patients considered to have IPF?
## Recommendation
It is recommended that biological signs of connective tissue disease be investigated if the diagnosis of IPF is considered.
It is proposed that a biological work-up be performed, including determinations of the following. 1) Differential blood cell count, C-reactive protein, serum creatinine, transaminases, c-glutamyltransferase and alkaline phosphatases. 2) Anti-nuclear antibodies, anti-citrullinated cyclic peptide antibodies and rheumatoid factor. 3) And depending on the clinical picture or if anti-nuclear antibodies, antibodies specific to Sjögren's syndrome (anti-SSA, anti-SSB), systemic sclerosis antibodies (anti-centromeres, antitopoisomerase-1 and anti-U3RNP), anti-synthetase antibodies, anti-thyroid antibodies, creatine phosphokinase and serum protein electrophoresis are detected.
## Comment
DIP is associated with a radiological and/or pathological pattern compatible with UIP [bib_ref] Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes, Park [/bib_ref] , and may be the first clinical manifestation of a connective tissue disease [bib_ref] Interstitial lung disease: are we missing formes frustes of connective tissue disease?, Cottin [/bib_ref]. Therefore, if the diagnosis of IPF is considered it is necessary to systematically look at extrapulmonary signs and biological markers in order to eliminate a connective tissue disease. If signs, symptoms or biological abnormalities suggesting a connective tissue disease occur during the course of the disease, the diagnosis of IPF should be challenged. Biological markers of an inflammatory syndrome or an extrapulmonary disorder should also be measured. Detection of antineutrophil cytoplasmic antibodies has been proposed [bib_ref] ANCA-associated lung fibrosis: analysis of 17 patients, Foulon [/bib_ref]. Precipitin detection is justified in the case of exposure to organic antigens or if hypersensitivity pneumonitis is suspected. The investigation of infectious agents, in particular by bronchoalveolar lavage (BAL), may be justified. Examinations that aim to identify a lymphoproliferative disorder (protein electrophoresis, immuno-electrophoresis, urinary immunofixation or cryoglobulinaemia) are justified if an ILD other than IPF is suspected.
## Comment
In IPF patients, BAL shows hypercellularity with an increased number of neutrophils and, frequently, an accompanying lower increase of the number of eosinophils. An increased number of lymphocytes evoke a diagnosis other than IPF [bib_ref] An official American Thoracic Society clinical practice guideline: the clinical utility of..., Meyer [/bib_ref] , including chronic hypersensitivity pneumonitis [bib_ref] Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis, Ohshimo [/bib_ref] , nonspecific interstitial pneumonia (suggesting connective tissue disease) or sarcoidosis. BAL contributes to the diagnosis primarily if the radiological examination does not show a typical UIP pattern, in particular if chronic hypersensitivity pneumonitis is suspected [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref]. A predominance of lymphocytes .30% does not favour IPF [bib_ref] Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis, Ohshimo [/bib_ref].
Question 4: When should genetic testing be performed in patients suspected of having IPF?
## Recommendation
If a diagnosis of IPF is suspected, it is recommended that tests are systematically performed during the medical interview to identify the presence of other causes of ILD within the family, and to search for clinical and biological signs suggesting a genetic cause (hepatic, cutaneous, mucosal and haematological abnormalities).
It is proposed that patients presenting with IPF in a familial context be referred to an outpatient clinic specialising in genetics to establish a pedigree and propose genetic molecular analysis primarily targeting, with the currently available of knowledge, the telomerase complex genes and the surfactant protein-C genes.
## Comment
Familial forms of IPF affecting ,5% of patients have been reported [bib_ref] Familial idiopathic pulmonary fibrosis. Evidence of lung inflammation in unaffected family members, Bitterman [/bib_ref] [bib_ref] Adult familial cryptogenic fibrosing alveolitis in the United Kingdom, Marshall [/bib_ref] [bib_ref] Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder..., Hodgson [/bib_ref] [bib_ref] Familial idiopathic pulmonary fibrosis: clinical features and outcome, Lee [/bib_ref]. The probability of a genetic cause seems to be higher in younger individuals (in particular those aged ,50 years).
Most frequently, the mode of genetic transmission of IPF in those familial cases is an autosomal dominant pattern of inheritance with variable penetrance [bib_ref] Adult familial cryptogenic fibrosing alveolitis in the United Kingdom, Marshall [/bib_ref] [bib_ref] Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder..., Hodgson [/bib_ref] [bib_ref] Clinical and pathologic features of familial interstitial pneumonia, Steele [/bib_ref] [bib_ref] Early interstitial lung disease in familial pulmonary fibrosis, Rosas [/bib_ref] [bib_ref] Genetic studies in familial fibrosing alveolitis. Possible linkage with immunoglobulin allotypes (Gm), Musk [/bib_ref]. A congenital form of dyskeratosis, characterised by a mutation of the telomerase complex genes (TERT and TERC), may be suggested by clinical and biological abnormalities, including macrocytosis, refractory anaemia due to erythroblastopenia, cryptogenic hepatic cirrhosis, abnormal cutaneous pigmentation, mucosal abnormalities such as leukoplakia of the tongue margin, or leukotrichia (premature greying of hair) [bib_ref] Telomere biology and telomere diseases: implications for practice and research, Young [/bib_ref]. Recommendation It is recommended that forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) should be assessed in patients being tested for IPF. It is proposed that total lung capacity, resting arterial blood gas at room air, 6-min walk test (6MWT) distance and percutaneous oxygen saturation should also be assessed.
## Comment
Pulmonary function tests performed at rest in IPF patients show several abnormalities: 1) pulmonary function restrictive pattern (decreased FVC and total lung capacity); 2) early decrease of DLCO and transfer coefficient of the lung for carbon monoxide; and 3) usually, normal arterial blood gas values at rest or hypocapnia (increased alveolar-arterial oxygen tension difference).
In addition, pulmonary function tests performed at exercise show a reduced exercise capacity, which may be assessed by measuring: exercise hypoxaemia (even if not present at rest); the distance walked during a 6MWT; the decrease of percutaneous oxygen saturation during exercise, notably during the 6MWT; and the decrease of maximal consumption of oxygen uptake and maximal power workload during exercise.
## Comment
HRCT of the chest is mandatory for the diagnosis of IPF. In ,50% of cases, HRCT shows a definite UIP pattern with honeycombing [fig_ref] FIGURE 2: High-resolution computed tomography scan demonstrating a typical example of usual interstitial pneumonia... [/fig_ref] [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref] [bib_ref] Pneumopathies interstitielles diffuses idiopathiques. Classification de Consensus International Multidisciplinaire de l, Cottin [/bib_ref] , which is sufficient for the diagnosis of IPF if the analysis is performed by a team of pulmonologists experienced in the field of IPF in a compatible clinical context. In other cases, the imaging features are not characteristic [fig_ref] FIGURE 3 a: b [/fig_ref] and video-assisted SLB is required to establish the diagnosis. In some cases, HRCT findings may be inconsistent with a UIP pattern . [fig_ref] TABLE 2: Diagnosis of idiopathic pulmonary fibrosis [/fig_ref] indicates the criteria used to define HRCT findings as definite or possible UIP. Honeycombing is required to consider a definite UIP pattern on HRCT. [fig_ref] TABLE 3: Chest high-resolution computed tomography methodsMandatoryNo injection of contrast medium Inspiratory apnoea slices... [/fig_ref] indicates how HRCT should be performed.
## Question 7:
In what patients should SLB be considered to establish the diagnosis of IPF?
## Recommendation
It is recommended that video-assisted SLB be considered in patients for whom the diagnosis of IPF is suspected, if a definite UIP pattern is not present on HRCT. The decision to perform a biopsy is taken during a multidisciplinary team discussion after careful evaluation of the operative risk. The potential risk associated with biopsy must be taken into account, especially due to the age of the patient, the presence of comorbidities, and the severity and progression of interstitial pneumonia.
## Comment
If the imaging findings are not typical of a UIP pattern, a definite diagnosis of IPF requires a histological UIP pattern to be demonstrated on video-assisted SLB (tables 4 and 5) and is based on the combination of radiological and histological findings [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref].
In some cases, HRCT only shows a possible UIP pattern but video-assisted SLB is not performed (because of contraindications or possible risk, or biopsy is not proposed or is declined by the patient). It is then impossible to establish the diagnosis of IPF according to the international recommendation criteria [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref].
Question 8: What is the role of multidisciplinary team discussion in the diagnosis of IPF and how is it conducted?
## Recommendation
During a multidisciplinary discussion involving pulmonologists, radiologists and pathologists experienced in the field of interstitial pneumonias, it is recommended that a definite diagnosis of IPF integrates clinical assessment, computed tomography features and, if available, pathological features .
It is recommended that complex cases be referred to expert centres (reference or competence centres), or to pulmonology departments experienced in ILDs.
## Comment
The diagnosis of IPF results from the combination of clinical, radiological, biological, respiratory function and, if available, pathological features and is established during multidisciplinary discussion. Ideally, the multidisciplinary discussion takes place in an expert or specialised centre, i.e. the reference centre or one of the competence centres for rare lung diseases, or a pulmonology department experienced in ILDs.
Question 9: How should prognosis be assessed in IPF patients?
## Recommendation
It is recommended that prognosis be assessed in IPF patients at the time of diagnosis based on: severity of dyspnoea; results of pulmonary function tests (FVC and DLCO); percutaneous oxygen saturation at the end of the 6MWT; extent of honeycombing on HRCT; signs of pulmonary hypertension at echocardiography; and using a score. Prognosis should also be assessed in IPF patients during follow-up based on: progression of symptoms; FVC and DLCO; fibrosis on HRCT; and, where applicable, on signs of pulmonary hypertension at echocardiography.
## Comment
The following factors have been associated with an increased risk of death in IPF patients [bib_ref] Clinical course and prediction of survival in idiopathic pulmonary fibrosis, Ley [/bib_ref]. 1) Older age and male sex. 2) Early signs and symptoms: including severity of dyspnoea, DLCO ,35-40% predicted, percutaneous oxygen saturation ,88% during a 6MWT at room air, extent of honeycombing on HRCT, including worsening of dyspnoea, .5% (absolute value) or 10% (absolute or relative value) decrease in FVC over 6 months [bib_ref] Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and..., Bois [/bib_ref] , .15% (absolute or relative value) decrease in DLCO over 6 months, .50 m decrease in distance walked during the 6MWT [bib_ref] Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important..., Bois [/bib_ref] , and worsening of fibrosis on HRCT.
[formula] [R] [L] [R] [L] a) b) [/formula]
The survival estimates at 1, 2 and 3 years can be predicted using the GAP (gender, age, physiology) score based on age, sex, FVC and DLCO (www.acponline.org/journals/annals/extras/gap/) [bib_ref] Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis, Bois [/bib_ref] [bib_ref] A multidimensional index and staging system for idiopathic pulmonary fibrosis, Ley [/bib_ref].
## Treatment of ipf
What medical treatments have been proposed to treat IPF? Prednisone, azathioprine and N-acetylcysteine triple therapy Recommendation It is recommended not to initiate a triple therapy with prednisone, azathioprine and N-acetylcysteine (NAC) in patients definitely diagnosed with IPF.
## Comment
In the randomised, placebo-controlled IFIGENIA(Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual) trial [bib_ref] IFIGENIA: effects of N-acetylcysteine (NAC) on primary end points VC and DL,CO, Demedts [/bib_ref] , an antioxidant dose (1.8 g?day -1 ) of NAC reduced the decrease of FVC and DLCO compared to placebo in a population of IPF patients who were also receiving a combination of prednisone and azathioprine. This trial was not designed to assess the benefits of triple therapy compared to placebo.
[formula] [R] [L] [R] [L] a) b) FIGURE 4 [/formula]
High-resolution computed tomography scans demonstrating patterns not consistent with usual interstitial pneumonia. a) Prominent and diffuse ground-glass attenuation with traction bronchiectasis in a patient with idiopathic nonspecific interstitial pneumonia. b) Ground-glass attenuation with mosaic distribution in a patient with hypersensitivity pneumonitis. The PANTHER (Prednisolone, Azathioprine and NAC: a study that evaluates response in IPF) trial assessed the efficacy of NAC antioxidant treatment in mild-to-moderate IPF [bib_ref] Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis, Raghu [/bib_ref]. The trial initially comprised three arms with similar sample sizes (triple therapy: azathioprine + prednisone + NAC versus NAC versus placebo), the main outcome being decrease in FVC at 60 weeks. The triple therapy arm was prematurely discontinued at 6 months after inclusion of 236 patients because of increased risks of all-cause mortality (p50.01) and unscheduled hospitalisation (p,0.001) compared to placebo.
## Nac monotherapy recommendation
It is possible to prescribe NAC treatment to some patients with a definite diagnosis of IPF, taking into account the benefit/risk ratio and the patient's preferences, if treatment with an approved drug is not indicated after having considered participation in a therapeutic clinical trial.
## Comment
The IFIGENIA trial [bib_ref] IFIGENIA: effects of N-acetylcysteine (NAC) on primary end points VC and DL,CO, Demedts [/bib_ref] did not assess the benefits of NAC monotherapy compared to placebo. Results of the ongoing PANTHER trial [bib_ref] Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis, Raghu [/bib_ref] , which currently comprises the NAC and placebo arms, will be released in 2014. Pending the results of ongoing clinical trials, monotherapy treatment with NAC may be considered on
## Indication
Absence of HRCT features sufficient to diagnose IPF # Setting Surgical centre experienced in the management of interstitial lung diseases and in performing video-assisted surgical lung biopsies Technique Video-assisted surgery whenever possible (excluding transbronchial biopsies) " Sampling In depth, in several lobes + , avoiding the extremity of the lingula and middle lobe HRCT: high-resolution computed tomography. # : theoretical indication, to be balanced during multidisciplinary team discussion with risk associated with biopsy, age and possible comorbid conditions, and to be discussed with the patient; " : to collect samples of an adequate size; + : lesions may differ between the lobes. : can be associated with acute exacerbation of idiopathic pulmonary fibrosis; " : an isolated or occasional granuloma and/or a mild component of organising pneumonia pattern may rarely coexist in lung biopsies with an otherwise UIP pattern; + : this scenario usually represents end-stage fibrotic lung disease where honeycombed segments have been sampled but where a UIP pattern might be present in other areas. Such areas are usually represented by overt honeycombing on high-resolution computed tomography (HRCT) and can be avoided by pre-operative targeting of biopsy sites away from these areas using HRCT. Reproduced from [bib_ref] An Official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and..., Raghu [/bib_ref] with permission from the publisher. an individual basis. NAC has not been approved for the treatment of IPF and may not be reimbursed by health insurance systems.
## Corticosteroid therapy recommendation
It is recommended not to use corticosteroid therapy (with or without immunomodulator therapy) in patients with a definite diagnosis of IPF, except in the context of acute exacerbation of the disease.
## Comment
No survival benefit has been demonstrated in patients treated with corticosteroids in controlled trials [bib_ref] Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy..., Douglas [/bib_ref] [bib_ref] Hospital-based historical cohort study of 234 histologically proven Japanese patients with IPF, Nagai [/bib_ref]. Corticosteroid monotherapy is associated with substantial long-term morbidity [bib_ref] Idiopathic pulmonary fibrosis: predicting response to therapy and survival, Gay [/bib_ref]. Due to methodological biases [bib_ref] Diffuse interstitial pneumonitis. Clinicopathologic correlations in 20 patients treated with prednisone/azathioprine, Winterbauer [/bib_ref] [bib_ref] Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a..., Raghu [/bib_ref] [bib_ref] Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone..., Johnson [/bib_ref] or conflicting results [bib_ref] Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary..., Collard [/bib_ref] [bib_ref] Survival in idiopathic pulmonary fibrosis-cytotoxic agents compared to corticosteroids, Pereira [/bib_ref] of studies assessing the efficacy of combination corticosteroid and immunomodulator therapy (e.g. azathioprine or cyclophosphamide) on patient's survival, this combination cannot be recommended in the treatment of IPF. Oral corticosteroid therapy up to 10 mg of prednisone per day is sometimes proposed to alleviate incapacitating cough [bib_ref] A study of the cough reflex in idiopathic pulmonary fibrosis, Hope-Gill [/bib_ref]. High-dose corticosteroid therapy is proposed to treat patients with acute exacerbation of IPF.
## Anticoagulation therapy recommendation
It is recommended not to prescribe oral anti-vitamin K anticoagulant agents to treat IPF. While specific data are lacking, oral anti-vitamin K agents are not contraindicated in patients with IPF if this treatment is indicated for other reasons (especially for cardiovascular indications).
## Comment
A Japanese trial conducted in patients with IPF compared corticosteroid monotherapy to combination corticosteroid and anticoagulant therapy (long-term warfarin treatment; unfractionated or low-molecular weight heparin in hospitalised patients) [bib_ref] Anticoagulant therapy for idiopathic pulmonary fibrosis, Kubo [/bib_ref]. Results suggested a survival benefit associated with the combination therapy but the study had major methodological flaws. A more recent and methodologically sound trial comparing warfarin to placebo was prematurely discontinued because of increased mortality (p50.005) and increased prevalence of adverse events in the warfarin group, without survival benefit [bib_ref] A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis, Noth [/bib_ref].
## Colchicine, cyclosporine a, interferon-c-1b and etanercept recommendation
It is not recommended to prescribe treatment with colchicine, cyclosporine A, interferon-c-1b or etanercept in patients definitely diagnosed with IPF.
## Comment
Several prospective clinical trials comparing colchicine to various therapeutic regimens did not demonstrate any clinical efficacy of colchicine in IPF [bib_ref] Colchicine, cyclophosphamide and prednisone in the treatment of mildmoderate idiopathic pulmonary fibrosis:..., Fiorucci [/bib_ref] [bib_ref] Long-term clinical effects of interferon gamma-1b and colchicine in idiopathic pulmonary fibrosis, Antoniou [/bib_ref] [bib_ref] Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized..., Douglas [/bib_ref]. A retrospective study conducted in 487 patients with IPF showed no effect of colchicine on survival [bib_ref] Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy..., Douglas [/bib_ref].
In two studies conducted in small groups of patients with IPF, who had received lung transplantation and whose immunosuppressive treatment included cyclosporine, the disease progressed in the nontransplanted lung [bib_ref] Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native..., Grgic [/bib_ref] [bib_ref] Progression of idiopathic pulmonary fibrosis in native lungs after single lung transplantation, Wahidi [/bib_ref].
In two randomised controlled trials, interferon-c-1b had no effect on disease progression [bib_ref] A placebo-controlled trial of interferon-c-1b in patients with idiopathic pulmonary fibrosis, Raghu [/bib_ref] and overall survival [bib_ref] Effect of interferon-c-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE):..., King [/bib_ref].
In a randomised controlled trial of etanercept conducted in patients with IPF, no difference was found regarding the primary end-point (change in FVC at 48 weeks) [bib_ref] Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial, Raghu [/bib_ref].
## Endothelin-1 receptor antagonists recommendation
It is not recommended to prescribe treatment with bosentan or macitentan in patients definitely diagnosed with IPF. It is recommended not to prescribe treatment with ambrisentan in patients definitely diagnosed with IPF.
## Comment
In a phase II randomised controlled trial of bosentan, an antagonist of endothelin-1 receptors A and B (ET A and ET B , respectively), there was no improvement in the primary end-point (modified 6MWT) [bib_ref] BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis, King [/bib_ref]. BUILD (Bosentan Use in Interstitial Lung Disease)-3, conducted in patients with IPF confirmed by lung biopsy [bib_ref] BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis, King [/bib_ref] , did not show any improvement in the primary end-point (time to IPF worsening or death), or in quality of life and dyspnoea in the bosentan group. The primary end-point (change in FVC) was also not reached in the MUSIC (Macitentan Use in an Idiopathic Pulmonary Fibrosis Clinical) trial that evaluated macitentan [bib_ref] Efficacy and safety of macitentan in idiopathic pulmonary fibrosis: results of a..., Raghu [/bib_ref] , another antagonist of ET A and ET B . In ARTEMIS-IPF [bib_ref] ARTEMIS-IPF: a placebo-controlled trial of ambrisentan in idiopathic pulmonary fibrosis, Raghu [/bib_ref] , ambrisentan, an ET A antagonist, had detrimental effects on the primary end-point (time to death or worsening of pulmonary function) and was associated with an increased rate of hospitalisations for respiratory complications. Ambrisentan is currently contraindicated in IPF, including IPF with severe pulmonary hypertension.
## Etanercept recommendation
It is not recommended to prescribe treatment with etanercept in patients definitely diagnosed with IPF.
## Pirfenidone recommendation
It is currently recommended to treat patients definitely diagnosed with mild-to-moderate IPF (defined as FVC o50% pred and DLCO o35% pred) with pirfenidone. This treatment should be initiated and supervised by a physician experienced in the diagnosis and management of IPF, and requires regular monitoring of clinical tolerance and liver enzymes. The patient must not smoke during pirfenidone treatment and patients should be warned against UV exposure.
## Comment
A pooled analysis of two phase III studies (006/Capacity 1 and 004/Capacity 2) conducted in patients with mild-to-moderate IPF showed a significant reduction in FVC decline at week 72 in patients treated with pirfenidone [bib_ref] Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials, Noble [/bib_ref]. Disease progression (defined as a o10% decrease in FVC absolute value, a o15% decrease in DLCO, or death) and decline in 6MWT performance were also reduced. In a phase III study conducted in Japan [bib_ref] Pirfenidone in idiopathic pulmonary fibrosis, Taniguchi [/bib_ref] , pirfenidone (1800 mg?day -1 ) significantly reduced FVC decline compared to placebo. Another phase III trial is ongoing in the USA (www.clinicaltrials.gov; identifier NCT01366209).
Pirfenidone was granted European marketing authorisation in 2011, and was marketed in France in 2012 for the treatment of patients with a clinically and radiologically confirmed diagnosis of mild-to-moderate IPF (FVC o50% pred and DLCO o35% pred). Pirfenidone should be initiated and supervised by specialist physicians experienced in the diagnosis and management of IPF.
Pirfenidone should not be administered to patients treated with fluvoxamine and patients with severe hepatic or renal impairment. The most commonly reported adverse reactions with pirfenidone were nausea, rash, fatigue, diarrhoea, dyspepsia, photosensitivity reaction and weight loss [bib_ref] Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials, Noble [/bib_ref]. Pirfenidone may also induce elevations in liver enzymes. Liver function tests should be performed prior to the initiation of treatment with pirfenidone, and subsequently at monthly intervals for the first 6 months and every 3 months thereafter.
Smoking has the potential to increase the activity of enzymes involved in pirfenidone metabolism and should be discontinued prior to and during treatment with pirfenidone. Concomitant use of omeprazole may theoretically result in changes in pirfenidone pharmacokinetics and should be avoided.
## Should ipf patients be vaccinated against influenza and pneumococcal infections? recommendation
It is recommended that annual influenza vaccination and anti-pneumococcal vaccination be performed in patients definitely diagnosed with IPF.
## Comment
Although no specific studies of these vaccinations have been conducted in the context of IPF, it is very likely that, like other patients suffering from chronic respiratory diseases, IPF patients are exposed to a high risk if they develop a pneumococcal infection or influenza. Anti-pneumococcal vaccinations may be performed using the polysaccharide pneumococcal vaccine.
## Should ipf patients receive supplemental oxygen therapy? recommendation
It is recommended to use long-term oxygen therapy in patients definitely diagnosed with IPF and with severe hypoxaemia at rest (severe chronic respiratory failure).
## Comment
Indirect evidence of benefits of oxygen therapy has been suggested by studies conducted in patients with other lung diseases and hypoxaemia. Two randomised controlled trials have reported a survival benefit in patients with chronic obstructive lung disease receiving long-term oxygen therapy. Supplemental oxygen therapy is usually indicated in severe chronic respiratory failure (arterial oxygen tension (PaO 2 ) f55 mmHg (7.3 kPa)), i.e. arterial oxygen saturation f88% measured at rest in stable conditions on two separate occasions or PaO 2 55-60 mmHg (7.3-8.0 kPa) if at least one of the following criterion is present: haematocrit .55%, signs of pulmonary hypertension and documented right heart failure. Long-term oxygen therapy is commonly used in patients with PaO 2 f55-60 mmHg (7.3-8.0 kPa) measured at rest in stable conditions on two separate occasions.
## Should ipf patients receive respiratory rehabilitation? recommendation
It is proposed that a respiratory rehabilitation programme should be initiated in patients definitely diagnosed with IPF in whom limitation of exercise capacity results in significant impairment.
## Comment
Several studies have reported improvement in walking distance, symptoms or quality of life in IPF patients following a respiratory rehabilitation programme [bib_ref] Short term improvement in exercise capacity and symptoms following exercise training in..., Holland [/bib_ref] [bib_ref] Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis, Nishiyama [/bib_ref]. Respiratory rehabilitation programmes may include exercise training, smoking cessation, psychosocial assistance and supportive care. Rehabilitation may not be feasible in patients with advanced disease.
## What is the indication for lung transplantation in ipf patients? recommendation
It is recommended to consider lung transplantation in all patients definitely diagnosed with IPF aged ,65 years if the disease is severe or worsening. It is recommended that the patient is given information about lung transplantation early in the course of the disease. Early assessment of the patient in a lung transplantation centre is advised.
## Comment
Lung transplantation improves survival in patients with advanced stage IPF [bib_ref] Lung transplantation for idiopathic pulmonary fibrosis, Mason [/bib_ref] [bib_ref] Lung transplantation in pulmonary fibrosis: challenging early outcomes counterbalanced by surprisingly good..., Keating [/bib_ref] [bib_ref] Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis, Thabut [/bib_ref]. International recommendations specify that transplantation should be considered in patients aged ,65 years if DLCO is ,39% pred and FVC has decreased by o10% over 6 months of follow-up [bib_ref] International guidelines for the selection of lung transplant candidates: 2006 update -a..., Orens [/bib_ref]. The (physiological) age limit of ,65 years is relative and depends on local practice; comorbid conditions should be taken into account.
What are the diagnostic criteria of acute exacerbation of IPF? Recommendation It is recommended to diagnose acute exacerbation of IPF in the case of recent worsening of dyspnoea (,30 days) associated with additional lung opacities on imaging, after other possible causes of respiratory function worsening have been ruled out (i.e. infection, pulmonary embolism and left heart failure).
## Comment
Acute exacerbation of IPF is characterised by acute (,30 days) worsening of dyspnoea with no identified cause (e.g. infection, pulmonary embolism, left heart failure or cardiac arrhythmia) in a patient definitely diagnosed with IPF. HRCT shows new opacities in addition to pre-existing abnormalities, in particular ground-glass opacities. Worsening of hypoxaemia is common (o10 mmHg decrease of PaO 2 ). Videoassisted SLB is usually considered too hazardous and is not performed in this context.
## Which treatments can be suggested to patients with acute exacerbation of ipf? recommendation
It is proposed to use high-dose corticosteroids to treat acute exacerbations of IPF. It is possible to use intravenous cyclophosphamide to treat acute exacerbations of IPF. There are insufficient data regarding the use of low-molecular weight heparin to treat acute exacerbations of IPF.
## Comment
Although no controlled trials have assessed their efficacy in this indication, high-dose corticosteroids are commonly prescribed to treat exacerbations of IPF [bib_ref] Idiopathic pulmonary fibrosis: increased survival with ''gastroesophageal reflux therapy'': fact or fallacy?, Raghu [/bib_ref]. Some observations have suggested that immunosuppressive agents might be beneficial. Cyclosporine A has also been used, but without convincing results. A benefit of intravenous cyclophosphamide has been suggested previously [bib_ref] Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses, Morawiec [/bib_ref].
Low-molecular weight heparins have not demonstrated any benefits in acute exacerbations of IPF, but this treatment is sometimes used. As a trial comparing warfarin to placebo was prematurely discontinued because of increased mortality and increased prevalence of adverse events in the warfarin group, without apparent survival benefit [bib_ref] A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis, Noth [/bib_ref] , long-term oral anticoagulant therapy is not recommended in IPF (see previous section). Wide-spectrum antibiotics may be used when infection has not been definitely ruled out. Anticoagulant therapy may be prescribed in the case of acute worsening of symptoms or if thromboembolic venous disease is suspected.
What is the role of invasive and noninvasive ventilation in the management of IPF? Recommendation It is not recommended to use invasive ventilation in patients definitely diagnosed with IPF and acute or chronic respiratory failure. It is possible to use invasive or noninvasive ventilation in a minority of patients with IPF and acute respiratory failure; in particular, if criteria for emergency lung transplantation are met, if exacerbation is the first manifestation of IPF, or in case of acute infection or reversible cause.
## Comment
Given the high mortality associated with mechanical ventilation in IPF [bib_ref] Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for..., Blivet [/bib_ref] [bib_ref] Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features, Kim [/bib_ref] [bib_ref] Outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care..., Saydain [/bib_ref] [bib_ref] Lung and chest wall mechanics in ventilated patients with end stage idiopathic..., Nava [/bib_ref] [bib_ref] Prognosis of patients with advanced idiopathic pulmonary fibrosis requiring mechanical ventilation for..., Stern [/bib_ref] [bib_ref] Outcome of patients admitted to the intensive care unit for acute exacerbation..., Al-Hameed [/bib_ref] [bib_ref] Outcome of mechanical ventilation for acute respiratory failure in patients with pulmonary..., Fumeaux [/bib_ref] [bib_ref] Mechanical ventilation in patients with end-stage idiopathic pulmonary fibrosis, Mollica [/bib_ref] [bib_ref] Outcomes of patients admitted to the intensive care unit with idiopathic pulmonary..., Rangappa [/bib_ref] , this therapy should only be used after discussion with the patients and their caregivers (ideally, during a previous visit) regarding goals of care, in particular reduction of unnecessary suffering. Intensive care is justified as a bridge to lung transplantation or if a reversible cause of worsening has been identified [bib_ref] Fibrose pulmonaire: dans quels cas et sur quels critères envisager une admission..., Mullier [/bib_ref].
Data on noninvasive ventilation in IPF are scarce. A retrospective study in which some patients with acute exacerbation of IPF were included suggests that, in this context, noninvasive ventilation may be preferred to invasive ventilation without increasing mortality [bib_ref] Noninvasive ventilation in acute exacerbation of idiopathic pulmonary fibrosis, Yokoyama [/bib_ref].
## Should ipf patients be investigated for pulmonary hypertension, if so how? recommendation
It is proposed that echocardiography be performed during the IPF diagnostic procedure and then annually to detect pulmonary hypertension in patients with IPF. It is proposed that right heart catheterisation be performed to diagnose pulmonary hypertension in patients definitely diagnosed with IPF: 1) prior to lung transplantation; 2) in cases of clinical deterioration, limitation of exercise capacity, decrease of DLCO (especially if DLCO is ,40% pred) and/or hypoxaemia disproportionate with regard to the restrictive ventilatory defect (in particular if emphysema is present); 3) if an accurate evaluation of prognosis is deemed essential; 4) if severe precapillary pulmonary hypertension is suspected at echocardiography (tricuspid regurgitation flow .3.5 m?s -1 ) and to discuss possible off-label treatment of pulmonary hypertension; and 5) if left ventricular disease with preserved systolic function is suspected.
## Comment
Precapillary pulmonary hypertension (mean pulmonary artery pressure (Ppa) o25 mmHg and pulmonary artery wedge pressure f15 mmHg) is present in ,10% of patients with IPF at the time of diagnosis, and 30-45% during evaluation prior to lung transplantation [bib_ref] Pulmonary hypertension in patients with idiopathic pulmonary fibrosis, Nathan [/bib_ref]. Severe pulmonary hypertension (mean Ppa o35-40 mmHg) [bib_ref] Pulmonary hypertension in chronic lung diseases, Seeger [/bib_ref] is present in 2-9% of patients with IPF [bib_ref] Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant, Shorr [/bib_ref] [bib_ref] Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis, Lettieri [/bib_ref]. Precapillary pulmonary hypertension is associated with increased mortality [bib_ref] Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis, Lettieri [/bib_ref] , dyspnoea and hypoxaemia, decreased exercise capacity and DLCO, and risk of acute exacerbation [bib_ref] Acute exacerbations and pulmonary hypertension in advanced idiopathic pulmonary fibrosis, Judge [/bib_ref]. Doppler echocardiography is the first-line noninvasive examination but its positive and negative predictive values for the diagnosis of pulmonary hypertension are low [bib_ref] Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease, Arcasoy [/bib_ref]. Whether right heart catheterisation is indicated in an IPF patient should be decided in expert centres [bib_ref] Pulmonary hypertension in patients with idiopathic pulmonary fibrosis, Nathan [/bib_ref].
## How should pulmonary hypertension be managed if present in a patient with ipf? recommendation
It is recommended that patients with IPF and pulmonary hypertension are investigated for resting hypoxaemia, thromboembolic venous disease and left heart failure, and that patients receive appropriate treatment if needed. Lung transplantation should also be considered.
In patients with IPF and moderate precapillary pulmonary hypertension (mean Ppa f35-40 mmHg at rest), it is not recommended to prescribe any specific treatment for pulmonary hypertension.
In patients with IPF and severe precapillary pulmonary hypertension (mean Ppa o35-40 mmHg at rest), it is possible to prescribe a specific treatment for pulmonary hypertension, preferably with sildenafil in a specialised centre, if pulmonary hypertension is held responsible for worsening of symptoms.
In patients with IPF and severe precapillary pulmonary hypertension (mean Ppa o35-40 mmHg at rest), it is recommended not to prescribe ambrisentan. Comment Causes of pulmonary hypertension other than IPF should always be explored. Lung or heart-lung transplantation should be considered depending on age and comorbid conditions. No treatment specific for pulmonary hypertension is recommended or approved in patients with IPF [bib_ref] Pulmonary hypertension in chronic lung diseases, Seeger [/bib_ref].
In two uncontrolled prospective studies of sildenafil conducted in some patients with IPF and pulmonary hypertension, walk distance and pulmonary haemodynamics improved after 8-12 weeks of treatment [bib_ref] A potential role for sildenafil in the management of pulmonary hypertension in..., Madden [/bib_ref] [bib_ref] Sildenafil improves walk distance in idiopathic pulmonary fibrosis, Collard [/bib_ref]. In the randomised controlled STEP-IPF (Sildenafil Trial of Exercise Performance in IPF) trial, comparing sildenafil therapy and placebo over 12 weeks, no significant improvement of the 6MWT (primary end-point) was observed [bib_ref] A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis, Zisman [/bib_ref] , but sildenafil significantly improved arterial oxygenation, DLCO, dyspnoea and quality of life, and could be useful in patients with right ventricular dysfunction at echocardiography [bib_ref] Sildenafil preserves exercise capacity in IPF patients with right ventricular dysfunction, Han [/bib_ref].
A randomised controlled trial, ARTEMIS-IPF (www.clinicaltrials.gov; identifier NCT00768300) [bib_ref] ARTEMIS-IPF: a placebo-controlled trial of ambrisentan in idiopathic pulmonary fibrosis, Raghu [/bib_ref] , showed a detrimental effect of ambrisentan, an ET A antagonist, on the primary end-point (time to death or worsening of respiratory function) and an increased number of hospitalisations for respiratory complications. This led to premature discontinuation of another trial of ambrisentan in IPF, ARTEMIS-PH (www.clinicaltrials.gov; identifier NCT00879229). Therefore, ambrisentan is contraindicated in IPF
patients. An open label study of riociguat in patients with ILD suggested an increase in cardiac output, with unclear clinical benefit [bib_ref] Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial, Hoeper [/bib_ref].
Should IPF patients be investigated for gastro-oesophageal reflux, if so how? How should gastrooesophageal reflux be managed in IPF patients? Recommendation It is proposed that a history or symptoms of gastro-oesophageal reflux be investigated during the medical interview of all patients definitely diagnosed with IPF. If gastro-oesophageal reflux is suspected, it is proposed to perform the appropriate tests and to comply with applicable recommendations for gastrooesophageal reflux management.
## Comment
Gastro-oesophageal reflux is common in patients with IPF [bib_ref] Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic..., Noth [/bib_ref] and is asymptomatic in 50% of cases [bib_ref] High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis, Raghu [/bib_ref] [bib_ref] Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis, Tobin [/bib_ref] [bib_ref] Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation, Sweet [/bib_ref] [bib_ref] Progression of idiopathic pulmonary fibrosis: lessons from asymmetrical disease, Tcherakian [/bib_ref]. Retrospective studies have reported stabilisation of pulmonary function and oxygen requirements in association with medical or surgical treatment of gastro-oesophageal reflux [bib_ref] Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation, Linden [/bib_ref]. A survival benefit in IPF patients treated with proton-pump inhibitors or H2 receptor antagonists has been reported previously [bib_ref] Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic..., Lee [/bib_ref]. The methodological weaknesses of this study, but also the interest of this research area, have been underlined [bib_ref] Idiopathic pulmonary fibrosis: increased survival with ''gastroesophageal reflux therapy'': fact or fallacy?, Raghu [/bib_ref] [bib_ref] Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for antireflux therapy?, Raghu [/bib_ref].
Available data are insufficient to recommend a particular management of gastro-oesophageal reflux in patients with IPF. The role of surgical treatment and the management of non-acid reflux remain unknown. Pirfenidone-omeprazole combination therapy should be avoided.
Should patients with IPF be investigated for emphysema, if so how? How should emphysema be managed in patients with IPF? Recommendation It is recommended to search for emphysema on the chest HRCT performed for the diagnosis of IPF to avoid underestimation of the severity of the disease if lung volumes are preserved. It is proposed that management of emphysema, if present, should be similar to that of emphysema in other settings, including smoking cessation, and inhaled bronchodilators should be used if airflow obstruction is present. No data are available to support specific drug therapy in the setting of combined pulmonary fibrosis and emphysema.
## Comment
Compared with IPF patients without emphysema, patients with combined pulmonary fibrosis and emphysema have preserved lung respiratory volumes, decreased carbon monoxide transfer and higher oxygen requirement. Disease evolution might be worse in patients with this syndrome compared to those with IPF alone [bib_ref] Combined pulmonary fibrosis and emphysema: a distinct under recognised entity, Cottin [/bib_ref] [bib_ref] Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial..., Mejia [/bib_ref] , but there are no reliable data showing that emphysema impacts survival. Diagnosis of combined pulmonary fibrosis and emphysema is important so as not to spuriously attribute the preservation of pulmonary volumes to a milder severity of disease. Pulmonary hypertension is particularly frequent and is the main predictor of mortality in patients with the syndrome [bib_ref] Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome, Cottin [/bib_ref]. Long-term oxygen therapy might be indicated. Monitoring of FVC and DLCO does not allow an accurate assessment of prognosis [bib_ref] Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis..., Schmidt [/bib_ref] [bib_ref] Coexistent emphysema delays the decrease of vital capacity in idiopathic pulmonary fibrosis, Akagi [/bib_ref].
No data are available to support recommendation of either specific management of emphysema in IPF patients, or specific management of fibrosis in patients presenting with combined pulmonary fibrosis and emphysema. Possible treatment (pirfenidone and NAC in monotherapy) must be assessed individually, taking into account side-effects, the absence of data on the potential benefit of this treatment in this indication, and the difficulty of evaluating disease evolution (little change in FVC).
Should IPF patients be explored for obstructive sleep apnoea syndrome, if so how? Recommendation It is recommended that ventilatory polygraphy be performed in patients definitely diagnosed with IPF if clinical signs suggest obstructive sleep apnoea syndrome.
## Comment
Several studies have shown a high rate of obstructive sleep apnoea syndrome in patients with IPF [bib_ref] A survey of nocturnal hypoxaemia and health related quality of life in..., Clark [/bib_ref] [bib_ref] Interstisyel akciger hastalarinda polisomnografi ile uyku ozelliklerinin degerlendirilmesi [Assessment of sleep with..., Aydogdu [/bib_ref] [bib_ref] Sleep-related breathing disorders in patients with idiopathic pulmonary fibrosis, Mermigkis [/bib_ref] , up to 88% in a series of 50 patients [bib_ref] Obstructive sleep apnea is common in idiopathic pulmonary fibrosis, Lancaster [/bib_ref]. Compared to polysomnography, medical interview has a much lower sensitivity to establish the diagnosis. Obesity is not always present. The clinical importance of detecting obstructive sleep apnoea syndrome is not demonstrated in IPF, especially if the syndrome is asymptomatic.
How should obstructive sleep apnoea syndrome be managed in patients with IPF? Recommendation No specific data on the management of sleep apnoea in patients with IPF are available. It is proposed that when present in a patient definitely diagnosed with IPF, obstructive sleep apnoea syndrome should be managed with the usual recommendations applicable in patients without IPF.
## Comment
Available data are insufficient to recommend a specific management of obstructive sleep apnoea syndrome in patients with IPF.
How should symptoms be managed in patients with IPF? Recommendation It is possible to prescribe a transient, low-dose oral corticosteroid therapy in patients with IPF presenting with incapacitating dry cough not alleviated by codeine. Efficacy and tolerance of this therapy should be monitored.
It is possible to prescribe ambulatory supplemental oxygen therapy in patients definitely diagnosed with IPF presenting with major dyspnoea at exercise and oxygen desaturation at exercise (percutaneous oxygen saturation ,88% during daily life activities or standardised exercise, such as the 6MWT).
It is possible to prescribe low-dose morphine derivatives in patients with IPF presenting with major dyspnoea, in the absence of hypercapnia, while monitoring the efficacy and tolerance of this treatment.
## Comment
Limited data suggest that oral corticosteroid therapy and thalidomide may alleviate chronic cough associated with IPF. High-dose corticosteroids or thalidomide are poorly tolerated and inadvisable. Lowdose morphine derivatives may be used in cases of major dyspnoea but side-effects of this treatment should be closely monitored [bib_ref] Low dose diamorphine reduces breathlessness without causing a fall in oxygen saturation..., Allen [/bib_ref]. Low-dose morphine derivatives (f30 mg oral morphine equivalents a day) are not associated with increased mortality in patients with chronic obstructive pulmonary disease and starting long-term oxygen therapy [bib_ref] Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective..., Ekstrom [/bib_ref]. No similar data are available in patients with IPF.
A small study has suggested that exercise capacity might be improved in patients with IPF and hypoxaemia at rest who were treated with oxygen therapy [bib_ref] Increased exercise capacity in hypoxemic patients after long-term oxygen therapy, Morrison [/bib_ref]. Two retrospective studies have shown that ambulatory oxygen therapy may significantly improve 6MWT performance and dyspnoea in patients with IPF [bib_ref] Ambulatory oxygen in interstitial lung disease, Visca [/bib_ref] [bib_ref] Ambulatory oxygen in idiopathic pulmonary fibrosis: of what benefit?, Frank [/bib_ref]. In those two studies, oxygen flow was increased stepwise until percutaneous oxygen saturation was o88% in one study and 90% in the other.
What examinations should be performed and at what frequency during follow-up of an IPF patient? Recommendation It is recommended that patients definitely diagnosed with IPF should have a clinical visit and undergo pulmonary function tests, including the measurement of FVC, every 3-6 months. It is proposed that chest computed tomography be performed: if acute exacerbation of IPF is suspected; if unexplained clinical changes occur; if lung cancer is suspected; and prior to lung transplantation.
## Comment
If no other cause can be identified, the following changes suggest worsening of IPF [bib_ref] Clinical course and prediction of survival in idiopathic pulmonary fibrosis, Ley [/bib_ref] [bib_ref] Relative versus absolute change in forced vital capacity in idiopathic pulmonary fibrosis, Richeldi [/bib_ref] : 1) progressive increase of the level of dyspnoea; 2) progressive decrease of FVC (especially by o10% of the relative or absolute value); 3) progressive decrease of DLCO (especially by o15% of the relative or absolute value); 4) worsening of signs of pulmonary fibrosis on computed tomography; 5) acute exacerbation of the disease.
Visits may be repeated every 3-6 months [fig_ref] TABLE 6: Main examinations that are useful for idiopathic pulmonary fibrosis [/fig_ref]. Visits to a specialised centre (reference centre, competence centre or hospital department experienced in ILDs) must take place at least annually or more frequently if deterioration occurs. 3 monthly visits may take place in the vicinity of the patient's home, alternating with visits to a specialised centre, preferably in the context of a formal or informal care network involving the treating general practitioner and the treating pulmonologist. Is the risk of lung cancer increased during follow-up in a patient with IPF? Recommendation The risk of lung cancer is increased in patients with IPF. It is proposed that the physician in charge of follow-up be made aware of the frequent occurrence of lung cancer in patients definitely diagnosed with IPF. It is recommended that smokers are urged to quit smoking and are informed about smoking cessation assistance. In patients definitely diagnosed with IPF and lung cancer, it is recommended that IPF is taken into account for treatment decisions.
## Comment
Compared with the risk of lung cancer in the general population, the relative risk of lung cancer in patients with IPF is increased by approximately seven-fold [bib_ref] Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study, Hubbard [/bib_ref]. Lung cancer prevalence in the IPF population is between 4.4% and 9.8% [bib_ref] Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study, Hubbard [/bib_ref] [bib_ref] Cryptogenic fibrosing alveolitis: clinical features and their influence on survival, Turner-Warwick [/bib_ref] [bib_ref] Cryptogenic fibrosing alveolitis and lung cancer: the BTS study, Harris [/bib_ref] , and a retrospective study reported a 55% 10-year risk of developing lung cancer [bib_ref] Cumulative incidence of and predictive factors for lung cancer in IPF, Ozawa [/bib_ref]. Neither specific screening nor specific management of lung cancer in IPF patients can be recommended.
Lung cancer management is made more difficult by IPF and by the risk of acute respiratory failure and/or acute exacerbation associated with treatments of cancer (surgical resection, radiation therapy and chemotherapy) [bib_ref] Idiopathic pulmonary fibrosis: phenotypes and comorbidities, Fell [/bib_ref].
## Should patients with ipf be investigated for other comorbid conditions? recommendation
It is proposed that comorbid conditions (cardiovascular disease, thromboembolic venous disease, diabetes and depression) be evaluated in patients definitely diagnosed with IPF, in order to inform the physician who is in charge of follow-up.
## Comment
Comorbid conditions, in particular those linked to smoking including cardiovascular disease, thromboembolic venous disease, diabetes and depression, are frequently present in patients with IPF [bib_ref] Idiopathic pulmonary fibrosis: phenotypes and comorbidities, Fell [/bib_ref]. Available data are insufficient to recommend systematic screening of such comorbid conditions, but informing the physician in charge of follow-up (general practitioner or pulmonologist responsible for the organisation of care) of the presence of a comorbid condition is important.
# Conclusion
Since the ATS/ERS/JRS/ALAT guidelines on the diagnosis and management of IPF were published in 2011, new data from major clinical studies has prompted IPF experts from several European countries to release updated recommendations in the form of national consensus statements or opinions [bib_ref] Evidence-based treatment strategies in idiopathic pulmonary fibrosis, Behr [/bib_ref] [bib_ref] Review of IPF diagnosis and management recommendations in Europe, Xaubet [/bib_ref].
The need to incorporate recent evidence into recommendations for the diagnosis and management of IPF was the basis of the present document. Our main objective was to provide French pulmonologists with an updated, practical, decision-making tool that could be used in the daily clinical care of patients with suspected or definitely diagnosed IPF.
This document complied with the specific national method and validation processes defined by the Haute Autorité de Santé as good clinical practice for the development of guidelines. The organisation of the three committees with specific missions ensured the involvement of prominent pulmonologists, radiologists and pathologists experienced in the diagnosis and/or management of IPF.
In France, the network of the reference centre and the competence centres for rare lung diseases is responsible for organising the care of patients with rare diseases, including IPF, in collaboration with local pulmonologists, general physicians and other specialists involved in diagnosis and management. These expert centres are geographically spread across all regions of France. The reference centre and the competence centres for rare lung diseases coordinated the entire process of preparation of the present guidelines, in order to standardise and optimise care, but the present recommendations accurately reflect the collective thinking of all the experts involved.
Another feature of the present document is that it gives clinicians guidance even when the compelling evidence for (or against) an examination or treatment is lacking. Formulations such as ''It is proposed to'' or ''It is possible to'' accompanied by a summary of the literature justifying these formulations should help the reader to exert informed clinical judgment and decide whether the related diagnostic or therapeutic intervention is appropriate in a given clinical situation.
The main differences between our recommendations and the 2011 guidelines originate from recently emerged evidence. 1) Triple therapy with a prednisone, azathioprine and NAC should not be initiated in patients with IPF as it has been shown to increase mortality. 2) Corticosteroid therapy is associated with substantial morbidity and, in combination with immunomodulator therapy, might increase mortality. Corticosteroid therapy is no longer an option for the treatment of IPF, except to alleviate incapacitating cough or to treat acute exacerbation of IPF. 3) Ambrisentan is now contraindicated in the treatment in IPF. 4) To date, pirfenidone is the only pharmacological treatment with demonstrated benefits in IPF patients, and the only treatment that has been approved and granted marketing authorisation for this indication.
We are confident that the present recommendations will help clinicians caring for IPF patients to base their practice on currently available evidence before the much needed updated international guidelines are released.
[fig] FIGURE 2: High-resolution computed tomography scan demonstrating a typical example of usual interstitial pneumonia pattern with honeycombing change and traction bronchiectasis, as well as subpleural and basal reticulation. No features are seen suggesting an alternative diagnosis. [/fig]
[fig] FIGURE 3 a: b) Representative examples of the lung biopsies. High-resolution computed tomography scans demonstrating possible usual interstitial pneumonia pattern with subpleural and basal reticulation, and traction bronchiectasis. No features are seen suggesting an alternative diagnosis. Video-assisted surgical lung biopsy demonstrated definite usual interstitial pneumonia pattern. IDIOPATHIC PULMONARY FIBROSIS | V. COTTIN ET AL. DOI: 10.1183/09059180.00001814 and precapillary pulmonary hypertension. 3) Signs and symptoms occurring during the clinical course: [/fig]
[table] TABLE 2: Diagnosis of idiopathic pulmonary fibrosis (IPF) [/table]
[table] TABLE 3: Chest high-resolution computed tomography methodsMandatoryNo injection of contrast medium Inspiratory apnoea slices Axial contiguous or non-reconstructed slices separated by f2 cm Slice thickness f2 mm Reconstruction field focused on lungs Image acquisition complying with European irradiation norms Archiving of image acquisition of millimetric slices on CD/DVD for further reading OptionalFrontal reconstruction in minimal intensity projection, 5-8 mm thick # Images in the prone position, if opacities linked to gravito-dependance hamper the analysis when in the supine position Expiration slices to exclude lobular air trapping " Coronal and sagittal reconstructions if volumetric acquisitions are available # : to differentiate bronchiolectasis from honeycombing; " : more frequent in patients with hypersensitivity pneumonitis. IDIOPATHIC PULMONARY FIBROSIS | V. COTTIN ET AL. DOI: 10.1183/09059180.00001814 [/table]
[table] TABLE 4: Indications and techniques of lung biopsy in patients with suspected idiopathic pulmonary fibrosis (IPF) [/table]
[table] TABLE 5: Histopathological criteria for usual interstitial pneumonia (UIP) pattern [/table]
[table] TABLE 6: Main examinations that are useful for idiopathic pulmonary fibrosis (IPF) diagnosis and management Transaminases, c-glutamyltransferase and alkaline phosphatases Occasional Video-assisted surgical lung biopsy (see text) Differential cell count of BAL (see text) TLC and arterial blood gas in room air at rest 6MWT with measurement of percutaneous oxygen saturation Depending on context Genetic testing (see text) Anti-neutrophil cytoplasmic antibodies Anti-SSA and anti-SSB antibodies Anti-centromere and anti-topoisomerase antibodies Anti-Mi-2, anti-U3RNP and anti-ARNt synthetase antibodies Creatine phosphokinase Anti-thyroid antibodies Precipitines (depending on disease presentation) Microbiology of BAL Electrophoresis of serum proteins, immuno-electrophoresis of serum proteins, urine immunofixation and cryoglobulinaemia Exploration for gastro-oesophageal reflux Exploration for sleep apnoea syndrome HRCT: high-resolution computed tomography; FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide; BAL: bronchoalveolar lavage; TLC: total lung capacity; 6MWT: 6-min walk test. IDIOPATHIC PULMONARY FIBROSIS | V. COTTIN ET AL. DOI: 10.1183/09059180.00001814 [/table]
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Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorité de Santé. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.
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0cfda516dbf3d946b5ec6031ee0c41e1031ba0c9
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pubmed
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The need for accurate D‐dimer reporting in COVID‐19: Communication from the ISTH SSC on fibrinolysis
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The need for accurate D‐dimer reporting in COVID‐19: Communication from the ISTH SSC on fibrinolysis
## | introduc ti on
The coronavirus disease 2019 (COVID-19) pandemic continues to claim many lives across the world. In the attempts to identify a reliable prognostic indicator, marked elevation of D-dimer has been a strong contender. [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref] [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] In many studies, D-dimers have consistently been shown to be the most significant marker for illness severity and death risk prediction. [bib_ref] D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19, Zhang [/bib_ref] [bib_ref] Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to..., Leonard-Lorant [/bib_ref] Despite the usefulness of this fibrinolytic marker, along with a recent letter by Gris et al, [bib_ref] Uncertainties on the prognostic value of D-dimers in COVID-19 patients, Gris [/bib_ref] we note several problems across the medical literature with D-dimer reporting creating confusion and potentially misleading data interpretation.
Since the arrival of the first monoclonal antibody-based assays in the 1980s, D-dimer measurements have consistently proven to be a reliable diagnostic tool. [bib_ref] Characterisation of a soluble D dimer-E complex in crosslinked fibrin digests, Gaffney [/bib_ref] Recent heightened awareness among the health care professionals and public about the risk of venous thromboembolism and disseminated intravascular coagulation, coupled with ease of use and accessibility of the D-dimer tests led to its increased popularity. The increased demand has led to proliferation of commercially available assays, but the manufacturers, and consequently workers, publishing their work have not been consistent with the reporting mechanisms of laboratory data, thus leading to confusion and causing outright errors. These issues have been recurring themes in the D-dimer saga. In over two dozen COVID-19 related papers published involving D-dimer levels this year, we noted the following problems:
- Most failed to identify the manufacturer or type of D-dimer assay used - Most did not clearly report the analytical performance of the assay (ie, variations in sensitivity, specificity, and linearity of the There are also issues with the specificity and sensitivity of the D-dimer assay based on the diagnostic purpose. A meta-analysis including 97 studies of patients with suspected deep vein thrombosis (DVT) reported an overall estimated sensitivity and specificity of D-dimer of 90.5% and 54.7%, respectively, but both estimates were subject to significant heterogeneity. [bib_ref] Variation in the diagnostic performance of D-dimer for suspected deep vein thrombosis, Goodacre [/bib_ref] Sensitivity and specificity also varied across the different types of tests and the clinical probability for DVT. [bib_ref] Variation in the diagnostic performance of D-dimer for suspected deep vein thrombosis, Goodacre [/bib_ref] For the diagnosis of DIC, D-dimer quantification is more crucial, where the variability can pose significant issues. [bib_ref] Harmonisation of D-dimera call for action, Longstaff [/bib_ref] FDPs can also affect D-dimer causing over-or underestimation of D-dimer. [bib_ref] D-dimer: standardization versus harmonization, Dempfle [/bib_ref] The poor specificity of D-dimer tests leads to high rates of false positive results but reliable negative test results, and explains why D-dimer screening is commonly used to exclude DVT.
## | in con s is ten cie s of units
D-dimer can be reported as fibrinogen equivalent units (FEU) or D-dimer units (DDU). [bib_ref] D-dimer: an overview of hemostasis and fibrinolysis, assays, and clinical applications, Olson [/bib_ref] One FEU compares the mass of the D-dimer to that of fibrinogen with a calibrator prepared from plasmin degradation of purified fibrinogen. [bib_ref] D-dimer: simple test, tough problems, Olson [/bib_ref] [bib_ref] Plasma D-dimer and venous thromboembolic disease, Righini [/bib_ref] DDU is an estimated mass of the D-dimer unit with purified D-dimer used as the calibrator. [bib_ref] D-dimer: an overview of hemostasis and fibrinolysis, assays, and clinical applications, Olson [/bib_ref] [bib_ref] Plasma D-dimer and venous thromboembolic disease, Righini [/bib_ref] FEU is approximately two-fold higher than that of DDU. If laboratory personnel or clinicians are not aware of this distinction, results interpretation can be inaccurate. Olson et al performed a survey among several US laboratories and noted that almost one-third of the laboratories changed the units from that recommended by the manufacturer. [bib_ref] D-dimer: simple test, tough problems, Olson [/bib_ref] Another web survey revealed that 28 different combinations of measure units are currently used for reporting D-dimer test results. [bib_ref] International survey on D-dimer test reporting: a call for standardization, Lippi [/bib_ref] Second, there is tremendous variability in the magnitude of units reported. Different publications use ng/mL, μg/mL, mg/L, and μg/L to report D-dimer results, which can cause considerable confusion among non-laboratory health care personnel. This heterogeneity in the reporting units was identified in the web survey, in which one-third each was using "ng/mL" and "mg/L," whereas 18% used "µg/L". 21
## | the prob lems with cutoffs
## | the need for harmonisati on than s tandardiz ation
Prothrombin time used in patients receiving vitamin K antagonists was in similar turmoil as D-dimer. Collaborative efforts in this area led to development and widespread use of the International Normalized Ratio. Similarly, our group has been investigating potential ways to generate standardization of D-dimer to help address current issues.
The presence of different D-dimer fragments and patient characteristics makes preparation of a "universal standard" not easy and straighfoward. [bib_ref] Harmonisation of D-dimera call for action, Longstaff [/bib_ref] [bib_ref] D-dimer: standardization versus harmonization, Dempfle [/bib_ref] [bib_ref] Standardization of D-dimer testing, Reber [/bib_ref] Harmonization rather than standardization of test results may be a possible solution to this conundrum. [bib_ref] D-dimer: standardization versus harmonization, Dempfle [/bib_ref] [bib_ref] A reference material for harmonisation of D-dimer assays. Fibrinogen subcommittee of the..., Nieuwenhuizen [/bib_ref] Harmonization would involve conversion of D-dimer values from different assays to a common scale, by applying a validated conversion factor. [bib_ref] A model for the harmonisation of test results of different quantitative D-dimer..., Meijer [/bib_ref] Major commitment of manufacturers is required to investigate kit performance in COVID-19 patients and develop new or updated methods if appropriate.
## | p otential utilit y in monitoring covid -19 patients
Consistent elevation in D-dimer in all hospitalized patients with COVID-19 has led some clinicians to use this marker to decide on low-intensity or high-intensity anticoagulation based on fold increase in D-dimers. [bib_ref] Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: report of the..., Oudkerk [/bib_ref] This approach is probably based on the presumption that all the D-dimers are coming from clot breakdown, which may not be the case in all patients. For the purpose of this communication, it is premature to confirm this is a safe strategy without evidence from randomized trials. Another clinical strategy is intensification of anticoagulation in patients who have increase in D-dimers despite prophylactic anticoagulation, which again is presumptive and not yet proved to be a safe approach.Last, some studies have already shown than decrease in D-dimers may signify the patient is improving and could mean downgrading the anticoagulation intensity. [bib_ref] The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome, Ranucci [/bib_ref] This is certainly a novel use for D-dimer measurements but requires serial monitoring with an accurate method. Currently, there is no evidence to prove that findings with one D-dimer kit will necessarily translate to other D-dimer kits, and harmonization will expectedly improve comparability.
## | recommendations
We can hence summarize here a set of indications that we recommend be used when reporting data on D-dimer testing, with special focus on studies in COVID-19, where D-dimer may evenly influence the clinical decision making.
- The type of the of the D-dimer assay (name and manufacturer) must always be clearly reported - The minimal analytical performance of the assay (including at least the functional sensitivity, total imprecision, linearity, and potential interference from FDPs) should be described
- A standardized measuring unit should be used for reporting data (FEU, as either "μg/L" or "mg/L")
- The cutoff value used in the study should be clearly indicated - The statistical analysis should be appropriately selected according to sample size and value distribution (normal or not)
## Co n fli c t o f i nte r e s t
All authors have no conflict of interest to report.
## Auth o r co ntr i b uti o n s
Dr. Thachil wrote the manuscript and Drs. Lonstaff, Favaloro, Lippi, Urano, and Kim participated in discussion and critical editing of the manuscript.
## O rci d
## Emmanuel j. favaloro
https://orcid.org/0000-0002-2103-1661
Paul Y. Kim https://orcid.org/0000-0002-0504-3064
## T wit ter
## Tetsumei urano @tetsuurano
Paul Y. Kim @kimpy79
## R e fe r e n c e s
[fig] D: -dimer is commonly used to exclude venous thromboembolism in patients with low clinical probability. A threshold or cutoff value is important for application of this exclusion. Once again, the -dimer cutoff level is dependent on the different assay methods and calibrators.18 -dimer users should be aware that cutoff values are not transferable between methods and even between institutions. The assay should ideally be validated in prospective studies or at least compared with already validated assays.19 The British Committee for Standards in Haematology guidelines state that testing a minimum of 200 subjects should be done before local approval of a -dimer assay,22 although this may be difficult to achieve in all laboratories. [/fig]
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http://www.jthjournal.org/article/S1538783622016579/pdf
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Affiliations: 1 Department of Haematology, Manchester University Hospitals, Oxford Road, Manchester, United Kingdom. 2 Haemostasis Section, Biotherapeutics, National Institute for Biological Standards and Control, United Kingdom. 3 Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), NSW Health Pathology, Sydney Centres for Thrombosis and Haemostasis, Westmead Hospital, Westmead NSW, Australia. 4 Section of Clinical Biochemistry, University of Verona, Verona, Italy. 5 Department of Medical Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan, 6 Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
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a6199d926431ee2e5024925c2c632006be8bb349
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pubmed
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Saudi Gastroenterology Association Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma: Summary of Recommendations
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Saudi Gastroenterology Association Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma: Summary of Recommendations
R ecognizing the high prevalence of hepatocellular carcinoma (HCC) in Saudi Arabia and the diffi culties often faced in accurate diagnoses, evidence-based management, and appropriate referral of HCC patients, a committee was formed at King Khalid University Hospital (KKUH) in Riyadh (fi rst three editors, AAA, HAK, TF) who wrote the fi rst draft of these guidelines. Th ese editors fi rst performed a widely based literature search on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC. Th e literature was examined critically and the available evidence was then classifi ed according to its strength.After approval and implementation of the initial guidelines at KKUH, it was decided to use these guidelines as the backbone for a national project for Saudi Arabia. Th ree other editors (FMS, MK, AJ) from three of the major hospitals in Saudi Arabia updated the document. After that, representative expert contributors were invited to review the document. Th ese contributors (listed at the end of this article), who are experts in diff erent specialties related to HCC management from diff erent institutions in Saudi Arabia, then further refi ned and updated the sections related to their expertise. Multiple meetings were then called to approve the fi nal document. An international expert in the area of HCC (KB) then reviewed the document and off ered useful suggestions and improvements. After that, the Saudi Gastroenterology Association formed a committee that reviewed these guidelines and approved them as the "Saudi Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma". Th e recommendations are based on the best available evidence but were tailored to the patients treated in Saudi Arabia.We have benefi ted from the two published European guidelines. Th e fi rst is the conclusion of the Barcelona-2000 European Association for the Study of the Liver Conference, 1 and the second is the guidelines published by the British Society of Gastroenterology. 2 In addition, we have benefi ted from the special dedicated supplement issue of Gastroenterology (November 2004) containing extensive reviews of the topic and from the American Association for the Study of the Liver (AASLD) guidelines that were recently published.3We hope that these guidelines will improve care for patients with HCC and facilitate the performance of excellent research on this important medical problem.Th e full guidelines, which are completely referenced and contain detailed recommendations, are available on the Annals of Saudi Medicine website (www.saudiannals.net). Th e full guidelines include a grading of recommendations based on the quality of the evidence for the rec-
R ecognizing the high prevalence of hepatocellular carcinoma (HCC) in Saudi Arabia and the diffi culties often faced in accurate diagnoses, evidence-based management, and appropriate referral of HCC patients, a committee was formed at King Khalid University Hospital (KKUH) in Riyadh (fi rst three editors, AAA, HAK, TF) who wrote the fi rst draft of these guidelines. Th ese editors fi rst performed a widely based literature search on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC. Th e literature was examined critically and the available evidence was then classifi ed according to its strength.
After approval and implementation of the initial guidelines at KKUH, it was decided to use these guidelines as the backbone for a national project for Saudi Arabia. Th ree other editors (FMS, MK, AJ) from three of the major hospitals in Saudi Arabia updated the document. After that, representative expert contributors were invited to review the document. Th ese contributors (listed at the end of this article), who are experts in diff erent specialties related to HCC management from diff erent institutions in Saudi Arabia, then further refi ned and updated the sections related to their expertise. Multiple meetings were then called to approve the fi nal document. An international expert in the area of HCC (KB) then reviewed the document and off ered useful suggestions and improvements. After that, the Saudi Gastroenterology Association formed a committee that reviewed these guidelines and approved them as the "Saudi Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma". Th e recommendations are based on the best available evidence but were tailored to the patients treated in Saudi Arabia.
We have benefi ted from the two published European guidelines. Th e fi rst is the conclusion of the Barcelona-2000 European Association for the Study of the Liver Conference, 1 and the second is the guidelines published by the British Society of Gastroenterology. [bib_ref] Guidlines for the diagnosis and treatment of hepatocellular carcinoma in adults, Ryder [/bib_ref] In addition, we have benefi ted from the special dedicated supplement issue of Gastroenterology (November 2004) containing extensive reviews of the topic and from the American Association for the Study of the Liver (AASLD) guidelines that were recently published. [bib_ref] Management of hepatocellular carcinoma, Bruix [/bib_ref] We hope that these guidelines will improve care for patients with HCC and facilitate the performance of excellent research on this important medical problem.
Th e full guidelines, which are completely referenced and contain detailed recommendations, are available on the Annals of Saudi Medicine website (www.saudiannals.net). Th e full guidelines include a grading of recommendations based on the quality of the evidence for the rec-ommendation. A summary of the guidelines is presented here.
## Epidemiology
In Saudi Arabia, liver cancer accounts for 6.1% of all newly diagnosed cancers, according to the most recent cancer registry covering the years 1999-2000.HCC was the second most common cancer affecting Saudi males and the eighth most common cancer affecting females with an overall age standardized rate of 4.5/100 000 population. The male to female ratio is 279:100. In Saudi Arabia, hepatocellular carcinoma accounts for 87.6% of all liver cancers. The median age at diagnosis is 65 years for males and 60 years for females. This incidence of HCC in Saudi Arabia is not surprising given the high prevalence of the two major risk factors, namely hepatitis B and hepatitis C infection. Patients with cirrhosis of any etiology, but especially with cirrhosis caused by hepatitis B or C are at high risk for the development of HCC and these patients should be the target of a screening program. Large studies are needed to further define the epidemiologic features of HCC in Saudi Arabia, but clearly the problem is large enough that more resources should be allocated to it.
## Clinical presentation
HCC usually presents with weight loss and right upper quadrant pain in addition to the symptoms and signs of underlying liver cirrhosis (weakness, abdominal swelling, non-specific gastrointestinal symptoms and jaundice), but physical findings will vary with the stage of the disease. If the tumor is small, no signs may be found except those related to the underlying cirrhosis. In more advanced cases, hepatomegaly is common, with the possibility of palpating a mass or a hard irregular liver surface which in turn may be tender. Special clinical scenarios that should raise the suspicion of HCC include acute deterioration of liver function in a patient with stable cirrhosis, new onset ascites, and acute intraabdominal bleeding. Investigations for HCC should be initiated in patients with stable cirrhosis if there is rapid deterioration of liver function, new onset ascites, weight loss, or increased jaundice.
## Diagnosis
Ultrasonography (US) should be the initial radiological investigation when HCC is suspected. Further imaging should be performed if an abnormality is found or if the suspicion of HCC is high even if the US is normal. A triphasic CT scan or MRI are the radiological procedures of choice to confirm the diagnosis of HCC. It is extremely important that the CT scan is done by a standard triphasic technique and is read by a trained abdominal radiologist.
The diagnosis of HCC may be positively made if the liver is cirrhotic, the lesion is larger than 2 cm in diameter, and either the alpha-fetoprotein (AFP) is higher than 400 ng/L and one imaging modality confirms early arterial enhancement and venous washout, or the AFP is normal and two imaging modalities confirm early arterial enhancement and venous washout. Although AFP is a poor screening tool for HCC it should be measured in all suspected cases. Levels below 400 ng/L may be seen in patients with active hepatitis without HCC. Levels above 1000 ng/L are more specific for HCC. A consistently rising AFP is highly suggestive of HCC.
A histological diagnosis is recommended only if a lesion is found in a non-cirrhotic liver and radiological investigations are not conclusive for hemangioma, focal nodular hyperplasia, or adenoma, or if the suspicion of HCC is high but the non-invasive criteria (mentioned above) are not satisfied. Otherwise, histological confirmation is not required.
## Evaluation and staging
Liver tumor weekly rounds should be started at every tertiary care center dealing with HCC patients. In this one-hour meeting, all cases of liver tumors should be discussed. The group should be composed The goals of these guidelines - To provide an evidence-based review of the diagnosis and management of hepatocellular carcinoma (HCC).
- To help initiate plans to prevent HCC.
- To enhance early and accurate diagnosis of patients with HCC.
- To provide a suggested evidence-based approach for the management of HCC patients.
- To facilitate a more effective referral system between primary/ secondary care physicians and tertiary care centers where advanced treatments are available.
- To help adopt a more effective triaging system of patients within tertiary care centers.
- To create a complementary system between the major tertiary care centers in which specific centers may specialize in certain aspects of management or care.
- To identify research questions that are applicable to our local circumstances and resources and to facilitate recruiting patients in these studies.
of a hepatologist, an oncologist, a hepatobiliary surgeon, and an interventional radiologist. The goal of the meeting is to discuss new cases of liver tumors and to reach a joint decision on the most appropriate management route for these patients. Weekly rounds should also improve recruitment in clinical trials and should serve in teaching residents and fellows.
Patients with a liver mass should be evaluated in the weekly liver tumor rounds. This evaluation will help determine the next step in obtaining a final diagnosis, determine the extent of hepatic involvement, rule out extra-hepatic disease, evaluate the general medical status and performance of the patient, and evaluate functional hepatic reserve.
Initial evaluation of patients with HCC should include a complete history, a full physical examination, initial laboratory tests including a complete blood count, random serum glucose, serum electrolytes, renal function, alpha fetoprotein, serum calcium, prothrombin time, and liver function tests, a chest x-ray (or a CT of the chest if there are suspicious lesions for metastases on the chest X-ray), and a bone scan (on initial visit only and every 9 months thereafter). Follow-up visits should also include all of the above at least every 3 to 6 months as long as the patient is in an active treatment arm of the management plan. Although each staging system has its own advantages and disadvantages, the CLIP (Cancer of the Liver Italian Program) score enjoys epidemiologic support and prospective validation while the BCLC (Barcelona Clinic Liver Cancer Classification System) is probably the best in planning future treatment plans. See the full guidelines for more information.
## Management
Patients with HCC should be managed in tertiary care centers where expertise is available. The management plan for patients with HCC should be constructed in a multi-disciplinary forum consisting of a hepatologist, oncologist, interventional radiologist, and a hepatobiliary surgeon. The decision on the best treatment modality should be based on the number of lesions, the size of lesions, the status of the underlying liver, the status of the portal vein, the performance status of the patient, the local expertise, and patient preferences [fig_ref] Figure 1: Management algorithms for hepatocellular carcinoma with no cirrhosis and Child-Pugh classes A,... [/fig_ref].
Indications for liver transplantation are: liver cirrhosis, a single lesion less than 5 cm or less than 3 lesions smaller than 3 cm each, no evidence of portal vein invasion or extra-hepatic spread, and no contraindications for liver transplantation. To prevent the patient from outgrowing these transplantation criteria while waiting on the transplant list, local ablative therapy or chemoembolization may be considered to control tumor growth. The utility of cadaveric liver transplantation in the management of HCC in Saudi Arabia is limited due to the relative lack of donors leading to long waiting list time. Living related transplantation should be explored in future studies in Saudi Arabia as an alternative for long waiting lists of cadaveric transplantation.
Indications for partial liver resection are: no cirrhosis or early cirrhosis with normal bilirubin and no signs of clinically relevant portal hypertension (defined as presence of varices, splenomegaly, platelet count <100 000 or a hepatic vein pressure gradient >10 mm Hg), no evidence of portal vein or its main branches invasion or extrahepatic spread, and a tumor that is technically resectable.
Indications for local ablative therapy are: the presence of three lesions or less that are smaller than 4 cm in diameter, no evidence of extra-hepatic spread, and a patient who is not a candidate for liver resection. The local ablative procedure of choice is radiofrequency ablation (RFA). RFA is more effective than alcohol injection (especially in lesions larger than 3 cm) but with a slightly higher risk. It may be associated with improved survival. Technical considerations in regards to the site of the lesion may favor one method over the other.
Indications of chemoembolization are: a single or multiple lesions larger than 4 cm and smaller than 10 cm, no evidence of advanced cirrhosis (Child class A or B, according to the Child-Pugh classification for assessment of liver function), and a patent portal vein with normal flow. Chemoembolization should be performed at baseline, 2 months, 6 months, and every 6 months thereafter for 6 cycles as long as the patient is responding.
Patients with vascular invasion, extra-hepatic spread, or diffuse multifocal disease should receive palliative care only and may be enrolled in trials of systemic chemotherapy. Octreotide cannot be recommended based on available evidence. Patients with Child-Pugh class C cirrhosis should be offered medical treatment only. A specialized palliative care team should be involved in the management of endstage HCC.
## Prevention
The vaccination of all children in Saudi Arabia against hepatitis B starting at birth should be maintained and further encouraged. Vaccination of people at risk for hepatitis B infection should be encouraged. Post-exposure prophylaxis for hepatitis B should be implemented in all hospitals. Post-exposure testing for hepatitis C using a PCR-based test and early treatment of hepatitis C should be implemented. Treatment with a pegylated interferon plus ribavirin should be considered for all patients with hepatitis C who have elevated liver enzymes and active hepatitis on liver biopsy and a positive HCV-RNA test. All patients with chronic hepatitis B, elevated liver enzymes, a liver biopsy showing active infl ammation or signifi cant fi brosis, and an HBV DNA more than 10 5 copies/mL should be considered for antiviral therapy using pegylated interferon monotherapy or antiviral therapy using lamivudine, adefovir or entecavir.
All patients with hepatitis B-related end-stage liver cirrhosis should be considered for long term lamivudine/adefovir therapy as this is expected to reduce their mortality and reduce the incidence of HCC. Screening using AFP and US should be implemented in all cirrhotic patients every 6 months. Screening of patients with chronic hepatitis B without evidence of cirrhosis cannot be recommended at this time but may be off ered in certain high-risk groups like patients older than 40 years of age and patients with a family history of HCC. Th ere is no evidence to recommend screening of patients with chronic hepatitis C without cirrhosis. Any patient with a positive US should undergo further imaging with a triphasic CT scan or an MRI.
## Research needs
Large epidemiologic studies identifying patterns of disease and clinico-pathological aspects of this disease are needed in Saudi Arabia. Also needed is a large study to assess the feasibility, eff ectiveness, and
[fig] Figure 1: Management algorithms for hepatocellular carcinoma with no cirrhosis and Child-Pugh classes A, B, and C cirrhosis (TACE: transarterial chemoembolization, HTN: hypertension) [/fig]
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Recognizing the high prevalence of hepatocellular carcinoma (HCC) in Saudi Arabia and the diffi culties often faced in accurate diagnoses, evidence-based management, and appropriate referral of HCC patients, a committee was formed at King Khalid University Hospital (KKUH) in Riyadh (fi rst three editors, AAA, HAK, TF) who wrote the fi rst draft of these guidelines. Th ese editors fi rst performed a widely based literature search on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC. Th e literature was examined critically and the available evidence was then classifi ed according to its strength. After approval and implementation of the initial guidelines at KKUH, it was decided to use these guidelines as the backbone for a national project for Saudi Arabia. Th ree other editors (FMS, MK, AJ) from three of the major hospitals in Saudi Arabia updated the document. After that, representative expert contributors were invited to review the document. Th ese contributors (listed at the end of this article), who are experts in diff erent specialties related to HCC management from diff erent institutions in Saudi Arabia, then further refi ned and updated the sections related to their expertise. Multiple meetings were then called to approve the fi nal document. An international expert in the area of HCC (KB) then reviewed the document and off ered useful suggestions and improvements. After that, the Saudi Gastroenterology Association formed a committee that reviewed these guidelines and approved them as the “Saudi Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma”. Th e recommendations are based on the best available evidence but were tailored to the patients treated in Saudi Arabia. We have benefi ted from the two published European guidelines. Th e fi rst is the conclusion of the Barcelona-2000 European Association for the Study of the Liver Conference, 1 and the second is the guidelines published by the British Society of Gastroenterology. 2 In addition, we have benefi ted from the special dedicated supplement issue of Gastroenterology (November 2004) containing extensive reviews of the topic and from the American Association for the Study of the Liver (AASLD) guidelines that were recently published. 3 We hope that these guidelines will improve care for patients with HCC and facilitate the performance of excellent research on this important medical problem. Th e full guidelines, which are completely referenced and contain detailed recommendations, are available on the Annals of Saudi Medicine website (www.saudiannals.net). Th e full guidelines include a grading of recommendations based on the quality of the evidence for the rec
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042f1f5fa52e693303de8f31a2d4127346c01552
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pubmed
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Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)
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Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA)
# Introduction
Age-related macular degeneration (AMD) has been described as the leading cause of legal blindness, affecting 10%-13% of adults over 65 years of age in North America, Europe, Australia and, recently, Asia. 1 2 AMD is a major medical and socioeconomic challenge worldwide and, based on increased life expectancy and a growing negative impact of environmental risk factors, particularly arteriosclerosis, obesity and smoking, its incidence is expected to at least double by 2020. [bib_ref] Prevalence of age-related macular degeneration in the United States, Friedman [/bib_ref] [bib_ref] A prospective study of cigarette smoking and age-related macular degeneration in women, Seddon [/bib_ref] [bib_ref] Progression of age-related macular degeneration: association with body mass index, waist circumference,..., Seddon [/bib_ref] [bib_ref] Associations of candidate genes to age-related macular degeneration among racial/ethnic groups in..., Klein [/bib_ref] [bib_ref] Prevalence and risk factors for age-related macular degeneration in Indians: a comparative..., Cheung [/bib_ref] The Global Burden of Disease Study 2010 reported an exponential increase of 160% in vision-related years lived with disability due to AMD, highlighting the overwhelming burden for societies overall. [bib_ref] Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and..., Vos [/bib_ref] Moreover, with an impact similar to AIDS, renal failure and stroke, AMD has a profound effect on the quality of life of those affected. [bib_ref] Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: quality-of-life findings: SST..., Miskala [/bib_ref] Fortunately, progress in AMD's diagnosis and therapy, based on advances in medical research has recently wrought a substantial paradigm shift in the management of neovascular AMD. Identification of a major pathogenetic feature, that is, the influence of vascular endothelial growth factor (VEGF), has opened an easily accessible therapeutic window. [bib_ref] Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium..., Spilsbury [/bib_ref] [bib_ref] Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody..., Krzystolik [/bib_ref] [bib_ref] Targeting VEGF-A to treat cancer and age-related macular degeneration, Ferrara [/bib_ref] Landmark clinical trials proved that intravitreal inhibition of VEGF-A can efficiently block the pathophysiological process of AMD, restore retinal morphology and increase/maintain neurosensory function in most patients with neovascular AMD. [bib_ref] Ranibizumab for neovascular age-related macular degeneration, Rosenfeld [/bib_ref] [bib_ref] Ranibizumab versus verteporfin for neovascular age-related macular degeneration, Brown [/bib_ref] Since the approval of anti-VEGF pharmacotherapy in 2006, the prevalence of legal blindness and visual impairment due to AMD has been considerably reduced, removing neovascular AMD from the list of incurable diseases. [bib_ref] Forecasting age-related macular degeneration through the year 2050: the potential impact of..., Rein [/bib_ref] [bib_ref] Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results..., Chang [/bib_ref] [bib_ref] Impact of availability of anti-vascular endothelial growth factor therapy on visual impairment..., Campbell [/bib_ref] The impressive benefit of antiangiogenic therapy has since been widely recognised. However, real-life outcomes have consistently been found to be less favourable than clinical trial results. [bib_ref] Significant improvements in near vision, reading speed, central visual field and related..., Frennesson [/bib_ref] [bib_ref] Incidence of legal blindness from age-related macular degeneration in denmark: year 2000..., Bloch [/bib_ref] [bib_ref] A systematic review of the adverse events of intravitreal anti-vascular endothelial growth..., Van Der Reis [/bib_ref] The community faces a huge dilemma in the management of AMD, with substantial controversies over the efficacy of substances, choice of therapeutic regimens and adequate monitoring needs. This is further aggravated by exponentially growing costs resulting from highly priced drugs, increasing patient numbers and long-term disease chronicity. [bib_ref] Medicare costs for neovascular age-related macular degeneration, Day [/bib_ref] [bib_ref] Avastin is as effective as Lucentis for wet AMD and could save..., Hawkes [/bib_ref] At the same time, one of the most successful therapeutic break-throughs in ophthalmology is currently at the centre of an array, of unresolved issues and the standard-of-care is vastly inconsistent.
Evidently, there are enormous variations in clinical practice, and considerable uncertainty about how the scientific evidence should be reduced to clinical practice in widely varying settings. The EURETINA community has, therefore, taken responsibility for bringing together experts in the field to develop a working guidance based on the best available scientific and clinical knowledge. The goal is to provide clinically sound, economically acceptable and unbiased diagnostic and therapeutic recommendations to brighten the horizon for patients and physicians worldwide.
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## Diagnostic procedures patients' history, clinical examination and self-monitoring rationale
Neovascular AMD is an acute onset and rapidly progressing disease which impacts central vision. Early detection of disease onset and continuous follow-up are mandatory because, visual loss becomes irreversible with delayed diagnosis and treatment. General ophthalmologic examination procedures, such as determination of best-corrected visual acuity (BCVA), stereoscopic ophthalmoscopy and home monitoring between routine visits should be implemented. Whenever neovascular AMD is suspected, advanced diagnostic measures such as fluorescein angiography (FA) and optical coherence tomography (OCT) must follow to confirm the diagnosis. Numerous clinical trials have shown that better final outcomes can be achieved with better initial visual acuity (VA). Unfortunately, in most trials as well as in real life, lesions nowadays are usually detected when there is already considerable visual loss. Therefore, awareness must be raised in individuals aged 50 years and older, and physicians should perform AMD screenings regularly.
## Evidence
The reduced efficacy of anti-VEGF therapy compared with academic trial results is commonly associated with poor initial diagnosis and/or discontinuous follow-up in routine clinical care. The mean annual number of injections increased slightly from 2008 to 2010, with 10 259 patients divided between six cohorts receiving 4.6, 5.1 and 5.5, bevacizumab or 6.1, 6.6 and 6.9, ranibizumab injections, but mean numbers of visits to an ophthalmologist and OCT examinations remained low. [bib_ref] Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular..., Holekamp [/bib_ref] In a Germany-based, multicentre, retrospective review of data from patients with suspected neovascular AMD visiting ophthalmology clinics over 18 months in 2008-2010, 10 sites collected data from 2498 patients with a mean VA of 0.4±0.3 at the time of diagnosis. The most frequent pathological findings detected by routine ophthalmic examination were fibrotic lesions, indicating late diagnosis of choroidal neovascularisation (CNV). [bib_ref] An epidemiological study of neovascular age-related macular degeneration in Germany, Krause [/bib_ref] A confirmed diagnosis of neovascular AMD was most frequently based on funduscopy (67.3%) or FA (39.6%). Disease activity in neovascular AMD is lifelong. Long-term outcomes 7-8 years after initiation of intensive ranibizumab therapy were assessed in patients originally treated with ranibizumab in landmark phase 3 trials (SEVEN-UP). Approximately 7 years after initiation of ranibizumab therapy in the ANCHOR or MARINA trials, one-third of patients had good visual outcomes, whereas another third had poor outcomes. [bib_ref] Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter..., Rofagha [/bib_ref] Compared with baseline, almost half the eyes were stable, whereas one-third had declined by 15 letters or more. Hence, even at this late stage in the therapeutic course, exudative AMD patients remain at risk for substantial additional visual decline. Active exudative disease was detected by spectral-domain OCT in 68% of study eyes, and 46% were receiving ongoing intraocular anti-VEGF treatments.
The AMD Detection of Onset of New Choroidal Neovascularisation Study (AMD DOC Study) evaluated the sensitivity of time-domain (TD) OCT relative to FA, in detecting new-onset neovascular AMD within 2 years from onset. The sensitivity of Amsler grid testing, preferential hyperacuity perimetry (PHP), OCT, and FA for detection of CNV was 0.40 for OCT ((95% CI (0.16 to 0.68)), 0.42 for supervised Amsler grid (95% CI 0.15 to 0.72) and 0.50 for PHP (95% CI 0.23 to 0.77)). The AMD DOC Study demonstrated that FA is still the best method for detecting new-onset CNV. [bib_ref] Detection of new-onset choroidal neovascularization, Do [/bib_ref] Nevertheless, selfmonitoring with regular Amsler grid testing is suggested between ophthalmological visits. PHP telemonitoring is a more standardised self-monitoring tool. The HOME study, a prospective, randomised clinical trial found that participants randomised to the home monitor had less vision loss at the time of CNV detection than those in standard care with about 90% maintaining a VAof 20/40 or better at the time of CNV detection. [bib_ref] Randomized trial of a home monitoring system for early detection of choroidal..., Chew [/bib_ref] The study also showed that when using the home monitoring device with standard care, CNV detection rates increased statistically significantly, and with smaller lesion size VA at detection was better than standard care alone. With subjective symptom realisation, BCVA at the time of detection was statistically significantly worse than an alert by the device, with a -11.5 letter loss. Increased intraocular pressure (IOP) is another issue in prolonged anti-VEGF therapy. In 528 eyes receiving 1796 intravitreal injections of bevacizumab, IOP was persistently elevated in 19 eyes (3.6%, 19/528) of 18 patients (4.2%, 18/ 424) with IOP elevated 30-70 mm Hg, 3-30 days after injection. Mean IOP was 42.6 mm Hg (range ; IOP elevations occurred after an average of 7.8 injections of bevacizumab (range [bib_ref] Prevalence of age-related macular degeneration in the United States, Friedman [/bib_ref] [bib_ref] A prospective study of cigarette smoking and age-related macular degeneration in women, Seddon [/bib_ref] [bib_ref] Progression of age-related macular degeneration: association with body mass index, waist circumference,..., Seddon [/bib_ref] [bib_ref] Associations of candidate genes to age-related macular degeneration among racial/ethnic groups in..., Klein [/bib_ref] [bib_ref] Prevalence and risk factors for age-related macular degeneration in Indians: a comparative..., Cheung [/bib_ref] [bib_ref] Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and..., Vos [/bib_ref] [bib_ref] Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: quality-of-life findings: SST..., Miskala [/bib_ref] [bib_ref] Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium..., Spilsbury [/bib_ref] [bib_ref] Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody..., Krzystolik [/bib_ref] [bib_ref] Targeting VEGF-A to treat cancer and age-related macular degeneration, Ferrara [/bib_ref] [bib_ref] Ranibizumab for neovascular age-related macular degeneration, Rosenfeld [/bib_ref]. Injected eyes (19/528) had a significantly higher incidence of elevated IOP than non-injected eyes (fellow eyes), 1/328, p<0.001. Identical observations were published for IOP increases with ranibizumab. [bib_ref] Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular..., Bakri [/bib_ref] Doctors should be aware that IOP might increase after repeated treatments.
## Recommendation
Doctors should initially ask patients who present with an onset of decreased vision or metamorphopsia, if they have a family history of AMD, and for their social history including smoking habits. Their complete history should be examined to identify systemic risk factors for anti-VEGF therapy and current medications. Standardised BCVA testing and stereoscopic biomicroscopy/ophthalmoscopy of the macula of both eyes is mandatory, as well as measurement of IOP at least every 6 months. Patients should be instructed to self-monitor their vision between routine office visits. By contrast with current home monitoring strategies, those with intermediate AMD (large drusen in one or both eyes) could benefit from home monitoring with PHP, whenever the device is available. Patients who have received treatment should be monitored at regular intervals, according to a standardised strategy, either monthly or following an individualised pro-re-nata (PRN) or treatand-extend regimen. Follow-up visits should include examination for new onset of a decrease in vision and nes or persistent metamorphopsia, changes in medical or social history and, most importantly, BCVA tests should be repeated using identical procedures. Further examination by OCT is required if stereoscopic fundus examination reveals clinical signs of retinal oedema, detachment of the retinal pigment epithelium (RPE) or haemorrhage. These recommendations are based on the Age-Related Eye Disease Study and HOME study (evidence level I) and levels II/III data for clinical management of early AMD.
## Angiography rationale
FA was the main, and for many years, the only diagnostic and follow-up tool for AMD patients. [bib_ref] Imaging in neovascular age-related macular degeneration, Gess [/bib_ref] Nowadays, many non-invasive techniques (such as spectral domain (SD) OCT, autofluorescence imaging) can provide detailed anatomical information and precise functional data. In spite of this, FA continues to play a key role in the diagnostic process, for example, providing the base for its clinical classification and the initiation of therapeutic management. The role of FA is to visualise retinal vasculature and neovascular retinal/choroidal proliferations as well as its dynamic features, such as perfusion and exudation. FA has been used in all phase 3 clinical trials for the initial diagnosis of neovascular AMD.
## Evidence
In the case of neovascular AMD, leakage of dye from pathological new vessels, into retinal structures appears as hyperfluorescence, which increases in intensity and extension throughout the examination duration. [bib_ref] Imaging in neovascular age-related macular degeneration, Gess [/bib_ref] This leakage is classified by its location (subfoveal, juxtafoveal, or extrafoveal) and by its features (classic, occult, or mixed). Classic CNV represents a lesion that has penetrated the RPE layer and is located in the subretinal space (figure 1), whereas occult CNV refers to a neovascular lesion located underneath the RPE (figure 2). In the case of dry AMD, the angiogram will show various grades of drusen (usually seen as early, intensely hyperfluorescence spots) and atrophy (a well-demarcated, hyperfluorescent areas resulting from increased visualisation of the adjacent choroidal fluorescence).
When assessing a patient with clinical suspicion of neovascular AMD, FA evaluation, if not contraindicated for systemic risks, is routinely mandatory. In fact, it is the only examination that can confirm the mere existence of a CNV, and is also used to evaluate the location and extent of classic and occult forms, particularly when it is coupled with indocyanine green angiography (ICGA). In addition to the location and the area of leakage, FA provides information about the dynamic exudative activity of the lesion. These features, particularly lesion size, have a well-recognised prognostic value and should be clarified in order to plan an appropriate treatment strategy. [bib_ref] Baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular..., Ying [/bib_ref] [bib_ref] Angiographic regression patterns after intravitreal ranibizumab injections for neovascular age-related macular degeneration, Tran [/bib_ref] [bib_ref] Characteristics of patients losing vision after 2 years of monthly dosing in..., Rosenfeld [/bib_ref] An angiogram is also essential to detect specific forms of AMD that present a more aggressive natural history and requires modification of the therapeutic approach. Retinal angiomatous proliferation (RAP) is characterised clinically by focal haemorrhage, oedema and lipid exudates within retinal layers. In more advanced stages, a serous or vascularised pigment epithelial detachment (PED) is detectable. [bib_ref] Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment, Koh [/bib_ref] ICGA reveals the area of focal hyperfluorescence arising from the deep capillary plexus forming the initial angiomatous lesion, which subsequently will form an anastomosis with the choroidal circulation (figure 3). ICGA is therefore vital to distinguish this lesion presentation and should be followed by SD-OCT focused on the lesion site. The other relevant example of a different subtype of exudative AMD is polypoidal choroidal vasculopathy (PCV). It is difficult to distinguish this entity clinically from other forms of occult CNV, even though, it presents more commonly with recurrent serous and haemorrhagic PED. The FA shows an ill-defined occult leakage pattern, whereas ICGA is able to delineate the polypoidal lesions in distinct detail (figure 4). As PCV is more common in patients of Asian and African descent, it should be considered in these patients.
## Recommendation
Once the initial diagnosis of CNV is established by FA, the effect of anti-VEGF therapy can be efficiently monitored by Classic choroidal neovascularisation is located above, the retinal pigment epithelium layer and is associated with intraretinal cystoid spaces and/or subretinal fluid. Due to its subretinal location, the neovascular net is delineated with distinct margins. Leakage in late-phase angiography confirms the biologic activity of the lesion (ophthalmoscopy, spectral domain-optical coherence tomography, early fluorescein angiography (FA), late FA).
non-invasive SD-OCT alone. [bib_ref] Agreement of time-domain and spectral-domain optical coherence tomography with fluorescein leakage from..., Khurana [/bib_ref] [bib_ref] Correlation of high-definition optical coherence tomography and fluorescein angiography imaging in neovascular..., Malamos [/bib_ref] [bib_ref] Relationship between angiographic and optical coherence tomographic (OCT) parameters for quantifying choroidal..., Sadda [/bib_ref] [bib_ref] Correlation of fundus fluorescein angiography and spectral-domain optical coherence tomography in identification..., Mathew [/bib_ref] Nonetheless, FA may be advisable, especially where OCT fails to provide reliable information, such as in high myopia, extrafoveal lesions or when dealing with fresh CNV reactivation at the borders of a fibrotic lesion. Additionally, FA and ICGA should be repeated in the case of a sudden clinical worsening, or in occurrence of haemorrhage or new PED. These recommendations are based on evidence levels II/III.
## Optical coherence tomography rationale
OCT, first used in the 1990s, is based on the properties of light waves reflected from and scattered by ocular tissues, which allows anatomical changes associated with exudative AMD to be visualised and measured. Since its introduction with the initial time-domain technology, the modality has continued to improve, with high-definition SD technology and swept source (SS) OCT, achieving greater resolution, repeatability and applicability than earlier OCT devices. Advanced OCT permits high-speed retina scanning that allows complete coverage of the macular area and generation of three-dimensional retinal images. Within a few years, of its introduction, OCT became a major element in both initial diagnosis and management of patients with exudative AMD. TD-OCT has been used in most of the phase 3 clinical trials for antiangiogenic therapy in AMD either as a second outcome examination for central retinal thickness (CRT) or for retreatment indications in trials with a flexible regimen. SD-OCT has so far been used exclusively in the HARBOR study comparing ranibizumab therapy in a fixed monthly and a flexible PRN regimen. OCT visualises structural changes of the retina and RPE as a high-resolution optical 'histology', in a static mode, however, without identification of vascular features or any representation of dynamic processes such as perfusion or leakage.
## Evidence
OCT supports the diagnosis of exudative AMD at initial presentation. Type 1 CNV (also called occult CNV) may have several manifestations in OCT (figure 5): The neovascular membrane is localised behind the RPE, creating a vascularised fibrovascular or serous PED. Subretinal fluid (SRF) presents as a dark virtual space between the retina and the RPE, often with disruption of the external limiting membrane-photoreceptor complex in the outer retina. Intraretinal exudation appears as round, dark, cystoid spaces within the retinal layers, but not all cystoid spaces are exudative features. Persistent cystoid spaces mostly have an irreversible degenerative nature. Pigment epithelium detachments are characterised by elevations of the RPE [fig_ref] Figure 6: Fluorescein angiography [/fig_ref]. Serous PED present as a smooth regular and sharply demarcated, dome-shaped hyporeflective RPE elevation, whereas fibrovascular PED appears to be filled with solid layers of material of medium or high reflectivity, separated by hyporeflective clefts. On OCT, RPE tears are typically seen as a discontinuity in a large PED, with the free edge of the RPE often curled under the PED. Type 2 CNV (also called classic CNV) is localised in the subretinal space (figure 7). Most eyes with type 2 CNV present a small 'discrete' PED associated with the highly reflective subretinal lesions (mainly located beneath the subretinal lesion). Increased thickness of the retina, SRF, cystoid spaces and PED are commonly observed. [bib_ref] Combined fluorescein angiography and spectral-domain optical coherence tomography imaging of classic choroidal..., Coscas [/bib_ref] RAP (also called type 3 CNV) is described as small erosion or elevated RPE, a flap sign, or, later, a focal funnel-shaped defect in the RPE, called 'kissing sign', accompanied by subretinal and/or intraretinal fluid (figure 8). [bib_ref] Angiographic analysis of retinal-choroidal anastomosis by confocal scanning laser ophthalmoscopy technology and..., Querques [/bib_ref] In PCV, the branching vascular network appears as RPE elevations, while the polypoidal lesions appear as sharper, dome-shaped protuberances, often associated with exudative findings (figure 9).
OCT is currently the most frequently used tool in the longterm management of exudative AMD. Comparisons of macular thickness and morphology over time allow a patient's response to treatment to be assessed. In the MARINA and ANCHOR studies, anti-VEGF intravitreal injections were based on a fixed regimen every 4 weeks and CRT measured by OCT was only a secondary outcome. Subsequently, individualised regimens based on the concept of treating patients only when necessary have since been investigated. Most subsequent clinical trials of anti-VEGF agents have used some variation on a PRN regimen, usually involving three consecutive monthly loading injections followed by further injections as needed, according to predefined retreatment criteria. [bib_ref] An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for..., Fung [/bib_ref] [bib_ref] Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular..., Holz [/bib_ref] [bib_ref] Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related..., Schmidt-Erfurth [/bib_ref] This concept of individualised or evaluation-based, as-needed therapy is reportedly the most commonly used treatment regimen in current clinical practice in Europe. The most frequent morphologic criterion for retreatment decisions has been defined as an increase in CRT. [bib_ref] Evaluation of ranibizumab-induced changes in high-resolution optical coherence tomographic retinal morphology and..., Kiss [/bib_ref] Recent analyses revealed that CRT does not correlate with BCVA in AMD, because the structure/function correlation is lost during follow-up as early as at month 3. [bib_ref] Morphologic parameters relevant for visual outcome during anti-angiogenic therapy of neovascular age-related..., Simader [/bib_ref] The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study, therefore, suggested patients should be retreated in a 'no tolerance' mode, that is, whenever any fluid was seen on TD-OCT. [bib_ref] Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results, Martin [/bib_ref] The same principle of tight retreatment based on any change in OCT was adopted in the HARBOR trial, but, using SD-OCT which usually leads to a higher retreatment frequency due to the increased number of scans potentially revealing intraretinal fluid or SRF. [bib_ref] Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in..., Busbee [/bib_ref] A comprehensive subgroup analysis of the VIEW study correlation of functional and anatomical data revealed that OCT biomarkers, which are generally correlated with reduced vision in neovascular AMD, were intraretinal cystoid spaces (IRC) at baseline, and persistent cystoid spaces at the end of the loading dose.Whenever IRC were present initially, BCVA, and the therapeutical gain in BCVA were limited, while eyes with SRF showed the best visual prognosis. Prognostic for the therapeutic benefit were IRC and fibrovascular PED at initial presentation, where RPE detachment is the primary pathognomonic feature, and secondary cyst formation under discontinued treatment is the biomarker associated with vision loss.These features were independent of the substance and the regimen used.
## Recommendation
BCVA alone is insufficient to detect a recurrence of activity of the neovascular membranes in neovascular AMD. FA can also be useful, in addition to OCT, in some ambiguous cases, particularly for type 2 CNV. New haemorrhage on fundus examination is also a sign of CNV activity. Nevertheless, OCT is actually the most useful tool for evaluating morphological changes because it best reflects recurrence of neovascular activity. Two types of assessment for neovascular activity can be distinguished: measurements and qualitative OCT observations. [bib_ref] Quantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular..., Keane [/bib_ref] CRT has been the most common measurement used in clinical studies, however, PRN treatment based on these measurements was invariably associated with reduced therapeutical benefit compared with a fixed continuous regimen. There is a large body of evidence that supports qualitative morphologybased OCT data as more sensitive than measurements for detecting of CNV activity. IRC, SRF and RPE detachments are important signs of activity in the neovascular membrane, independent of CRT. In a 'real life' PRN protocol, all these features are usually considered as criteria for reinjection of anti-VEGF substances. Compared with the former TD-OCT technology, current SD-OCT or SS-OCT technologies which provide raster-scanning imaging, are more sensitive for detecting of subtle morphological changes and, thus, permit early treatment of exudative recurrence. The common recommendation is, therefore, to monitor disease activity using SD-OCT, and on a monthly base. The concept of a 'zero tolerance' on OCT criteria is emerging, because of the rapid progression of exudative features and progressive loss of vision when initiation of treatment is delayed. [bib_ref] Optical coherence tomography changes before the development of choroidal neovascularization in second..., Amissah-Arthur [/bib_ref] However, persistent IRC should be considered signs of irreversible retinal degeneration and should not trigger further retreatment. These recommendations are based on evidence levels I (CATT, VIEW, HARBOR) and evidence levels II.
## Therapeutic strategies intravitreal pharmacotherapy
Pegaptanib Rationale VEGF increases vascular permeability, enhances the inflammatory response and induces angiogenesis. [bib_ref] The biology of VEGF and its receptors, Ferrara [/bib_ref] The isoform VEGF 165 has been particularly implicated in blood-retinal barrier breakdown and pathological intraocular neovascularisation. Pegaptanib sodium, Macugen, is a short RNA oligonucleotide, an aptamer that binds with high specificity and affinity only to the isoform VEGF165. The rationale is to selectively inhibit pathological leakage and angiogenesis. [bib_ref] Pegaptanib sodium for the treatment of neovascular age-related macular degeneration, Moshfeghi [/bib_ref] Pegaptanib is well tolerated in humans and has a mean intravitreal half-life of 10 days.
## Evidence
The VEGF Inhibition Study in Ocular Neovascularisation (VISION) Study completed at the end of 2004 marked a new era for the treatment of neovascular AMD. The study showed the safety and efficacy of intravitreal inhibition of VEGF for the treatment of neovascular AMD over 1 year. [bib_ref] Pegaptanib for neovascular age-related macular degeneration, Gragoudas [/bib_ref] It was a doublemasked, sham-controlled, dose-ranging phase 3 clinical trial including 0.3, 0.1 and 3.0 mg doses. The control group was given the usual care including photodynamic therapy (PDT) monotherapy. Patients received intravitreal injections at 6-week intervals independent of the neovascular activity. Seventy per cent of those receiving pegaptanib at 0.3 mg lost fewer than 15 letters of VA, compared with 55% of the control group (p<0.001). The risk of severe loss of VA (loss of 30 letters or more) was reduced from 22% in the sham-injection group to 10% in the group receiving 0.3 mg of pegaptanib ( p<0.001)(3). Patients receiving pegaptanib lost a mean of −9 letters over 1 year compared with a loss of −14 letters in the sham-injection group. Despite continued treatment, progressive growth and persistent leakage of the neovascular lesion was seen angiographically in most of the patients. At 54 weeks, every patient in the pegaptanib groups was re-randomised to continuous further pegaptanib treatment or sham treatment. Patients from the usual care group were assigned to continuous usual care, one of the three groups of pegaptanib doses or the sham-injection group. At 2 years, 59% of eyes receiving a dose of 0.3 mg lost <15 letters versus 45% of the usual care sham-injected eyes. [bib_ref] Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib..., Chakravarthy [/bib_ref] Six per cent of eyes in the pegaptanib group improved by three lines compared with 2% of the sham-injected group. At 2 years, a mean vision loss of −10 letters was found in all subgroups treated with pegaptanib at 0.3 mg, with a mean of nine treatments applied per year.
The ocular and systemic safety profile of the drug was very good. Related to the intravitreal injection procedure, specific risks, such as endophthalmitis (1.3% of treated cases during the first year, 0.7% during the second year), traumatic lens injury (0.6% during the first year, 0.2% during the second year) and retinal detachment (0.7% during the first year, 1.2% during the second year) were reported. [bib_ref] Guidance for the treatment of neovascular age-related macular degeneration, Schmidt-Erfurth [/bib_ref] This was the first evidence that anti-VEGF therapy is effective and safe in AMD.
## Recommendation
Macugen was approved for all lesion types in neovascular AMD by the Food and Drug Administration (FDA) for the USA in December 2004, and by the European Medicines Agency for countries in the European Union (EU) in January 2006. The therapeutic benefit was favourable compared with the one obtained with PDT monotherapy, with few treatments needed with PDT. The chance of a statistically significant improvement in VA was relatively low (6%). The visual benefits of preventing visual loss shown in the VISION Study were largely exceeded by the next anti-VEGF therapy; that is, ranibizumab. This marked difference in efficacy may be because pegaptanib does not inhibit other bioactive isoforms of VEGF, such as the soluble 110 and 121 VEGF fragment in vivo. Therefore, due to its poorer efficacy compared with other currently available anti-VEGF drugs, pegaptanib is no longer recommended for the treatment of exudative AMD. These recommendations are based on the VISION study data (evidence level I). [bib_ref] Guidance for the treatment of neovascular age-related macular degeneration, Schmidt-Erfurth [/bib_ref]
## Ranibizumab rationale
Ranibizumab is a recombinant, humanised Fab fragment of a monoclonal antibody with a high affinity for VEGF A. The binding site is located at amino acid sites 88-89. Ranibizumab binds and inactivates all isoforms of VEGF, including the soluble VEGF isoforms 110, 121 and 165 and the tissue-bound isoforms 189 and 206. While bevacizumab was developed for long systemic retention in the treatment of metastatic cancer, ranibizumab was designed for rapid systemic clearance by removing the Fc fragment from the parent molecule. [bib_ref] Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an..., Chen [/bib_ref] Additionally, the affinity of the compound for VEGF was enhanced by modification of five amino acids. In animal models, intravitreal injection effectively reduced retinal and choroidal neovascular growth as well as leakage from established vessels. [bib_ref] Safety and efficacy of intravitreal injection of ranibizumab in combination with verteporfin..., Husain [/bib_ref] Ranibizumab, with its molecular weight of 76 kDa, was found to penetrate the retina well after intravitreal injection. [bib_ref] Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration, Gaudreault [/bib_ref] With a short intravitreal half-life time of 2-4 days, and a rapid systemic clearance, the systemic safety of ranibizumab is extremely high. [bib_ref] Safety evaluation of repeated intravitreal injections of bevacizumab and ranibizumab in rabbit..., Zayit-Soudry [/bib_ref] Ranibizumab monotherapy has, therefore, become the reference standard for treatment of CNV.
## Evidence
Fixed regimens were evaluated in the MARINA, ANCHOR, PIER and EXCITE studies. Seven hundred and sixteen patients with minimally classic or purely occult CNV, and evidence of presumed recent disease progression, were included in the MARINA study, a randomised, multicenter, sham-controlled phase 3 trial. Patients received monthly injections of 0.3 or 0.5 mg of ranibizumab or sham treatment continuously over 24 months. At 12 months, 95% of ranibizumab-treated eyes compared with 62% of sham-treated eyes, lost <15 letters in VA. [bib_ref] Ranibizumab for neovascular age-related macular degeneration, Rosenfeld [/bib_ref] Visual improvement by >15 letters was found in 34% of eyes treated with a dose of 0.5 mg and B). At 24 months, 90% of eyes in the 0.5 mg group had continued to maintain stable vision without loss of >15 letters compared with 53% in the control group. [bib_ref] Characteristics of patients losing vision after 2 years of monthly dosing in..., Rosenfeld [/bib_ref] A mean improvement of seven letters was documented at 24-month follow-up. Thirty-three per cent of eyes in the 0.5 mg dose group improved by >15 letters with 42% ending up with a VA of 20/40 or better. Ranibizumab prevented further CNV growth and decreased the mean area of leakage angiographically in both dose groups. Typically, the functional and anatomical effects were seen rapidly within the first 3 months of intervention, and were maintained throughout the entire follow-up of 24 months. Additionally, patients treated with ranibizumab reported large improvements in near vision, distance vision and vision-specific dependency in quality-of-life questionnaires (NEI-VFQ-25). [bib_ref] Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results..., Chang [/bib_ref] The ANCHOR study included 423 patients with predominantly classic subfoveal CNV due to AMD in a prospective, randomised phase 3 trial design. [bib_ref] Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results..., Brown [/bib_ref] Monthly injections of ranibizumab at 0.3 or 0.5 mg were compared with standard PDT, which was indicated at 3-month intervals if leakage was seen angiographically. Ninety per cent of all eyes treated with ranibizumab at 0.5 mg lost less than 15 letters compared with 66% of eyes maintaining vision with PDT treatment alone at 24 months. Forty-one per cent of eyes in the 0.5ä-mg dose group improved by >15 letters and 12% improved by >30 letters, compared with 6% of PDT-treated eyes trated with PDT . Additionally, these ranibizumab-treated patients demonstrated a mean improvement of 11 letters at 24 months, and 38% had a final outcome of 20/40 or better. Initial VA, or lesion size, had no impact on vision prognosis. The PIER study, a phase 3b trial, included 182 patients with all lesion types and evaluated the efficacy and safety of monthly ranibizumab at three doses followed by dosing every 3 months. While patients in the sham group lost a mean of 16 letters during 12 months of follow-up, patients receiving either dose of ranibizumab remained stable at baseline VA. [bib_ref] Guidance for the treatment of neovascular age-related macular degeneration, Schmidt-Erfurth [/bib_ref] Ninety per cent in the group receiving the 0.5 dose lost <15 letters compared with 49% in the sham group; 13% versus 10% gained >15 letters. [bib_ref] Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER..., Regillo [/bib_ref] As the overall VA, returned to baseline from month 3 to month 12 after switching to quarterly dosing, this reduction appears to suggest that quarterly dosing is inferior to monthly dosing. This was subsequently confirmed by the EXCITE study. [bib_ref] Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related..., Schmidt-Erfurth [/bib_ref] Patients (n=353) with all types of CNV were randomised (1:1:1) to receive doses of ranibizumab at 0.3 mg quarterly, 0.5 mg quarterly or 0.3 mg monthly. Treatment comprised a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection). [bib_ref] Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related..., Schmidt-Erfurth [/bib_ref] Mean VA gain over baseline was observed for the entire 12-month trial in all groups. At month 12 compared with month 3, the VA gain was slightly decreased with quarterly dosing (by −2.2 and −3.1 letters with 0.3 mg and 0.5 mg of ranibizumab, respectively) (figure 12A -C).
Flexible regimens were evaluated in the subsequent trials including PrONTO, CATT, SECURE and HARBOR. The small, open-label, prospective, non-randomised PrONTO study assessed three consecutive monthly injections followed by OCT-guided variable-interval dosing (at >1 month intervals). [bib_ref] An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for..., Fung [/bib_ref] Retreatment criteria were a 5-letter loss and fluid as detected by OCT; >100 mm increase in CRT; new-onset classic CNV; new macular haemorrhage; or persistent macular fluid detected by OCT >100 mm increase in central thickness (CRT) new-onset classic CNV new macular haemorrhage or persistent macular fluid detected by OCT. Although VA outcomes were similar to those of the MARINA and ANCHOR trials with fewer intravitreal injections, substantial trial design differences limit comparisons. Despite small and open-label, this study suggested that flexible OCT-guided retreatment could sustain visual gain with fewer injections, a concept which has since become a popular model in clinical practice, particularly in Europe.
The investigators in the randomised CATT trials set out to assess the relative efficacy and safety of ranibizumab and bevacizumab and to determine whether an as-needed regimen, compared with a monthly regimen, would compromise long-term VA. [bib_ref] Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results, Martin [/bib_ref] The treatment protocol was much tighter than used previously, and is often referred to as 'zero tolerance'. Radial scanning by TD-OCT was used in the trial and any fluid on OCT was added to the usual retreatment criteria. At 12 months, patients treated with monthly ranibizumab with 11.7 injections, and with ranibizumab as needed with 6.9 injections, gained ANCHOR study. Mean (±SE) changes in the number of letters read as a measure of visual acuity from baseline through 12 months. The tracking of mean changes in visual acuity scores over time showed that the values in each of the ranibizumab groups were significantly superior to those in the verteporfin group at each month during the first year ( p<0.001) (figure 2) On average, visual acuity of ranibizumab-treated patients increased by +5.9 letters in the 0.3 mg group and +8.4 letters in the 0.5 mg group at 1 month after the first treatment and increased further over time to a gain of +8.5 letters in the 0.3 mg group and +11.3 letters in the 0.5 mg group by 12 months. By contrast, the verteporfin group had an average loss in visual acuity at each month after the first month, with a mean loss of 9.5 letters by 12 months. Printed with permission from ref 13.
+8.5 and +6.8 letters, respectively. [bib_ref] Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results, Martin [/bib_ref] Based on the trial design, PRN using ranibizumab was considered to be non-inferior. However, a meta-analysis combining the data from all the groups, as well as the data from the IVAN study, a similar trial in the UK with different retreatment protocol, found that discontinuous was inferior to continuous treatment. [bib_ref] Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from..., Chakravarthy [/bib_ref] As the latter also included data from bevacizumab, the findings might have been different, if ranibizumab had been used alone, were in this analysis.
In the CATT year 2 data, when the monthly ranibizumab group was re-randomised into a continuous monthly treatment and as-needed treatment, the as-needed group lost −1.8 letters as compared with those staying with monthly treatment. Over the entire 2 years, the vision gain was very similar to the year 1 data with +8.8 and +6.7 letters in the monthly and as needed, respectively. [bib_ref] Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results, Martin [/bib_ref] In other words, changing to as needed in year 2 lost all the benefit of the monthly treatment from year 1. SECURE [bib_ref] The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related..., Silva [/bib_ref] and HORIZON [bib_ref] HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to..., Singer [/bib_ref] are prospective extension studies that were designed to assess the long-term safety and efficacy of intravitreal injections of 0.5 mg of ranibizumab in patients with neovascular AMD. HORIZON is a multicentre, open-label, 24-month extension study following patients who had completed the MARINA, ANCHOR, or FOCUS (RhuFAb V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) trials. It is to evaluate long-term safety, tolerability and efficacy of multiple intravitreal injections of 0.5 mg ranibizumab to patients as needed, SECURE is a phase 4.2-year extension study in patients with AMD who had completed 1 year of treatment with ranibizumab in the EXCITE [bib_ref] The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related..., Silva [/bib_ref] or SUSTAIN 77 studies. The results from the SECURE study corroborate the findings from the HORIZON study, [bib_ref] HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to..., Singer [/bib_ref] where there was an incremental decline in the BCVA gains achieved with monthly ranibizumab treatment in the previous studies, leading to an overall gradual decline in BCVA by −7.5 letters (ranibizumab-treated initial group) at the study end. This VA decline highlights the progressive nature of neovascular macular disease and shows a strict need for continuous follow-up monitoring and rigorous objective retreatment criteria. Continued follow-up in the SEVEN-UP study also suggested a long-term persistence of disease activity in the majority of patients. [bib_ref] Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular..., Holz [/bib_ref] The extension studies have provided further data on the safety of ranibizumab treatment. Intravitreal injections of ranibizumab were associated with a low incidence of endophthalmitis (0.9%) in the SECURE study [bib_ref] The SECURE study: long-term safety of ranibizumab 0.5 mg in neovascular age-related..., Silva [/bib_ref] consistent with the rates reported in the HORIZON study (0.2% for presumed endophthalmitis). [bib_ref] HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to..., Singer [/bib_ref] The rates are also consistent with those reported at 2 years in previous neovascular AMD studies (MARINA, 1.0%; ANCHOR, 1.1%). In the SECURE study, arterial thromboembolic events (ATEs) (categorised under adverse effects (AE) of special interest, and including haemorrhagic cerebrovascular conditions, ischaemic cerebrovascular conditions, myocardial infarction, and arterial embolic and thrombotic events) occurred in 5.6% of the patients receiving ranibizumab. These data are similar to the rate of ATEs (according to the Anti-platelet Trialists Collaboration criteria) reported in patients receiving ranibizumab in the ANCHOR and MARINA studies (4.4%-5%) and the HORIZON study (5.3% in the ranibizumab-treated initial patients). [bib_ref] Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter..., Rofagha [/bib_ref] Additionally, the LUMINOUS programme was initiated as part of an ongoing pharmacovigilance programme for ranibizumab, it was designed to assess long-term safety, efficacy, treatment patterns, and health-related quality-of-life outcomes in a large number of patients treated with ranibizumab in routine clinical practice across the world. [bib_ref] Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter..., Rofagha [/bib_ref] (ClinicalTrials.gov identifier: NCT01318941).
The HARBOR study is the only trial that has included SD-OCT monitoring into a PRN regimen compared with monthly treatment. [bib_ref] Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in..., Busbee [/bib_ref] The study evaluated the 12-month efficacy and safety of 0.5 and 2.0 mg intravitreal dosing of ranibizumab monthly and on an as-needed (PRN) basis in treatment-naive patients with subfoveal neovascular AMD. Patients (n=1098) were randomised to receive ranibizumab 0.5 or 2.0 mg ranibizumab injections intravitreally, monthly or on a PRN basis after three monthly loading doses. At month 12, the mean change from baseline in BCVA for the four groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥15 letters from baseline at month 12 in the four groups was 34.5%, 30.2%, 36.1% and 33.0%. The mean change from baseline in central foveal thickness at month 12 was −172, −161.2, −163.3 and −172.4 μm. The mean number of injections was 7.7 and 6.9 for the 0.5 mg PRN and 2.0 mg PRN groups. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and similar between groups, without any safety risks documented. At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified non-inferiority (NI) comparison. Vision in all treatment groups improved clinically meaningfully (+8.2 to +10.1 letters), and all groups had improved anatomic outcomes, with the PRN groups requiring approximately four fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). [fig_ref] Figure 3: A retinal angiomatous proliferation is characterised by an early hyperfluorescent spot at... [/fig_ref]. No new safety events were observed despite a fourfold dose escalation in the study. Therefore, the HARBOR study confirmed that 0.5 mg of ranibizumab dosed monthly provides optimum results in patients with neovascular AMD, and that there is no great disadvantage in using a PRN regimen instead of continued monthly injections 55 provided that strict monthly monitoring is provided using SD-OCT technology.
Treat-and-extend is another flexible strategy suggested to reduce retreatment numbers. After three initial monthly ranibizumab or bevacizumab injections, and then to continue with monthly injections until there was no CNV activity (subretinal/ intraretinal fluid, loss of >5 letters, or persistent/recurrent retinal haemorrhage) in a prospective cohort study of 120 patients. [bib_ref] Anti-VEGF treatment in neovascular age-related macular degeneration: a Treat-and-Extend Protocol Over 2..., Abedi [/bib_ref] When there was no leakage activity, the interval to the next visit/injection was extended by 2 weeks to a maximum of 12 weeks. When there was CNV activity, this interval was shortened by 2 weeks. Mean VA change from baseline was +9.5±10.9 and +8.0±12.9 letters after 12 and 24 months, respectively, with, on average, 8.6±1.1 visits/injections in the first year, and 5.6±2.0 in the second year. After 12 and 24 months, 97.5% and 95.0% of patients, respectively, lost <15 letters. This 'inject-and-extend' protocol with fewer injections and visits delivered outcomes similar to those of the pivotal clinical trials of monthly ranibizumab with fewer injections and fewer visits. Treat-and-extend trials are currently underway in Europe. Although undertreatment is the major issue, complications from overtreatment should also be considered because, since a substantially increased rate of geographic atrophy (GA) was documented with monthly use of ranibizumab had new GA lesions after 2 years compared with only 15% of eyes treated in the as-needed arm.
## Recommendation
Lucentis has been approved by the FDA since July 2006 for all lesion types in neovascular AMD in the USA since July 2006. An approval by the European Medicines Agency (EMA) for countries in the EU was granted in January 2007. The approved dose is 0.5 mg of ranibizumab. Giving injections continuously monthly for 2 years on a PRN regimen with strict monthly monitoring using SD-OCT and retreatment, whenever any evidence of fluid is noted by retinal imaging has been found to be the regimen that secures the optimum results in vision outcome. The official product label in Europe recommends monthly intravitreal injections continued until maximum VA is achieved for three consecutive monthly assessments. Thereafter, patients should be monitored monthly for VA. Treatment is to be resumed when monitoring indicates loss of VA due to wet AMD. Monthly injections should then continue until stable VA is reached again for three consecutive monthly assessments. Current usage in Europe is based on OCT monitoring and cessation of treatment when fluid is absent on OCT. Treat-and-extend is being evaluated in prospective clinical trials. Development of GA should be observed during prolonged treatment.
The recommendations are based on the ANCHOR, MARINA, PIER, EXCITE, HARBOR and CATT study data (evidence level I) as well as the SECURE and HORIZON study data (evidence level II).
## Bevacizumab rationale
Bevacizumab is a full-length recombinant monoclonal antibody that binds all VEGF isoforms. It was developed to inhibit pathological angiogenesis in tumours and tumour growth and is approved by the FDA and EMA for the intravenous treatment of metastatic colorectal cancer and other cancer types. [bib_ref] Bevacizumab in the treatment of colorectal cancer, Cilley [/bib_ref] Cancer patients receiving systemic bevacizumab are commonly found to have an increased risk of cardiovascular events, stroke and gastrointestinal bleeding. [bib_ref] Systemic administration of bevacizumab increases the risk of cardiovascular events in patients..., Stefanadis [/bib_ref] A mathematical model comparing the time-dependent relative elimination of ranibizumab, bevacizumab and aflibercept was used to determine the theoretical peak and binding activities when the drugs were injected every 28 days. The intravitreal half-lives of ranibizumab, bevacizumab, and aflibercept were estimated to be 3.2, 5.6 and 4.8 days, respectively. The relative molar binding activities of ranibizumab, bevacizumab and aflibercept were 1, 0.05 to 0.2, and 140, respectively, indicating a lower binding affinity for bevacizumab. [bib_ref] Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal..., Stewart [/bib_ref] The systemic retention is prolonged because the Fc-portion of the substance binds to an endothelial cell receptor and is recycled. Intravitreal bevacizumab has recurrently been found to lower systemic VEGF concentrations much more than ranibizumab. Because bevacizumab and VEGF have similar bindings patterns, it is hypothesised that bevacizumab may be as effective as ranibizumab in the treatment of neovascular AMD and other types of intraocular neovascularisation, and may provide a less expensive alternative to approved substances specifically adapted for intraocular use. [bib_ref] Plasma levels of vascular endothelial growth factor and pigment epithelium-derived factor before..., Matsuyama [/bib_ref] [bib_ref] Vascular endothelial growth factor plasma levels before and after treatment of neovascular..., Carneiro [/bib_ref] [bib_ref] Plasma levels of vascular endothelial growth factor before and after intravitreal injection..., Zehetner [/bib_ref] [bib_ref] Cost-effectiveness of bevacizumab and ranibizumab for newly diagnosed neovascular macular degeneration, Stein [/bib_ref] Evidence Since 2005, many uncontrolled and retrospective case series have indicated that bevacizumab has a beneficial effect in the treatment of neovascular AMD. [bib_ref] Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for..., Rosenfeld [/bib_ref] [bib_ref] Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration, Avery [/bib_ref] [bib_ref] Intravitreal bevacizumab therapy for neovascular age-related macular degeneration: a pilot study, Abraham-Marin [/bib_ref] Bevacizumab has been split from the original vial into single doses containing 1.25 mg in a volume of 0.05 mL. Intraocular use has incidentally been associated with clusters of non-infectious mild to severe ocular inflammation (153 patients reported, no serious sequelae) and a single cluster of infectious endophthalmitis (12 patients), the latter associated with inappropriate pharmacy dispensing of the drug. A sterile preparation of single doses is mandatory with timely usage to prevent contamination spreading and aggregates forming, which leads to enhanced intraocular inflammatory reactions. [bib_ref] Ocular and systemic safety of bevacizumab and ranibizumab in patients with neovascular..., Johnson [/bib_ref] Evidence level I data for bevacizumab are exclusively derived from NI trials comparing bevacizumab with ranibizumab in the treatment of neovascular AMD aimed at reducing drug-related costs in clinical practice. The CATT study was a single-masked, NI trial, in which 1208 patients with neovascular AMD were randomised to intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed, with monthly evaluation. At 1 year, with a difference of five letters, monthly bevacizumab was equivalent to monthly ranibizumab, with +8.0 and +8.5 letters gained. [bib_ref] Ranibizumab and bevacizumab for neovascular age-related macular degeneration, Martin [/bib_ref] Bevacizumab as needed was equivalent to ranibizumab as needed with +5.9 and +6.8 letters gained. Nevertheless, the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive, and NI was not achieved. The mean decrease in CRT was greater in the ranibizumab monthly group (196 μm) than in the other groups . Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab ( p>0.20). However, the proportion of patients with serious systemic adverse events ( primarily hospitalisations) was higher with bevacizumab than with ranibizumab (24.1% vs 19.0%; risk ratio, 1.29; 95% CI 1.01 to 1.66). Subsequently, 1107 patients were followed during year 2, and the patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. [bib_ref] Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results, Martin [/bib_ref] The mean gain in VA was similar for both drugs (bevacizumab-ranibizumab difference, −1.4 letters; 95% CI), but greater for monthly than for as-needed treatment (difference, −2.4 letters; 95% CI −4.8 to −0.1; p=0.046). The proportion of eyes without fluid was 13.9% in the bevacizumab as-needed group, against 45.5% in the ranibizumab monthly group (drug, p=0.0003; regimen, p<0.0001 with statistically significantly more eyes treated with ranibizumab demonstrating resolution of fluid). Generally, switching from monthly to as-needed treatment resulted in a greater mean decrease in vision during year 2 (−2.2 letters; p=0.03) and a lower proportion without fluid (−19%; p<0.0001). Rates of death and arteriothrombotic events were similar for both drugs ( p>0.60) after 2 years, but the proportion of patients with one or more systemic serious adverse events was again higher with bevacizumab than with ranibizumab (39.9% vs 31.7%; adjusted risk ratio, 1.30; 95% CI 1.07 to 1.57; p=0.009). Treatment as needed, generally resulted in less gain in VA, whether instituted at enrolment or after 1 year of monthly treatment. The differences between BCVA values at 2 years increased compared with the year 1 outcomes with monthly ranibizumab scoring highest and as-needed bevacizumab scoring lowest. Retreatment indications were based on loss in BCVA or morphologic evidence of fluid in the macula based on TD-OCT without clear definition of the type and localisation of fluid 'no tolerance' regimen, and no clear biomarkers were identified by the protocol (figure 14A-C).
In the IVAN study, 610 patients were assigned randomly to ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with three consecutive injection series and monthly review. One year after randomisation, the comparison between bevacizumab and ranibizumab was inconclusive and bevacizumab did not meet the NI criteria (bevacizumab minus ranibizumab −1.99 letters, 95% CI −4.04 to 0.06) [bib_ref] Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from..., Chakravarthy [/bib_ref] [bib_ref] Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of..., Chakravarthy [/bib_ref] Moreover, discontinuous treatment also did not reach the NI level (−1.63 letters, −4.01 to 0.75; p=0.18), that is, the reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of the chosen drug. Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 (6%) of 314 participants) and bevacizumab (12 (4%) of 296; OR 1.69, 95% CI 0.80 to 3.57; p=0.16), or those given continuous (12 (4%) of 308) and discontinuous treatment (20 (7%) of 302; 0.56, 0.27 to 1.19; [fig_ref] Figure 4: Marked intraretinal exudates and/or haemorrhage seen clinically are associated with multiple hyperfluorescent... [/fig_ref] CATT study. (A) The mean change in visual acuity from enrolment over time in patients treated with the same dosing regimen for 2 years. While ranibizumab monthly, becacizumab monthly and ranibizumab as needed meet the non-inferiority level, treatment with bevacizumab as needed led to inconclusive results and non-inferiority was not proven. At 2 years, the mean increase in letters in visual acuity from baseline was +8.8 in the ranibizumab monthly group, +7.8 in the bevacizumab monthly group, +6.7 in the ranibizumab as-needed group and +5.0 in the bevacizumab as-needed group. Main gain was greater for monthly than for as-needed treatment. Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 with −2.2 letters. (B) Differences in mean change in visual acuity at 2 years and 95% CIs in patients treated with the same dosing regimen for 2 years. The difference in mean improvements for patients treated with bevacizumab relative to those treated with ranibizumab was −1.4 letters. The difference in mean improvements for patients treated by an as-needed regimen relative to those treated monthly was −2.4 letters. (C) The mean change in total foveal thickness from enrolment over time by dosing regimen within drug group: (A) ranibizumab and (B) bevacizumab. Mean gain was greater for monthly than for as-needed treatment. The proportion without fluid ranged from 13.9% in the bevacizumab as-needed group to 45.5% in the ranibizumab monthly group. Printed with permission from ref 54.
p=0.13). Mortality was lower with continuous than discontinuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p=0.05), but did not differ by drug group (0.96, 0.46 to 2.02; p=0.91).
With respect to safety, pooled analyses of the CATT and IVAN studies showed that mortality was lower with ranibizumab, but neither outcome differed significantly between drugs with the size of the respective study population ( p=−0.34 and p=−0.55). Increased odds of experiencing a serious adverse event with bevacizumab observed in the CATT persisted in the meta-analysis ( p=−0.016). Most importantly, the CATT and IVAN studies were not powered to identify small, but clinically significant differences in the safety of the two compounds [fig_ref] Figure 5: Spectral domain-optical coherence tomography [/fig_ref].
The GEFAL study was a multicenter, prospective, NI, doublemasked, randomised, clinical trial performed at 38 French ophthalmology centres. [bib_ref] Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL..., Kodjikian [/bib_ref] Patients were randomly assigned to receive intravitreal bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding and dispensing treatments. Patients were followed for 1 year, with a loading dose of three monthly intravitreal injections, followed by an as-needed regimen (1 injection in the case of active disease) for the remaining 9 months with monthly follow-up. Five hundred and one patients were assigned randomly. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% CI −1.16 to +4.93, p<0.0001). The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group ( p=0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab ( p=0.27). There were no statistically significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram or change in choroidal neovascular area, but ranibizumab tended to have a better anatomic outcome. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group ( p=0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups.
Safety is a topic of controversy discussed issue in the use of bevacizumab. Experimental studies revealed that systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. The recommendation was, therefore, to determine cardiovascular safety profiles to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk. [bib_ref] Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis-implications for cardiovascular..., Winnik [/bib_ref] In human studies, Avery et al 96 found that the systemic exposure after the third monthly intravitreal injection was 13-fold greater for aflibercept and 70-fold greater for bevacizumab than for ranibizumab. Another report reviewed differences in both ocular and systemic safety between intravitreal bevacizumab and ranibizumab in the setting of neovascular AMD. [bib_ref] Ocular and systemic safety of bevacizumab and ranibizumab in patients with neovascular..., Johnson [/bib_ref] Serious adverse events associated with either bevacizumab or ranibizumab injections are generally rare. Acute intraocular inflammation tends to occur more frequently following bevacizumab injection. Systemic absorption of bevacizumab is greater than with ranibizumab, and many studies have shown that specific risk or age groups of patients have an increased risk of systemic adverse events when receiving bevacizumab compared with those receiving ranibizumab. A systemic review based on Medline, Embase and the Cochrane Library evaluated whether bevacizumab is as safe as ranibizumab, and whether bevacizumab can be justifiably offered to patients as a treatment for AMD with robust evidence of no differential risk. [bib_ref] A safety review and meta-analyses of bevacizumab and ranibizumab: off-label versus goldstandard, Schmucker [/bib_ref] Registered clinical trials that investigated bevacizumab or ranibizumab in direct comparison, or against any other control group (indirect comparison), and had a minimum follow-up of 1 year were included. Direct comparison (3 trials, 1333 patients): The 1-year data show a significantly higher rate of ocular AE with bevacizumab than with ranibizumab (relative risk (RR)=2.8; 95% CI 1.2 to 6.5). The proportion of patients with serious infections and gastrointestinal disorders was also higher with bevacizumab than with ranibizumab (RR=1.3; 95% CI 1.0 to 1.7). Arterial thromboembolic events were equally distributed among the groups. Indirect comparison: Ranibizumab versus any control (5 trials, 4054 patients). The 2-year results of three landmark trials showed that while absolute rates of serious ocular AE were low (≤2.1%), relative harm was significantly raised (RR=3.1; 95% CI 1.1 to 8.9). Bevacizumab versus any control (three trials, 244 patients): the safety profile of bevacizumab could not be judged due to the poor quality of AE monitoring and reporting in the trials. In summary, evidence from head-to-head trials raised concern about an increased risk of ocular and systemic adverse events with bevacizumab. The need for studies that are powered not just for efficacy, but also for defined safety outcomes based on the signals detected in systematic reviews must be emphasised.
## Recommendation
The CATT and IVAN results indicate that ranibizumab and bevacizumab both confer solid visual function benefits. With monthly use of both drugs, NI has been proven with optimal [fig_ref] Figure 5: Spectral domain-optical coherence tomography [/fig_ref] IVAN study. Mean differences in best corrected distance visual acuity at 2 years by drug (top) and by regimen (bottom). Black dashed line shows non-inferiority limit of −3.5 letters. Mean differences estimated with data from visits 0, [bib_ref] Prevalence of age-related macular degeneration in the United States, Friedman [/bib_ref] [bib_ref] Associations of candidate genes to age-related macular degeneration among racial/ethnic groups in..., Klein [/bib_ref] [bib_ref] Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: quality-of-life findings: SST..., Miskala [/bib_ref] [bib_ref] Targeting VEGF-A to treat cancer and age-related macular degeneration, Ferrara [/bib_ref] [bib_ref] Forecasting age-related macular degeneration through the year 2050: the potential impact of..., Rein [/bib_ref] [bib_ref] Significant improvements in near vision, reading speed, central visual field and related..., Frennesson [/bib_ref] [bib_ref] Medicare costs for neovascular age-related macular degeneration, Day [/bib_ref] visual outcomes. Direct comparison among as-needed treatments also demonstrated NI, although on a generally lower level. Bevacizumab, as needed, failed to meet NI equivalence to monthly ranibizumab, that is, bevacizumab used in a PRN regimen did not reach the superior visual outcome achievable with monthly ranibizumab. Therefore, choice of the proper (fixed monthly) regimen is relevant when off-label bevacizumab is used. How much reduction in ocular efficacy one would be willing to sacrifice for reducing the number of injections and/or costs might depend on individual circumstances.
No major safety issues have emerged, but conclusive data are lacking, and none of the trials were powered for safety. Nevertheless, evidence from head-to-head trials consistently raises concerns about an increased risk of ocular and systemic adverse events with bevacizumab. Bevacizumab's impact on plasma concentrations of VEGF and its prolonged half-life in the circulation are proven. Therefore, the individual physical condition of each patient should be considered in the choice of the adequate therapy with the notion that patients included in clinical trials do not reflect the common risk profile of the real-world population. Bevacizumab is substantially less expensive, but each treatment decision is-legally and medically-based on an individual agreement between treating physician and patient, and must be the consequence of a comprehensive discussion of treatment alternatives and incalculable risks. Informed consent after discussing the optimal benefit, comfort and risks and the off-label status of the drug is mandatory. [bib_ref] The off-label use of medication: the latest on the Avastin-Lucentis debacle, Jansen [/bib_ref] Currently, there is a conflict on Avastin between the cost-conscious health authorities in EU member states and the EU drug regulators. There are several examples of cost-cutting solutions by health authorities, which risk undermining the fundamental principles of the regulatory framework. Meanwhile patients and doctors shoulder the risk.
These recommendations are based on the CATT and IVAN data (evidence level I).
## Aflibercept rationale
Aflibercept, unlike the monoclonal antibodies, bevacizumab and ranibizumab, is a soluble decoy receptor fusion protein. In aflibercept, the second binding domain of the native VEGF receptor 1 and the third binding domain of VEGF receptor 2 are attached to the Fc component of human ICG. [bib_ref] VEGF-Trap: a VEGF blocker with potent antitumor effects, Holash [/bib_ref] Therefore, the binding affinity of aflibercept (KDa=0.49 pmol/L) is higher than that of ranibizumab (KDa=0.46 pmol/L) and bevacizumab (KDa=0.58 pmol/L). The molecular size of aflibercept of 115 kDa results in an intravitreal half-life of 7.1 days, a calculated bioactivity in human eyes of 2.5 months and a serum halflife of 18 days due to the presence of an Fc portion. The compound binds to all VEGF-A isoforms and VEGF-B, with higher affinity than their native receptors. [bib_ref] Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands..., Papadopoulos [/bib_ref] Aflibercept and ranibizumab have been found to be equally effective in blocking endothelial cell proliferation, and 10-fold more potent than bevacizumab. [bib_ref] Comparing protein VEGF inhibitors: in vitro biological studies, Yu [/bib_ref] Aflibercept also binds to placental growth factor (PlGF) present on endothelial cells and leucocytes. [bib_ref] Predicted biological activity of intravitreal VEGF Trap, Stewart [/bib_ref] In preclinical studies, the compound suppressed CNV and VEGF-induced vascular breakdown in mice and rats. However, prolonged and high-doses administration led to loss of endothelial cells and pericytes. [bib_ref] Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss..., Inai [/bib_ref] Intravenous therapy in the first clinical trial was associated with systemic toxicity, such as proteinuria and hypertension. [bib_ref] A phase I trial of an IV-administered vascular endothelial growth factor trap..., Nguyen [/bib_ref]
## Evidence
The first intravitreal phase I study showed that aflibercept decreased macular oedema and SRF for at least six weeks and was well tolerated. [bib_ref] A phase I study of intravitreal vascular endothelial growth factor trap-eye in..., Nguyen [/bib_ref] A subsequent phase 2 clinical trial, CLEAR-IT2, compared monthly with quarterly intravitreal aflibercept at 0.5 and 2.0 mg. With both doses, monthly treatment was functionally and anatomically more efficient than quarterly treatment, initially and after a PRN regimen, until week 52. [bib_ref] The 1-year results of CLEAR-IT 2, a phase 2 study of vascular..., Heier [/bib_ref] Approval of aflibercept for the treatment of neovascular AMD was based on two parallel phase 3 pivotal trials, VIEW 1 and VIEW 2. Two thousand four hundred and nineteen patients with treatment-naive neovascular AMD were included in these double-masked, multicentre, parallel-group, activecontrolled, randomised trials. Eyes with new-onset subfoveal or juxtafoveal CNV comprising at least 50% of the total lesion size and a BCVA level between 20/40 and 20/320 Snellen equivalents were randomised 1:1:1:1 to two doses (0.5 and 2.0 mg) and two regimen (monthly and eight-weekly with 2.0 mg) of aflibercept. There was one control arm receiving ranibizumab (0.5 mg) at monthly intervals for 52 weeks. The primary endpoint was defined as NI in the proportion of patients maintaining BCVA. Secondary outcomes were change in BCVA and a reduction in CRT on OCT. At 52 weeks, all aflibercept groups, independent of doses and regimen, were non-inferior to the control group with equal maintenance of vision in 95% of eyes. [bib_ref] Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration, Heier [/bib_ref] A mean improvement of +8.7 letters (0.5 mg/q4 ranibizumab) in the control group compared with a mean change in BCVA of +9.3 letters with 2 mg aflibercept every 4 weeks and +8.4 letters every 8 weeks. In the integrated analysis of VIEW 1 (US centres) and VIEW 2 (centres in Canada, South America, Europe, Asia, Australia) all regimens were within 0.5 letters of the reference arm ranibizumab. Notably, in the VIEW 1 study alone, which included 1217 patients, the four weekly aflibercept regimen provided a benefit that was statistically superior to that seen in the other groups, with a visual gain of +10.9 letters. [bib_ref] Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration, Heier [/bib_ref] Lesions in the VIEW 1 trial were primarily smaller and associated with higher initial BCVA scores. Anatomically, all treatment groups demonstrated a similar rapid decline in CRT by −130 to −157 mm. In the eight-weekly aflibercept groups, bimonthly fluctuations in CRT were seen with recurrent exudation between extended aflibercept injections. Ocular and systemic adverse events were similar across all treatment groups with no statistically significant differences in Anti-Platelet Trialists' Collaboration (APTC) ATE events or AE rates.
A capped PRN regimen was applied to the 2457 patients in the complete trial from week 52 to week 96. [bib_ref] Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the..., Schmidt-Erfurth [/bib_ref] Criteria for retreatments were new or persistent fluid on OCT, an increase in CRT of 100 mm or more, or loss of five Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more, compared with the best previous score with fluid on OCT, new classic CNV seen by FA or haemorrhage on ophthalmoscope, and a mandatory 'capped' injections at an interval of 12 weeks since the previous treatment. The proportion of maintenance in BCVA ranged between 91% and 92% at week 96 for all groups. Mean BCVA gains were between +6.6 (aflibercept 0.5 mg) and +7.9 letters (ranibizumab q4), 7.6 letters (aflibercept q4 and q8) confirming NI for aflibercept and the eight-weekly retreatment regimen. [fig_ref] Figure 6: Fluorescein angiography [/fig_ref]. Overall, a mean loss of 0.8-1.7 letters was seen in all groups after the switch from a fixed to a capped flexible regimen. The retreatment frequency was similar for both substances during the capped PRN year, with 4.1/4.2 (aflibercept 2q4 and 2q8) and 4.7 (ranibizumab) injections. Less patients with pronounced disease activity requiring at least six reinjections during the second year received aflibercept (2 mg) (14%-16%) than ranibizumab (26.5%) treatments. Accordingly, more aflibercept-treated than ranibizumab-treated eyes were seen without retinal fluid at weeks 52 and 96. [bib_ref] Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the..., Schmidt-Erfurth [/bib_ref] Recent subgroup analyses of the VIEW trials suggested a superior morphologic efficiency of aflibercept in reducing intraretinal fluid and SRF as well as reducing RPE elevation. One retrospective assessment of eyes with persistent subfoveal fluid, despite previous treatments with ranibizumab suggested that at 6 months, mean BCVA and CRT improved significantly upon a switch to intravitreal aflibercept. [bib_ref] Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal..., Kumar [/bib_ref] However, most case series have indicated that 2.0 mg aflibercept leads to anatomic improvements in patients with long-standing persistent fluid, who have received other anti-VEGF agents, but BCVA conditions usually remained unchanged. Most of these analyses were retrospective in design and did not specify the previous anti-VEGF regimen and continuity in detail.
## Recommendation
FDA approval of aflibercept for the treatment of neovascular AMD at a recommended intravitreal dose of 2.0 mg was granted in 2012. The suggested regimen is monthly injections for the initial 3 months followed by a fixed dosing every eight weeks. The label also highlights that no additional efficacy was demonstrated when aflibercept was dosed every 4 weeks compared with every 8 weeks. In the VIEW 1 study, however, monthly aflibercept provided statistically superior visual gains. Many interventional studies suggest a superior anatomic efficacy of aflibercept compared with ranibizumab and bevacizumab.
The EU label recommends three initial injections at monthly intervals, followed by eight weekly injections without any subsequent monitoring. After 12 months of treatment, the injection intervals may be prolonged, depending on the functional and anatomical condition of the individual patient. Control intervals for evaluation may be adjusted at the treating ophthalmologist's discretion. The bimonthly fluctuations in BCVA and CRT values are small when averaged but are more impressive individually. This suggests patients with more intensive desease activity who can benefit from a monthly regimen, as noted in the VIEW 1 study, should be identified. Beyond the first year, increased dosing with continued monthly/bimonthly injections may be needed in eyes with morphologic signals, such as PED and IRC, which are likely associated with aggressive progression of CNV disease. Evidence level I is provided by the VIEW I and II studies. Photocoagulation and PDP for neovascular AMD Rationale Photocoagulation relies on the high transparency of the neurosensory retina and the melanin pigment content of the RPE to exert a selective effect on the outer layers of the retina. Such photocoagulation can be used to obtain immediate closure of subretinal neovascular membranes (CNV) resulting in permanent cessation of exudation, haemorrhage and vessel growth. An alternative method of closing subretinal CNV is PDT, which combines intravenous infusion of a photosensitive dye that releases free oxygen radicals when exposed to targeted illumination of the area of the fundus where the new vessels are located. Activation of the photosensitiser occurs at light intensities below the threshold for thermal coagulation, and PDT, therefore, leads to less collateral tissue damage than photocoagulation. Both treatment modalities have been tested at highly powered levels in AMD associated with subfoveal CNV under the foveal centre or close to the fovea.
## Photocoagulation therapy
Evidence Photocoagulation therapy for neovascular AMD was developed gradually and mostly on a case-to-case basis, until it was tested on a large scale against sham photocoagulation in the Macular Photocoagulation Study (MPS) in the USA and in randomised studies in the UK 117 and France.These studies were conducted in an era, when photocoagulation was the only effective form of treatment for neovascular AMD. In the MPS, the long-term visual prognosis for extrafoveal CNV lesions that were well delineated on fluorescein angiograms, and no parts of which were closer than 200 mm from the centre of the foveal avascular zone, was significantly improved by prompt intense and confluent photocoagulation covering the entire CNV. After 5 years, severe visual loss (30 ETDRS letters or more) occurred in 46% of treated eyes, as opposed to 64% of untreated eyes.Recurrence of CNV caused most of the visual loss between the early post-treatment period and 5 years after photocoagulation in the treatment group. A subsequent MPS examined the effect of photocoagulation of CNV lesions that extended to within 1- 199 mm of the centre of the foveal avascular zone. After 1 year, severe visual loss had occurred in 31% of treated eyes and in 45% of untreated eyes. After 5 years, the respective proportions were 54% and 57%, persistent or recurrent CNV activity being responsible for most of the additional loss. [bib_ref] Factors prognostic of visual outcome in patients with subretinal hemorrhage, Bennett [/bib_ref] Finally, an MPS of laser photocoagulation for subfoveal CNV extending under the centre of the foveal avascular zone showed that eyes that had not undergone prior photocoagulation suffered an immediate loss of vision after treatment, but gained a relative long-term benefit.After 24 months, the proportion of patients who had suffered such severe visual loss was still only 20% in the treated group, but it was 37% in the untreated group. The results apply only to CNV with a classic component, a well-defined margin on FA, and the greatest linear diameter of less than 3.5 disk diameters. Green argon laser (514 nm) was eventually considered state-of-the-art for photocoagulation of CNV because the summary experience of trying laser light of other colours and absorption characteristics is that the fundamental effect on CNV and the adjacent tissue components is the same. Green 532-nm frequency-doubled Nd-YAG laser have replaced argon laser and are now the standard in photocoagulation for CNV because they are more compact, and spectral shift has little or no effect on the tissue, these are now the standard in photocoagulation for CNV.
## Photodynamic therapy
The principle of PDT of CNV in AMD has led to the clinical development and marketing of a single pharmaceutical product (Visudyne, Novartis Pharma AG, Basel, Switzerland) with the active ingredient verteporfin. Semi-selective accumulation of verteporfin in proliferating endothelial cells and subsequent activation of the drug by 689 nm light in the part of the fundus where the CNV is found, enables closing of the new vessels without damage to the overlying neurosensory retina or its blood vessels. The vessels of the underlying normal choroidal vessels are closed to varying degrees, but the choroidal vessels recover and become perfused again within a few weeks after treatment. This temporary closure does not in itself appear to cause any immediate damage to the retina. The long-term morphological response of the CNV is variable, from flattening of the retina and lasting quiescence after a single treatment, to recurrence of CNV activity within a few months, and disease progression despite several retreatments. Years after initiation of PDT for neovascular AMD outer retinal atrophy and scarring is often seen in the area of the CNV where PDT was administered.
Evidence that PDT is of functional benefit to patients with neovascular AMD stems from two parallel, identically designed randomised controlled double-masked 2-year clinical trials, which were reported together in the peer-reviewed literature and are known as the TAP Study. [bib_ref] Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin:..., Bressler [/bib_ref] The study showed that PDT, administered promptly at baseline and optionally, depending on CNV activity, again every 3 months, was safe and effective in that it reduced the risk of moderate (15 ETDRS letters) and severe (30 ETDRS letters) loss of BCVA. The outcome was most favourable in eyes with predominantly classic (type 2) CNV: 59% of treated eyes lost less than 15 letters over 2 years versus 31% in the sham group. The number of treatments given was 3.4 in the first year and 2.2 in the second year. A phase 3 randomised, controlled, double-masked, 2-year trial known as the VIP trial was conducted in eyes with occult (type 1) CNV and no classic component or evidence of recent disease progression. A phase 3 randomised, controlled, double-masked 2-year trial known as the VIP trial was conducted.A retrospective subgroup analysis showed benefit of PDT in eyes with lesions smaller than four MPS disk areas or VA worse than 20/50, where treatment was associated with loss of 15 or more ETDRS letters in 25% of eyes compared with 51% of eyes in the sham treatment group. A subsequent trial of PDT in occult-only CNV failed to confirm a treatment benefit of PDT. [bib_ref] Verteporfin PDT for subfoveal occult CNV in AMD: two-year results of a..., Kaiser [/bib_ref] Acute severe VA loss was the only clinically significant adverse event observed in PDT studies in AMD with CNV, such acute loss of more than 20 ETDRS letters occurring in less than 5% of the patients. Two randomised trials of PDT combined with ranibizumab failed to show a benefit of combination therapy over ranibizumab monotherapy. A recent retrospective study suggests that rescue therapy with the combination of an intravitreal anti-VEGF agent and PDT may benefit eyes that have failed anti-VEGF monotherapy by improving vision, eliminating fluid and reducing the need for anti-VEGF retreatment. 127
## Recommendation
Laser photocoagulation therapy and verteporfin PDP have shown benefits compared with the natural course in selected subtypes and stages of neovascular AMD. While largely superseded by intravitreal pharmaceutical VEGF inhibition, these two older forms of CNV treatment remain a rational therapeutic option for selected patients in whom VEGF inhibition is not advisable. Although the evidence is based on studies of wet AMD with neovascularisation under or very near the foveal centre, application of photocoagulation or PDT for subretinal new vessels is likely to be considered in current clinical practice in less common conditions, such as peripapillary CNV and, in the case of photocoagulation, in conditions such as extrafoveal CNV in pregnant women in whom neither PDT nor intravitreal VEGF inhibitors have been shown to be safe. Evidence I is provided by MPS, TAP and VIP studies.
## Radiation therapy rationale
Radiation therapy, as monotherapy or combined with anti-VEGF treatment, has also been studied as a new option for the treatment of neovascular AMD. Although anti-VEGF treatments provide patients with impressive benefits in terms of VA, all require regular intravitreal injections and they generally suppress rather than eliminate the disease activity. As replicating tissue is more susceptible to the effects of radiation than non-replicating tissue, choroidal neovascular lesions, which consist of proliferating endothelial cells, are more sensitive to radiation treatment than normal non-proliferating capillary endothelial cells and larger vessels. [bib_ref] Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET), Dugel [/bib_ref] The role of radiation therapy for neovascular AMD was explored as early as 1993, and the rationale for this approach was based on the known effects of radiation therapy on tumour microvasculature. Radiation treatment is able to prevent proliferation of vascular tissue by its anti-inflammatory, antiangiogenic and antifibrotic properties. Radiation used for medical therapies can be divided into two main categories depending on its method of delivery to the tissue. Brachytherapy uses a radiation source delivered directly to the lesion by surgery. The source is usually an isotope which produces ionising radiation as it decays and emits energy. Teletherapy (external beam therapy) uses radiation formed into a beam which can be projected at an internal body tissue from an external source. The source can also be an isotope, but more recently electronically produced ionising radiation has been used. [bib_ref] Radiation therapy for neovascular age-related macular degeneration, Petrarca [/bib_ref] Evidence Initial studies investigated external beam radiation to treat neovascular AMD. While some studies showed results better than the natural history, the results do not compare favourably with those in the anti-VEGF era. This may be because of collateral damage to ocular tissue, and the difficulty of targeting macular lesions with a technology that was designed for larger lesions, such as tumours. Another factor could be the time delay before radiation has an effect. There is historical evidence that treatment with external beam radiation therapy and plaque brachytherapy for AMD can prevent progression of CNV membranes. However, the VA results have been less impressive, which is likely due to inaccurate targeting in the case of external beam radiotherapy or difficulty in optimising the seed placement in plaque brachytherapy. [bib_ref] 16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for..., Moshfeghi [/bib_ref] Currently, two different approaches to radiation therapy are being investigated: epimacular brachytherapy (EMBT) (VIDION) and stereotactic radiosurgery (IRay system). [bib_ref] Radiation therapy for neovascular age-related macular degeneration, Petrarca [/bib_ref] Radiotherapy produces a delayed response, but has a much longer duration of action. Therefore, there is a good scientific rationale for a synergistic response. Anti-VEGF therapy inhibits growth factors in the local area, while radiotherapy inhibits the local inflammatory cell population and induces an apoptotic effect on vascular endothelium. The overall result from these two approaches has the potential to offer a faster and more complete recovery of functional vision.
EMBT is designed as a system to deliver intraocular radiation by placing the source of radiation close to the CNV complex at the macula. This device uses β radiation from a strontium-90/ yttrium-90 source, and as β radiation has a rapid decline in dose with increasing distance from the source, it limits the radiation exposure to a defined region with little damage to adjacent tissues. The β radiation used in epimacular brachytherapy is delivered via pars plana vitrectomy (PPV) surgery. Once the vitreous has been removed, the surgeon positions the probe over the CNV lesion. The probe is held in position for approximately 4 min and then removed. Delivery of radiation to neighbouring structures is low with this method. The macular lesion, the optic nerve and the lens receive, respectively, 24 grey (Gy), 2.4 Gy and 0.00056 Gy. [bib_ref] Radiation therapy for neovascular age-related macular degeneration, Petrarca [/bib_ref] The MERITAGE study was a prospective, multicentric interventional, non-controlled, clinical trial designed to evaluate the safety and efficacy of EMBT for the treatment of chronic, active neovascular AMD. Fifty-three eyes of 53 participants with CNV requiring frequent anti-VEGF retreatments were included. Participants underwent PPV with a single 24-Gy dose of EMB delivered by the method described above. Participants were retreated with ranibizumab monthly as needed (PRN), using predefined retreatment criteria. Before enrolment, participants received an average of 12.5 anti-VEGF injections. After a single treatment with EMB, 81% maintained stable vision, with a mean of 3.49 anti-VEGF retreatments in 12 months. Mean±SD change in VA was −4.0±15.1 ETDRS letters. The authors concluded that EMBT produces stable VA in most participants with previously treated disease, and may reduce the need for frequent anti-VEGF retreatments. [bib_ref] Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE study: twelve-month safety..., Dugel [/bib_ref] The CABERNET study was a multicentric, randomised, active-controlled, phase 3 clinical trial with the same objective. There were 494 participants with treatment-naive neovascular AMD. Participants with classic, minimally classic, and occult lesions were randomised in a 2:1 ratio to an EMBT or a ranibizumab monotherapy control arm. Participants in the EMB arm received two mandated, monthly loading injections of 0.5 mg ranibizumab. The control arm received three mandated, monthly loading injections of ranibizumab and then quarterly injections. Both arms also received monthly as-needed (PRN) retreatment. At 24 months, 77% of the EMBT group and 90% of the control group lost fewer than 15 letters. This end point was non-inferior, using a 20% margin and a 95% CI for the group as a whole and for classic and minimally classic lesions, but not for occult lesions. Mean VA change was −2.5 letters in the EMBT arm and +4.4 letters in the control arm. At least one serious adverse event occurred in 54% of the participants in the EMB arm, most commonly postvitrectomy cataract, versus 18% in the control arm. Mild, non-proliferative radiation retinopathy occurred in 3% of the EMB participants, but in no case was it vision-threatening. The authors concluded that 2-year efficacy data did not support the routine use of EMB for treatmentnaive patients with neovascular AMD, despite an acceptable safety profile. [bib_ref] Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET), Dugel [/bib_ref] More recently, investigators have revisited external beam therapy, using a technique called stereotactic radiotherapy or radiosurgery. This treatment directs beams from different angles relative to the target area, thereby minimising the exposure to surrounding healthy tissue, and at the same time precisely targeting the radiation energy onto the lesion. The system is designed to overcome the traditional disadvantages of external beam therapy by dividing the dose into several separate beams that pass into the eye via different locations on the sclera. [bib_ref] 16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for..., Moshfeghi [/bib_ref] The patient is secured in position with a head restraint and the eye is continually tracked during treatment. [bib_ref] Radiation therapy for neovascular age-related macular degeneration, Petrarca [/bib_ref] In the INTREPID study, 230 patients with AMD, a history of a maximum of 3 years' duration of CNV, and at least three anti-VEGF injections in the previous year were enrolled. Patients were randomised into three groups. The first group received 16 Gy irradiation, with a mandatory ranibizumab injection at the beginning of the study. The second group received 24 Gy irradiation and one ranibizumab injection as in the first group, while the control group received sham irradiation and one mandatory ranibizumab injection. All groups were allowed to have ranibizumab injections on an as-needed basis during the 12-month follow-up. At month 12, the primary end point of the study was met showing a 30% less need for anti-VEGF retreatment in the active compared with sham treatment group. Furthermore, a subgroup analysis of the patients revealed that patients with smaller lesions and high macular volume needed 55% fewer reinjections.
## Recommendation
At present, the only scientific argument to support the use of irradiation for the treating of neovascular AMD is the reduction in the number of retreatments necessary, but its delivery methods, efficacy and safety results are still controversial and need further investigations.
## Surgical treatment for haemorrhagic amd rationale
Subretinal haemorrhage (SRH) is a rare, but devastating complication of neovascular AMD. [bib_ref] Pathophysiology and management of subretinal hemorrhage, Hochman [/bib_ref] Damage to overlying photoreceptors has been found to occur within 24 h and degeneration of outer retinal layers within 3 days. [bib_ref] Experimental subretinal hemorrhage in rabbits, Glatt [/bib_ref] The natural history of submacular haemorrhage (SMH) associated with neovascular AMD usually leads to poor VA. To date, intravitreal injections of anti-VEGF drugs have been the gold standard for the treatment of CNV secondary to AMD. Notwithstanding, clinical trials conducted for drug approval, such as the MARINA and ANCHOR studies of ranibizumab, excluded patients with predominantly haemorrhagic lesions. Several other studies that evaluated the benefits for haemorrhagic AMD of anti-VEGF drugs reported limited success in the patients affected. [bib_ref] Intravitreal bevacizumab therapy for neovascular age-related macular degeneration with large submacular hemorrhage, Stifter [/bib_ref] A complete mechanical elimination of the subretinal blood clot with or without extraction of the underlying neovacular complex is the rationale for submacular surgery in haemorrhagic AMD.
## Evidence
Natural history studies found that 80% of patients had worsened vision, with a decline of mean VA from 20/240 to 20/ 1250: 38% developed fibrous tissue proliferation, 25% an atrophic scar and 22% an RPE rip. [bib_ref] Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration, Avery [/bib_ref] Decreased long-term visual outcome has been associated with an increased thickness of SMH, increased area of SRH and recurrent SMH. [bib_ref] Factors prognostic of visual outcome in patients with subretinal hemorrhage, Bennett [/bib_ref] [bib_ref] Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration, Avery [/bib_ref] The use of antithrombotic medications was also associated with an increased risk of SMH, which can be of up to 11.6 times higher in patients with AMD. [bib_ref] Subretinal hemorrhages associated with age-related macular degeneration in patients receiving anticoagulation or..., Kuhli-Hattenbach [/bib_ref] Shultz et al 138 classified of SMH in a review article. A small haemorrhage was defined as a haemorrhage that does not extend to the vascular arcades, a medium haemorrhage as one that does extend to the vascular arcades, and a massive haemorrhage as one that extends past the vascular arcades to the periphery. A thin SMH was classified as less than 500 m in thickness, and a thick one as more than 500 m in thickness.
Many surgical modalities are available nowadays, including vitrectomy with manual clot extraction, vitrectomy with subretinal recombinant tissue plasminogen activator (rtPA), and pneumatic displacement with and without intravitreal rtPA. The treatment options for a small haemorrhage that does not extend to the vascular arcades are intravitreal anti-VEGF and pneumatic displacement with or without intravitreal rtPA. [bib_ref] Treatment for submacular hemorrhage associated with neovascular age-related macular degeneration, Shultz [/bib_ref] Several studies have investigated pneumatic displacement as an initial monotherapy to treat SMH and have reported successful displacement of haemorrhage with gas and prone positioning alone. Fibrin has been shown to form 1 h after experimentally created SRH in animal models. Therefore, rtPA has been used to liquefy SMH and to aid in its removal or displacement. [bib_ref] Intravitreous injection of tissue plasminogen activator and gas in the treatment of..., Hattenbach [/bib_ref] Hassan et al reported on 14 patients with AMD and related SMH of less than 3 weeks duration, who were treated with intravitreal rtPA (25-100 mg), expansile gas and prone positioning. In all patients, the haemorrhage cleared within 5 days. By final follow-up, 67% of eyes improved by at least two Snellen lines. [bib_ref] Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic..., Hassan [/bib_ref] Hattenbach et al prospectively evaluated 43 eyes with AMD and related SMH with less than 1 month's duration. All patients were treated with intravitreal rtPA (50 mg) and sulfa hexafluoride followed by prone positioning. The best postoperative VA compared with preoperative VA improved by two or more Snellen lines in 19 eyes (44%) and remained stable in 24 eyes (56%). The authors noted that SMH of ≤14-days' duration was associated with a better gain of lines of vision.
In 2007, Chen et al reported the results of a retrospective case series of 104 eyes that had received intravitreal injection of 100−30 mg of rtPA and expansile gas, and underwent prone positioning. In 64% of the eyes, the best VA improved at least two Snellen lines at the 3-month follow-up. The most common cause was AMD (86%), but the eyes with SMH unrelated to AMD had better VA outcomes. [bib_ref] Management of submacular hemorrhage with intravitreal injection of tissue plasminogen activator and..., Chen [/bib_ref] Medium-sized SMH extends to the vascular arcades and can be managed by either pneumatic displacement with or without intravitreal rtPA or PPV. In 1988, De Juan and Machemer were the first to perform PPV on four patients with AMD and SMH of 1-week to 1-year duration. All the operations were successful in removing SMH, but resulted in poor VA outcomes. [bib_ref] Vitreous surgery for hemorrhagic and fibrous complications of age-related macular degeneration, De Juan [/bib_ref] Peyman and colleagues first described the use of subretinal rtPA (12.5 mg) as an adjuvant to PPV in three patients. They suggested that rtPA could reduce surgical manipulation of the retina and allow removal of the haemorrhage with smaller retinotomies. VA improved in one patient and was stabilised in the other two patients. [bib_ref] Tissue plasminogen activating factor assisted removal of subretinal hemorrhage, Peyman [/bib_ref] Ibanez et al reported the results of a comparison between mechanical clot extraction with an extrusion cannula or forceps through a retinotomy and tPA-assisted drainage in 47 patients. No statistically significant differences in VA outcomes were found, with most patients having a final VA worse than 20/200. [bib_ref] Surgical management of submacular hemorrhage. A series of 47 consecutive cases, Ibanez [/bib_ref] When rtPA was injected using a bent 36-gauge needle, and there was no waiting time for intraoperative clot lysis, all 11 eyes had clearance of SMH cleared in all 11 eyes, and 45% of eyes had a postoperative VA of 20/200 or better. VA improved compared with preoperative vision in 8 of 11 eyes with a mean follow-up of 6.5 months. [bib_ref] Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-gas exchange..., Haupert [/bib_ref] SMH recurred in 27% of the eyes. The results of the Submacular Surgery Trials for predominantly haemorrhagic subfoveal CNV secondary to AMD were released in 2004. PPV was followed by removal of the entire lesion (including the CNV membrane, blood and scar tissue), subretinal rtPA at the surgeon's discretion (rtPA used in 38%; left for 40 min) and air or gas. The authors reported no benefit of submacular surgery relative to observation with respect to achieving stable or improved VA. However, they did report a reduced risk of severe vision loss (loss of ≥6 lines). Patients receiving surgery had higher rates of retinal detachment and cataract extraction compared with observation. [bib_ref] Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings:..., Bressler [/bib_ref] Treating massive SMH is a challenge. The submacular surgery trials excluded patients with SMH greater than 9 disk areas. [bib_ref] Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings:..., Bressler [/bib_ref] Oshima et al defined massive haemorrhage as extending to the periphery and involving at least two quadrants with haemorrhagic and bullous retinal detachment. In eight patients, intravitreal rtPA was injected 12-24 h prior to PPV, and eyes were examined for evidence of clot liquefaction followed by PPV. Heavy liquid was injected to displace haemorrhage through the retinotomies into the vitreous cavity for removal. The vitreous cavity was filled with perfluoropropane and the patient was instructed to remain face down for at least 24 h. Improvement in VA was seen in seven of eight patients and recurrence of SRH in one patient after 14 months. [bib_ref] Pars plana vitrectomy with peripheral retinotomy after injection of preoperative intravitreal tissue..., Oshima [/bib_ref] In a study with similar conditions, Fine et al examined 15 eyes that had undergone 20-gauge PPV and subretinal rtPA (25 mg) with a 39-gauge needle for 30-45 min. Four of the 15 patients had an inferior 180°-360°retinotomy during the primary procedure with excision of the clot with vitrectom or fragmatom. Patients received either long-acting gas (n=12) or silicone oil (n=3), and were positioned semiprone after the operation for 2 weeks. Nine of the 15 patients required other surgical interventions. Although the improvement in VA at 1 year was modest, the authors stated that it was favourable compared with the natural history. [bib_ref] Surgical outcomes after massive subretinal hemorrhage secondary to age-related macular degeneration, Fine [/bib_ref] Complications associated with vitrectomy include retinal detachment, proliferative vitreoretinopathy, epiretinal membrane, RPE tear, progression of cataract, vitreous haemorrhage, creation of a macular hole, and recurrence of SMH. [bib_ref] Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings:..., Bressler [/bib_ref] As the use of anti-VEGF drugs for neovascular AMD is well established, their use combined with PPV and subretinal rtPA has also been investigated. Treumer et al injected bevacizumab into the subretinal space of 12 patients followed by PPV and subretinal rtPA (10-20 mg). Air-fluid exchange was performed and patients were positioned prone for 1 day. Displacement of SMH was achieved in 75% of patients and mean improvement of VA was logMAR 0.96 at 12 weeks. [bib_ref] Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related..., Treumer [/bib_ref] Arias et al reported results of PPV with intravitreal bevacizumab in 15 eyes. Subretinal rTPA was injected for thick SMH and intravitreal rTPA for thin SMH (at the end of surgery). They reported that all patients had improved VA at final follow-up. [bib_ref] Transconjunctival sutureless vitrectomy with tissue plasminogen activator, gas and intravitreal bevacizumab in..., Arias [/bib_ref]
## Recommendation
As there is no consensus on the optimal treatment, and data from studies often conflict, no general recommendation can be given for the treatment of haemorrhagic AMD. A classification of SMH based on size appears practical. Pneumatic replacement may be useful in small haemorrhages, while medium-sized clots may require a surgical approach including vitrectomy. Massive haemorrhage has a genuinely unfavourable prognosis. Attention should be given to the fellow eye to prevent active disease, and a haemorrhagic event in the eye that sees better. Evidence levels are generally low with levels II-III.
[fig] Figure 2: Occult choroidal neovascularisation is located underneath the retinal pigment epithelium layer. By fluorescein angiography (FA), an area of stippled, or pinpoint hyperfluorescence with leakage in late phases, are seen. Indocyanine green angiography (ICGA) (right lower image) may visualise the neovascular pattern of the occult lesion (ophthalmoscopy, early FA, late FA, ICGA). [/fig]
[fig] Figure 3: A retinal angiomatous proliferation is characterised by an early hyperfluorescent spot at the level of the retinal vasculature, mostly at the site of a focal haemorrhage and progressive intraretinal leakage. The concomitant optical coherence tomography scan reveals a pigment epithelium detachment and intraretinal cystoid expansions. [/fig]
[fig] Figure 4: Marked intraretinal exudates and/or haemorrhage seen clinically are associated with multiple hyperfluorescent polyps angiographically in polypoidal chorioidopathy. Indocyanine green angiography (ICGA) is often helpful in delineating the polypoidal components despite haemorrhage (ophthalmoscopy, early fluorescein angiography (FA), ICGA, late FA). [/fig]
[fig] Figure 5: Spectral domain-optical coherence tomography (SD-OCT) reveals a fibrovascular pigment epithelial detachment and a serous retinal detachment in a patient with age-related macular degeneration affected by a type 1 choroidal neovascularisation (scanning laser ophthalmoscopy, SD-OCT). [/fig]
[fig] Figure 6: Fluorescein angiography (FA) and spectral domain-optical coherence tomography (SD-OCT) identify a minimally classic choroidal neovascularisation with the classic component in the nasal portion of the macular area and the occult component in the temporal area (FA, SD-OCT). [/fig]
[fig] Figure 7: Spectral domain-optical coherence tomography (SD-OCT) features of type 2 (classic) choroidal neovascularisation (CNV) associated with exudative age-related macular degeneration are shown: fluorescein angiography (FA) visualises a small type 2 neovascular membrane. On SD-OCT, CNV appears between the retina and the retinal pigment epithelium, associated with some exudative cystoid spaces and increased central retinal thickness. (FA, SD-OCT). [/fig]
[fig] Figure 8: In retinal angiomatous proliferation, fluorescein angiography (FA) shows a hot-spot in the macular area. On spectral domain-optical coherence tomography (SD-OCT), a focal pigment epithelial detachment and intraretinal cystoid spaces are the pathognomonic features. (FA, SD-OCT). [/fig]
[fig] Figure 9: Spectral domain-optical coherence tomography (SD-OCT) features of polypoidal choroidopathy are shown: Indocyanine green angiography (ICGA) identifies a hyperfluorescent polypoidal lesion. A punctuate haemorrhage associated with the hot-spot on angiography suggests a retinal angiomatous proliferation. SD-OCT shows a dome-shaped elevation, the sign of a polypoidal lesion. (ICGA, scanning laser ophthalmoscopy, SD-OCT). with a decrease of -10.4 letters in the sham-injection group ( p<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. The average benefit associated with ranibizumab over that of sham injection was approximately 17 letters in each dose group at 12 months, and 20-21 letters at 24 months. (B) Mean (±SE) changes in choroidal neovascularisation and leakage. The mean change from baseline in each of the ranibizumab-treated groups differed significantly from that in the sham-injection group at 12 and 24 months ( p<0.001 for each comparison) in favour of ranibizumab treatment. Printed with permission from ref 13. [/fig]
[fig] Figure 12: EXCITE study. (A, B) Proportion of patients with (A) visual acuity loss (<15 letters) or (B) gain (≥15 letters) over time in the intent-to-treat patient population (last observation carried forward (LOCF)) of EXCITE. Best-corrected visual acuity (BCVA) increased from baseline to month 12 by +4.9, +3.8, and +8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. After three initial monthly ranibizumab injections, monthly (0.3 mg) and quarterly (0.3 mg/0.5 mg) ranibizumab treatments maintained BCVA in patients with choroidal neovascularisation secondary to age-related macular degeneration. At month 12, BCVA gain in the monthly regimen was higher than that of the quarterly regimens. The non-inferiority of a quarterly regimen was not achieved with reference to 5.0 letters.(C) Mean change from baseline over time of central retinal thickness as assessed by optical coherence tomography scan in the intent-to-treat patient population ( LOCF) of EXCITE. Vertical bars represent SE of the mean. The mean decrease in central retinal thickness from baseline to month 12 in the intention-to-treat population was −96.0 mm in 0.3 mg quarterly, −105.6 mm in 0.5 mg quarterly, and −105.3 mm in 0.3 mg monthly group. Printed with permission from ref 50. [/fig]
[fig] Figure 13: HARBOR study. (A) Mean change from baseline to month 12 in best-corrected visual acuity (BCVA). *Vertical bars are ±1 SE of the unadjusted mean. Mean number of injections was analysed for patients who received at least 1 ranibizumab injection in the study eye. At month 12, the mean change from baseline in BCVA for the four groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg pro-re-nata (PRN)), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1% and 33.0%, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5 mg PRN and 2.0 mg PRN groups, respectively. (B) Mean change from baseline to month 12 in central foveal thickness (CFT) by spectral-domain optical coherence tomography. Vertical bars are ±1 SE of the unadjusted mean. The mean change from baseline in CFT at month 12 in the 4 groups was −172, −161.2, −163.3, and −172.4 μm, respectively. Printed with permission from ref 55. [/fig]
[fig] Figure 16: VIEW studies. (A) Mean change from baseline in best-corrected visual acuity (BCVA). The inset shows the difference in least square mean (with 95% CI) between intravitreal aflibercept arms and ranibizumab (aflibercept minus ranibizumab) for BCVA change from baseline to week 96, full analysis set. Outcomes for the aflibercept and ranibizumab groups were similar at weeks 52 and 96. Mean BCVA gains were 8.3-9.3 letters at week 52 and 6.6-7.9 letters at week 96. Patients received, on average, 16.5, 16.0, 16.2 and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6 and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. (B) Mean change from baseline central retinal thickness, full analysis set. Bimonthly fluctuations in central retinal thickness (CRT) are seen during the fixed regimen in year 1 in the 2q8 arm. During the second year with a capped pro-re-nata regimen, variations in CRT become larger with a quarterly fluctuation pattern. Printed with permission from ref 111. [/fig]
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https://bjo.bmj.com/content/bjophthalmol/98/9/1144.full.pdf
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Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients. Trial registration number NCT01318941.
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pubmed
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European guidance for the diagnosis and management of osteoporosis in postmenopausal women
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European guidance for the diagnosis and management of osteoporosis in postmenopausal women
Guidance is provided in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis.
# Introduction
Osteoporosis is defined as a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Although the diagnosis of the disease relies on the quantitative assessment of bone mineral density (BMD), which is a major determinant of bone strength, the clinical significance of osteoporosis lies in the fractures that arise. In this respect, there are some analogies with other multifactorial chronic diseases. For example, hypertension is diagnosed on the basis of blood pressure, whereas an important clinical consequence of hypertension is stroke.
Common sites for osteoporotic fracture are the spine, hip, distal forearm and proximal humerus. The remaining lifetime probability in women at the menopause of a fracture at any one of these sites exceeds that of breast cancer (approximately 12%), and the likelihood of a fracture at any of these sites is 40% or more in developed countries [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] [bib_ref] Long-term risk of osteoporotic fracture in Malmo, Kanis [/bib_ref] , a figure close to the probability of coronary heart disease. In the year 2000, there were estimated to be 620,000 new fractures at the hip, 574,000 at the forearm, 250,000 at the proximal humerus and 620,000 clinical spine fractures in men and women aged 50 years or over in Europe. These fractures accounted for 34.8% of such fractures worldwide [bib_ref] An estimate of the worldwide prevalence and disability associated with osteoporotic fractures, Johnell [/bib_ref]. Osteoporotic fractures also occur at many other sites including the pelvis, ribs, and distal femur and tibia. Collectively, all osteoporotic fractures account for 2.7 million fractures in men and women in Europe at a direct cost of 36 billion Euros [bib_ref] on behalf of the Committee of Scientific Advisors of the International Osteoporosis..., Kanis [/bib_ref].
Osteoporotic fractures are a major cause of morbidity in the population. Hip fractures cause acute pain and loss of function, and nearly always lead to hospitalisation. Recovery is slow and rehabilitation is often incomplete, with many patients permanently institutionalised in nursing homes. Vertebral fractures may cause acute pain and loss of function, but may also occur without serious symptoms. Vertebral fractures often recur, however, and the consequent disability increases with the number of fractures. Distal radial fractures also lead to acute pain and loss of function, but functional recovery is usually good or excellent.
It is widely recognised that osteoporosis and the consequent fractures are associated with increased mortality, with the exception of forearm fractures [bib_ref] A population based study of survival after osteoporotic fractures, Cooper [/bib_ref]. In the case of hip fracture, most deaths occur in the first 3-6 months following the event, of which 20-30% is causally related to the fracture event itself. The estimates of deaths from Sweden that are causally related to hip fracture are appreciable and suggest that more than 1% of all deaths are due to hip fracture [bib_ref] The components of excess mortality after hip fracture, Kanis [/bib_ref] , somewhat higher than the percentage of deaths attributed to pancreatic cancer and somewhat lower than the percentage of deaths attributed to breast cancer [fig_ref] Table 2: Principal causes of death from selected diseases in Swedish men and women... [/fig_ref].
A general approach to quantifying the burden of disease, favoured by the WHO and World Bank, is to assess the disability incurred by disease, including deaths due to the disorder as well as the disability that arises in survivors. The approach, based on disability and life-years lost (DALYs), permits a comparison with other disease states. show the burden in Europe compared with that for other chronic diseases. Osteoporosis accounted for more DALYs than rheumatoid arthritis, but fewer than osteoarthritis. With regard to neoplastic diseases, the burden of osteoporosis was greater than for all sites of cancer, with the exception of lung cancers [bib_ref] An estimate of the worldwide prevalence and disability associated with osteoporotic fractures, Johnell [/bib_ref]. The high societal and personal costs of osteoporosis pose challenges to public health and physicians, particularly since most patients with osteoporosis remain untreated. The aims of this guidance are to stimulate a cohesive approach to the management of osteoporosis in Europe. Although the guidance is focussed on postmenopausal women, the same general principles apply to men as well as women.
## Bone mineral measurements and diagnosis of osteoporosis
The objectives of bone mineral measurements are to provide diagnostic criteria, prognostic information on the probability of future fractures, and a baseline on which to monitor the natural history of the treated or untreated patient. BMD is the amount of bone mass per unit volume (volumetric density), or per unit area (areal density), and both can be measured in vivo by densitometric techniques.
Techniques to measure bone mineral A wide variety of techniques is available to assess bone mineral that are reviewed elsewhere [bib_ref] Role of dual-energy X-ray absorptiometry in the diagnosis and treatment of osteoporosis, Blake [/bib_ref] [bib_ref] Quality and performance measures in bone densitometry. I. Errors and diagnosis, Engelke [/bib_ref] [bib_ref] Quality and performance measures in bone densitometry. II. Fracture risk, Gluer [/bib_ref]. The most widely used are based on X-ray absorptiometry in bone, particularly dual-energy X-ray absorptiometry (DXA) since the absorption of X-rays is very sensitive to the calcium content of the tissue of which bone is the most important source. Other techniques include quantitative ultrasound (QUS), quantitative computed tomography (QCT), both applied to the appendicular skeleton and to the spine, peripheral DXA, digital X-ray radiogrammetry, radiographic absorptiometry, and other radiographic techniques. Other important determinants of bone strength for both cortical and trabecular bone include macro-and microarchitecture. X-ray-based technology is becoming available to estimate these components of bone strength.
Dual-energy X-ray absorptiometry (DXA) is the most widely used bone densitometric technique. It is versatile in the sense that it can be used to assess bone mineral content of the [bib_ref] An estimate of the worldwide prevalence and disability associated with osteoporotic fractures, Johnell [/bib_ref] , with kind permission from Springer Science + Business Media). IHD ischaemic heart disease, COPD chronic obstructive pulmonary disease, OA osteoarthritis, RA rheumatoid arthritis, BPH benign prostatic hyperplasia whole skeleton as well as of specific sites, including those most vulnerable to fracture [bib_ref] Role of dual-energy X-ray absorptiometry in the diagnosis and treatment of osteoporosis, Blake [/bib_ref] [bib_ref] Non invasive assessment of bone mineral and structure: state of the art, Genant [/bib_ref] [bib_ref] Performance evaluation of a dual energy X-ray bone densitometer, Mazess [/bib_ref]. The term bone mineral content describes the amount of mineral in the specific bone site scanned. This can then be used to derive a value for BMD by dividing the bone mineral content by the area measured. This is, therefore, an areal density (g/cm 2 ) rather than a true volumetric density (g/cm [bib_ref] An estimate of the worldwide prevalence and disability associated with osteoporotic fractures, Johnell [/bib_ref] since the scan is two-dimensional. Areal BMD accounts for about two-thirds of the variance of bone strength as determined in vitro on isolated bones, such as the vertebral body or proximal femur. Dual-energy X-ray absorptiometry can also be used to visualise lateral images of the spine from T4 to L4 to detect deformities of the vertebral bodies. Vertebral fracture assessment (VFA) may improve fracture risk evaluation, since many patients with vertebral fracture may not have a BMD T-score classified as osteoporosis. This procedure involves less radiation and is less expensive than a conventional X-ray examination. VFA has a sensitivity and specificity of about 90% for the detection of grade 2 and 3 fractures, according to the semiquantitative method of Genant. Whereas whole body bone, fat and lean mass can also be measured using DXA, these measurements are useful for research, but do not assist in the routine diagnosis or assessment of osteoporosis.
The performance characteristics of many measurement techniques have been well documented [bib_ref] Meta-analysis of how well measures of bone mineral density predict occurrence of..., Marshall [/bib_ref]. For the purpose of risk assessment and for diagnosis, the characteristic of major importance is the ability of a technique to predict fractures. This is traditionally expressed as the increase in the relative risk of fracture per standard deviation unit decrease in bone mineral measurementtermed the gradient of risk.
There are significant differences in the performance of different techniques at different skeletal sites. In addition, the performance depends on the type of fracture that one wishes to predict [bib_ref] Meta-analysis of how well measures of bone mineral density predict occurrence of..., Marshall [/bib_ref] [bib_ref] Bone density at various sites for prediction of hip fractures. The Study..., Cummings [/bib_ref]. For example, BMD assessments by DXA to predict hip fracture are more predictive when measurements are made at the hip rather than at the spine or forearm [fig_ref] Table 3: Age-adjusted increase in risk of fracture [/fig_ref]. For the prediction of hip fracture, the gradient of risk provided by hip BMD is 2.6. In other words, the fracture risk increases 2.6-fold for each SD decrease in hip BMD. Thus, an individual with a Z-score of −3 at the hip would have a 2.6 3 or greater than 15-fold higher risk than an individual of the same age with a Z-score of 0. Where the intention is to predict any osteoporotic fracture, the commonly used techniques are comparable: the risk of fracture increases approximately 1.5-fold for each standard deviation decrease in the measurement. Thus, an individual with a measurement of 3 standard deviations below the average value for age would have a 1.5 3 or greater than 3-fold higher risk than an individual with an average BMD. Note that the risk of fracture in individuals with an average BMD is lower than the average fracture risk, since BMD is normally distributed in the general population, whereas the risk of fracture increases exponentially with decreasing BMD.
The widespread clinical use of DXA, particularly at the proximal femur and lumbar spine (central DXA), arises from many prospective studies that have documented a strong gradient of risk for fracture prediction. For example, a widely cited meta-analysis [bib_ref] Meta-analysis of how well measures of bone mineral density predict occurrence of..., Marshall [/bib_ref] indicated that the risk of hip fracture increased 2.6-fold for each standard deviation decrease in BMD at the femoral neck. The gradient of risk is even higher in women at, or just after the menopause [bib_ref] Predictive value of bone mineral density for hip and other fractures, Johnell [/bib_ref]. These gradients of risk are higher than those derived using many other techniques, and the use of central DXA predicts other types of fracture with as high a gradient of risk as other competing techniques. The vast amount of information available for central DXA has meant that it has now become the reference standard. The adoption of DXA as a reference standard provides a platform on which the performance characteristics of less well established methodologies can be compared.
The performance characteristics of ultrasound are similar. Most studies suggest that measurements of broadband ultrasound attenuation (BUA) or speed of sound (SoS) at the heel are associated with a 1.5-to 2-fold increase in risk for each standard deviation decrease in BMD. Comparative studies indicate that these gradients of risk are very similar to those provided by peripheral assessment of BMD at appendicular sites by absorptiometric techniques to predict any osteoporotic fracture [bib_ref] Meta-analysis of how well measures of bone mineral density predict occurrence of..., Marshall [/bib_ref].
## Diagnostic thresholds
The following four general descriptive categories are given below for adult men and women using measurements of DXA at the femoral neck. 1. Normal: a value for BMD that is higher than 1 standard deviation below the young adult female reference mean (T-score greater than or equal to −1 SD). 2. Low bone mass (osteopenia): a value for BMD more than 1 standard deviation below the young female adult mean, but less than 2.5 SD below this value (T-score <−1 and >−2.5 SD). 3. Osteoporosis: a value for BMD 2.5 SD or more below the young female adult mean (T-score less than or equal to −2.5 SD). 4. Severe osteoporosis (established osteoporosis): a value for BMD 2.5 SD or more below the young female adult mean in the presence of 1 or more fragility fractures.
The recommended reference range is the NHANES III reference database for femoral neck measurements in women aged 20-29 years [bib_ref] Prevalence of low femoral bone density in older US adults from NHANES..., Looker [/bib_ref] [bib_ref] Updated data on proximal femur bone mineral levels of US adults, Looker [/bib_ref] , as previously recommended by the International Osteoporosis Foundation [bib_ref] Glüer CC for the Committee of Scientific Advisors, International Osteoporosis Foundation (2000)..., Kanis [/bib_ref].
These diagnostic criteria for osteoporosis are similar to those previously proposed by the World Health Organization in 1994 [bib_ref] The diagnosis of osteoporosis, Kanis [/bib_ref] , but differ by specifying a reference site (the femoral neck), providing a young normal reference range, and by accommodating diagnostic criteria for men.
The original 1994 WHO criteria provided for diagnosis of osteoporosis at the hip, lumbar spine or forearm. Data arising with the development of new measurement techniques applied to many different skeletal sites indicate that the same T-score derived from different sites and techniques yield quite different information on fracture risk The intersite correlations, though of statistical significance, are inadequate for predictive purposes. These considerations have led to the adoption of a reference site [bib_ref] Glüer CC for the Committee of Scientific Advisors, International Osteoporosis Foundation (2000)..., Kanis [/bib_ref]. This does not preclude the use of other sites and technologies in clinical practice, though it should be recognised that the information derived from the T-score will differ from that provided by BMD at the femoral neck.
Diagnostic thresholds differ from intervention thresholds for several reasons. First, the fracture risk varies markedly in different populations. For example, in women with a T-score of −2.5 SD, the probability of hip fracture is 5 times greater at the age of 80 years than at the age of 50 years. Other factors that determine intervention thresholds include the presence of clinical risk factors, and high indices of bone turnover. Intervention thresholds will also be determined in part by the cost and benefits of treatment.
## Prevalence of osteoporosis
The prevalence of osteoporosis in Sweden using the WHO criteria is shown for Swedish men and women in [fig_ref] Table 4: Prevalence of osteoporosis at the age intervals shown in Sweden using female-derived... [/fig_ref]. Approximately 6% of men and 21% of women aged 50-84 years are classified as having osteoporosis. The prevalence of osteoporosis in men over the age of 50 years is 3 times less frequent than in women-comparable to the difference in lifetime risk of an osteoporotic fracture in men and women.
The prevalence of osteoporosis utilising either the total hip or the femoral neck is rather similar in women, suggesting that this site could eventually supplant the use of femoral neck BMD when adequate meta-analyses have delineated the performance of total hip BMD to estimate fracture risk.
## Measurement of multiple skeletal sites
A number of guidelines favour the concurrent use of BMD at the proximal femur and at the lumbar spine for patient assessment. Patients are defined as having osteoporosis on the basis of the lower of two T-scores. For example, the International Society for Clinical Densitometry recommends that patients who have a BMD test receive scans of both the lumbar spine and hip [bib_ref] International Society for Clinical Densitometry (2006) vertebral fracture risk: results from the..., Binkley [/bib_ref]. Patients are characterised as having osteoporosis where the T-score is −2.5 SD or less at the spine, femoral neck or total hip. The prediction of fracture is, however, not improved by the use of multiple sites . Selection of patients on the basis of a minimum value from 2 or more tests will, however, increase the number of patients selected. The same result can be achieved by less stringent criteria for the definition of osteoporosis, by defining osteoporosis, for example, as a T-score of ≤−2.0 SD rather than ≤−2.5 SD. This would undermine, however, the value of a single diagnostic threshold.
## Osteopenia
It is recommended that diagnostic criteria be reserved for osteoporosis and that osteopenia should not be considered to be a disease category. Provision is still, however, made for the description of osteopenia. This is intended more for descriptive purposes for the epidemiology of osteoporosis rather than as a diagnostic criterion. Also, the identification of osteopenia will capture the majority of individuals who will develop osteoporosis in the next 10 years.
# Limitations
There are a number of limitations in the general application of DXA for diagnosis that should be recognised . The presence of osteomalacia, a complication of poor nutrition in the elderly, will underestimate total bone mass because of decreased mineralisation of bone. Osteoarthrosis or osteoarthritis at the spine or hip are common in the elderly, and contribute to the density measurement, but not necessarily to skeletal strength. Heterogeneity of density due to osteoarthrosis, previous fracture or scoliosis can often be detected on the scan and in some cases excluded from the analysis. Some of these problems can be overcome with adequately trained staff and rigorous quality control. As mentioned, the image is two dimensional and therefore provides an areal BMD rather than a volumetric BMD. The computation of BMD is sensitive to changes in bone size. For example, areal bone density will overestimate volumetric bone density in individuals with large bones. In adults, this error is fortuitously beneficial since larger bones in general have higher strength. Thus, this "error" may improve fracture prediction in adults.
## General management
## Mobility and falls
Immobilisation is a very important cause of bone loss. Immobilised patients may lose as much bone in a week when confined to bed as they would otherwise lose in a year. For this reason immobility should wherever possible be avoided. The amount of weight-bearing exercise that is optimal for skeletal health in patients with osteoporosis is not known, but exercise forms an integral component of management . Physiotherapy is an important component of rehabilitation after fracture. At all times, increased strength may prevent falls by improving confidence and coordination as well as maintaining bone mass by stimulating bone formation and by decreasing bone resorption. Such measures can be coupled with a programme to reduce the likelihood of falls in those at high risk. Risk factors for falling are shown in
## Nutrition
There is a high prevalence of calcium, protein and vitamin D insufficiency in the elderly. Vitamin D supplements can reduce the risk of falling provided the daily dose of vitamin D is greater than 700 IU . Whereas a gradual decline in caloric intake with age can be considered as an appropriate adjustment to the progressive reduction in energy expenditure, the parallel reduction in protein intake may be detrimental for maintaining the integrity and function of several organs or systems, including skeletal muscle and bone. Calcium and vitamin D supplements decrease secondary hyperparathyroidism and reduce the risk of proximal femur fracture, particularly in the elderly living in nursing homes. Intakes of at least 1,000 mg/day of calcium, 800 IU of vitamin D and of 1 g/kg body weight of protein can be recommended in the general management of patients with osteoporosis .
Sufficient protein intakes are necessary to maintain the function of the musculoskeletal system, but they also decrease the complications that occur after an osteoporotic fracture. Correction of poor protein nutrition in patients with a recent hip fracture has been shown to improve the subsequent clinical course by significantly lowering the rate of complications, such as bedsores, severe anaemia, and intercurrent lung or renal infection. The duration of hospital stay of elderly patients with hip fracture can thus be shortened.
[41]. Neurological, heart disorders 7.
History of falls 8. Medication 9.
Cognitive impairment
## Major pharmacological interventions
The most commonly used agents in Europe are raloxifene, the bisphosphonates alendronate, ibandronate and risedronate, agents derived from parathyroid hormone and strontium ranelate. Until recently, hormone replacement treatment was also widely used. They have all been shown to reduce the risk of vertebral fracture. Some have been shown to also reduce the risk of non-vertebral fractures, in some cases specifically fractures at the hip ( showed that raloxifene had no effect on cardiovascular death, and on the incidence of coronary heart disease and stroke, . In summary, the overall risk benefit ratio of raloxifene is favourable and the drug is approved widely for the prevention and treatment of postmenopausal osteoporosis.
## Bisphosphonates
Bisphosphonates are stable analogues of pyrophosphate characterised by a P-C-P bond. A variety of bisphosphonates has been synthesised, the potency of which depends on the length and structure of the side chain. Bisphosphonates have a strong affinity for bone apatite, both in vitro and in vivo, which is the basis for their clinical use. They are potent inhibitors of bone resorption and produce their effect by reducing the recruitment and activity of osteoclasts and increasing their apoptosis. The potency of bisphosphonates in inhibiting bone resorption varies greatly from compound to compound and ranges 10,000-fold in vitro, so that the doses used clinically also vary. The mechanism of action on osteoclasts includes inhibition of the proton vacuolar adenosine triphosphatase (ATPase) and alteration of the cytoskeleton and the ruffled border. Aminobisphosphonates also inhibit several steps of the mevalonate pathway, thereby modifying the isoprenylation of guanosine triphosphate binding proteins. Oral bioavailability of bisphosphonates is low, between 1 and 3% of the dose ingested, and is impaired by food, calcium, iron, coffee, tea and orange juice. Bisphosphonates are quickly cleared from plasma, about 50% being deposited in bone and the remainder excreted in urine. Their half-life in bone is very prolonged.
Alendronate 70 mg once weekly and risedronate 35 mg once weekly are the most commonly used bisphosphonates worldwide. In the FIT study, alendronate was shown to reduce the incidence of vertebral, wrist and hip fractures by approximately half in women with prevalent vertebral fractures [51-53]. In women without prevalent vertebral fractures, there was no significant decrease in clinical fractures in the overall population, but the reduction was significant in the one-third of patients who had a baseline hip BMD T-score lower than −2.5 SD [54]. Risedronate has been shown in women with prevalent vertebral fractures to reduce the incidence of vertebral and non-vertebral fractures by 40-50% and 30-36% respectively . In a large population of elderly women, risedronate decreased significantly the risk of hip fractures (by 30%), an effect that was greater in osteoporotic women aged 70-79 years (−40%), and not significant in women over the age of 80 years without evidence of osteoporosis .
Ibandronate given daily (2.5 mg) reduces the risk of vertebral fractures by 50-60%, whereas an effect on nonvertebral fractures was only demonstrated in a post hoc analysis of women with a baseline of BMD T-score below −3 SD [58, 59]. Bridging studies have shown that oral ibandronate 150 mg once monthly is equivalent or superior to daily ibandronate in increasing BMD and decreasing biochemical markers of bone turnover, giving rise to its approval for the treatment of postmenopausal osteoporosis [bib_ref] Efficacy and tolerability of oncemonthly oral ibandronate in postmenopausal osteoporosis: 2 year..., Reginster [/bib_ref]. Similarly, bridging studies comparing intermittent intravenous ibandronate with daily oral treatment has lead to the approval of intravenous ibandronate (3 mg) every 3 months for the treatment of postmenopausal osteoporosis [bib_ref] Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the..., Delmas [/bib_ref].
Based on the result of a phase II study [bib_ref] Intravenous zoledronic acid in postmenopausal women with low bone mineral density, Reid [/bib_ref] , a large phase III trial has been recently completed in over 7,500 postmenopausal osteoporotic patients assessing the efficacy of yearly infusion of zoledronate 5 mg over 3 years. Compared with the placebo group, zoledronate was found to reduce the incidence of vertebral fractures by 70% and that of hip fractures by 40% [bib_ref] Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis, Black [/bib_ref] , and is now available for the treatment of postmenopausal osteoporosis. Intravenous zoledronate has also been shown to decrease the risk of fracture and attendant mortality when given shortly after a first hip fracture [bib_ref] Zoledronic acid and clinical fractures and mortality after hip fracture, Lyles [/bib_ref].
The overall safety profile of bisphosphonates is favourable. Oral bisphosphonates are associated with mild gastrointestinal disturbances, and some aminobisphosphonates (alendronate and pamidronate) can rarely cause oesophagitis. Intravenous aminobisphosphonates can induce a transient acute phase reaction with fever, bone and muscle pain that ameliorates or disappears after subsequent courses. Osteonecrosis of the jaw has been described in cancer patients receiving high doses of intravenous pamidronate or zoledronate. The incidence in osteoporotic patients treated with oral and intravenous bisphosphonates appears to be extremely low (in the order of 1/100,000 cases), and its causal relationship with bisphosphonate therapy has not been established.
## Peptides of the parathyroid hormone family
The continuous endogenous production of parathyroid hormone (PTH), as seen in primary or secondary hyperparathyroidism, or its exogenous administration, can lead to deleterious consequences for the skeleton, particularly on cortical bone. However, intermittent administration of PTH (e.g. with daily subcutaneous injections) results in an increase in the number and activity of osteoblasts, leading to an increase in bone mass and in an improvement in skeletal architecture at both cancellous and cortical skeletal sites.
The intact molecule (amino acids 1-84) and the 1-34 N-terminal fragment (teriparatide) are used for the management of osteoporosis. Based on their respective molecular weights, the equivalent dose of the teriparatide, relative to the 1-84 molecule is 40% (i.e. 20 and 40 μg of teriparatide are equivalent to 50 and 100 μg of 1-84 PTH respectively).
Treatment with either agent has been shown to reduce significantly the risk of vertebral fractures, whereas teriparatide has been shown to have an effect also on non-vertebral fractures. The recommended doses are respectively 20 μg of teriparatide and 100 μg of PTH (1-84) daily, given as a subcutaneous injection [bib_ref] Effect of parathyroid hormone (1-34) on fractures and bone mineral density in..., Neer [/bib_ref] [bib_ref] Parathyroid hormone (1-84) and treatment of osteoporosis, Shrader [/bib_ref].
Treatment with PTH has been studied when given for 18 to 24 months and beneficial effects on non-vertebral fractures with teriparatide have been shown to persist for up to 30 months after stopping teriparatide. [bib_ref] Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment, Prince [/bib_ref].
The most common reported adverse events in patients treated with PTH or teriparatide are nausea, pain in the limbs, headache and dizziness. In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following the injection of PTH or teriparatide. Serum calcium concentrations reach a maximum between 4 and 6 h and return to baseline 16-24 h after each dose. The change is small and routine monitoring of serum calcium during therapy is not required. PTH and teriparatide may cause small increases in urine calcium excretion, but the incidence of hypercalciuria does not differ from that in placebo-treated patients. However, these agents should be used with caution in patients with active or recent urolithiasis because of their potential to exacerbate the disorder. Isolated episodes of transient orthostatic hypotension are also reported. They typically resolve within minutes to a few hours, and do not preclude continued treatment.
The use of peptides of the PTH family is contra-indicated in conditions characterised by abnormally increased bone turnover (e.g. pre-existing hypercalcaemia, metabolic bone diseases other than primary osteoporosis, including hyperparathyroidism and Paget's disease of the bone, unexplained elevation of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton or in patients with skeletal malignancies or bone metastasis). Severe renal impairment is also a contra-indication. Studies in rats have indicated an increased incidence of osteosarcoma, with longterm administration of very high doses of teriparatide from the time of weaning. These findings appear to have not been considered relevant for patients treated with very much smaller doses of teriparatide.
## Strontium ranelate
Strontium ranelate is a recently registered agent that is marketed for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral and hip fractures. There is some evidence that strontium ranelate both inhibits bone resorption and stimulates bone formation, suggesting that the agent may uncouple the bone remodelling process when used in the treatment of osteoporosis. Studies conducted for up to 5 years have shown the fracture efficacy of strontium ranelate, at spinal and non-vertebral sites, in a wide range of patients, from osteopenia sufferers to women over the age of 80 years, including osteoporotic patients with or without a prior vertebral fracture. Reduction in hip fracture rates has also been shown in women over the age of 74 years with low bone density at the femoral neck. The decrease in fracture rates observed with strontium ranelate is of similar magnitude to that described for oral bisphosphonates [bib_ref] The effects of strontium ranelate on the risk of vertebral fracture in..., Meunier [/bib_ref] [bib_ref] Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with..., Reginster [/bib_ref].
The recommended daily dose is one 2-g sachet once daily by mouth. The absorption of strontium ranelate is reduced by food, milk and its derivative products and the drug should be administered, therefore, between meals. Ideally, it should be taken at bed-time, preferably at least two hours after eating. No dosage adjustment is required in relation to age or in patients with mild to moderate renal impairment (creatinine clearance 30-70 ml/min). Strontium ranelate is not recommended for patients with severe renal impairment (creatinine clearance below 30 ml/min).
Adverse events observed with strontium ranelate are usually mild and transient. The most common adverse events are nausea and diarrhoea, which are generally reported at the beginning of treatment and usually disappear after the third month of treatment).
An increase in the incidence of venous thromboembolism (VTE; relative risk 1.42; CI = 1.02, 1.98) has been reported when pooling all phase III studies in osteoporosis. A causal relationship between VTE and the use of strontium ranelate has not been established and regulatory authorities have not considered a history of VTE as a contra-indication to the use of strontium ranelate. However, strontium ranelate should be used with caution in patients at increased risk of VTE, including those with a past history. When treating patients with an increased risk of developing risk of VTE, particular attention should be given to possible signs and symptoms of VTE and appropriate preventive measures taken.
The effects of the major pharmacological interventions on vertebral and hip fracture risk are summarised in [fig_ref] Table 7: Study details and antifracture efficacy [/fig_ref].
## Combination and sequential treatments
These treatment regimens include the concomitant or sequential use of compounds sharing the same mode of action (e.g. two or more inhibitors of bone resorption) or agents with differing activities (e.g. an inhibitor of resorption plus an anabolic agent). The hope that synergies might be found by combination treatments has not yet been realised.
Most of the current findings suggest that the combination of two inhibitors of bone resorption results in a more pronounced decrease in bone resorption that induces a greater increase in BMD than either agent alone. Whether this results in a better effect on fracture risk has not been adequately addressed. None of the published trials has been designed and powered to detect differences in fracture rates between treatment groups [bib_ref] Is there any interest in combining treatments in osteoporosis?, Rabenda [/bib_ref].
If low doses of hormone replacement treatment (HRT) are used for a limited period of time for the management of climacteric symptoms, concomitant use of bisphosphonates may provide an appropriate reduction in bone turnover that may not be achieved with low doses of HRT alone. The combination of SERMs and bisphosphonates does not appear to be deleterious for bone, but the use of the combination remains questionable in terms of fracture reduction and from a pharmaco-economic perspective.
Patients pre-treated with inhibitors of bone resorption, who have not achieved a full therapeutic response, are good candidates for treatment with anabolic agents. The increase in bone turnover that follows the introduction of teriparatide in patients treated with an anti-resorptive agent is similar to that observed in treatment-naïve patients as is the pattern of response in BMD, with the exception of a 6-month delay in the increase in spinal and hip BMD in patients previously exposed to alendronate [bib_ref] Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate, Ettinger [/bib_ref].
An important question is whether the combination of an anti-resorptive agent and an anabolic drug, such as PTH, would provide a therapeutic advantage by exploiting the different mechanisms of action on bone, and thereby optimise the beneficial effects on fracture. When assigning patients to daily treatment with PTH (1-84, 100 μg/day) alone, alendronate (10 mg/day) alone, or both, volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the PTH alone group was about twice that found in either of the other groups. Thus, there was no evidence of synergy between PTH and alendronate [bib_ref] The effects of parathyroid hormone and alendronate alone or in combination in..., Black [/bib_ref]. The authors considered that the changes in the volumetric density of trabecular bone, the cortical volume at the hip (significantly increased in the PTH group, but not in the other treatment groups) suggest that the concurrent use of alendronate may reduce the anabolic effects of PTH. A similar conclusion was reached in men, in that alendronate impaired the effects of PTH to increase BMD at the lumbar spine and femoral neck. These results suggest that, if therapy with PTH is contemplated, it should be used alone and not with alendronate [bib_ref] The effects of parathyroid hormone, alendronate, or both in men with osteoporosis, Finkelstein [/bib_ref]. Whether this can be extrapolated to other bisphosphonates or other anti-resorptive agents remains unclear. Notwithstanding, some preliminary studies suggest that SERMs (raloxifene) or other bisphosphonates (risedronate) may not reduce the anabolic effects of PTH to the same extent [bib_ref] Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month..., Deal [/bib_ref]. The apparent absence of the synergistic effect of PTH and alendronate should not obscure the potential benefit of using an inhibitor of resorption after treatment with PTH. Indeed, there are data that suggest that the administration of an inhibitor of resorption (bisphosphonate or SERM) after treatment with PTH maintains or even potentiates the skeletal benefit observed during PTH treatment [bib_ref] One year alendronate after one year of parathyroid hormone (1-84) for osteoporosis, Black [/bib_ref].
## Other pharmacological interventions
## Calcitonin
Calcitonin is an endogenous polypeptide hormone that inhibits osteoclastic bone resorption [bib_ref] Effect of calcitonin on bone mass and fracture rates, Reginster [/bib_ref]. Salmon calcitonin is approximately 40-50 times more potent than human calcitonin, and the majority of clinical trials have been performed with salmon calcitonin [bib_ref] Intranasal salcaltonin: a review of its pharmacological properties and role in the..., Plosker [/bib_ref]. For clinical use it can be administered either by injection or nasal application, which provides a biological activity of 25-50% compared with the injectable formulation (200 IU nasal calcitonin would be equivalent to 50 IU of the injectable formulation).
Calcitonin modestly increases BMD at the lumbar spine and forearm [bib_ref] Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis, Cranney [/bib_ref]. Calcitonin likely reduces the risk of vertebral fracture; however, the magnitude of the impact on these fractures remains questionable [bib_ref] A randomized trial of nasal spray salmon calcitonin in postmenopausal women with..., Chesnut [/bib_ref]. An effect on non-vertebral fractures remains equivocal [bib_ref] A randomized trial of nasal spray salmon calcitonin in postmenopausal women with..., Chesnut [/bib_ref] [bib_ref] Evidence for efficacy of drugs affecting bone metabolism in preventing hip fracture, Kanis [/bib_ref]. In addition, calcitonin may have an analgesic effect in women with acute vertebral fracture, which appears to be independent of its effect on osteoclastic resorption [bib_ref] Intranasal salcaltonin: a review of its pharmacological properties and role in the..., Plosker [/bib_ref].
In conclusion, the drawbacks of repeated injections and the high costs of the nasal formulation preclude the longterm use of calcitonin as a first-line treatment of osteoporosis. Analgesic properties may, however, be an interesting option for acute pain following a spinal fracture.
## Hormone replacement therapy
Oestrogens reduce the accelerated bone turnover induced by the menopause, and prevent bone loss at all skeletal sites regardless of age and duration of therapy. Results from observational studies and randomised placebo-controlled trials have shown that oestrogens decrease the risk of vertebral and non-vertebral fractures (including hip fracture) by about 30%, regardless of baseline BMD [42, [bib_ref] Hormone replacement therapy and prevention of non-vertebral fractures: a metaanalysis of randomized..., Torgerson [/bib_ref] [bib_ref] Effects of estrogen plus progestin on risk of fracture and bone mineral..., Cauley [/bib_ref]. When hormone replacement therapy (HRT) is stopped, bone loss resumes at the same rate as after the menopause, but fracture protection may persist arguably for several years [bib_ref] Effect of withdrawal of hormone replacement therapy on bone mass and bone..., Sornay-Rendu [/bib_ref] [bib_ref] Two to three years of hormone replacement treatment in healthy women have..., Bagger [/bib_ref].
The Women's Health Initiative (WHI) suggests, however, that the long-term risks of HRT outweigh the benefits. In this large cohort of postmenopausal women in their 60s, the combined use of conjugated oestrogen and medroxyprogesterone acetate was associated with a 30% increased risk of coronary heart disease (CHD) and breast cancer, and with a 40% increase in stroke [bib_ref] Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal..., Roussow [/bib_ref] [bib_ref] Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's..., Wassertheil-Smoller [/bib_ref] [bib_ref] Influence of estrogen plus progestin on breast cancer and mammography in healthy..., Chlebowski [/bib_ref]. There was also a slight increase in the risk of dementia [bib_ref] Estrogen plus progestin and the incidence of dementia and mild cognitive impairment..., Shumaker [/bib_ref] , and no clinically meaningful effect on health-related quality of life such as sleep disturbance or vasomotor symptoms [bib_ref] Effects of estrogen plus progestin on health-related quality of life, Hays [/bib_ref]. In a subsequent analysis, the increase in breast cancer risk was much less in women not previously exposed to HRT [bib_ref] Influence of estrogen plus progestin on breast cancer and mammography in healthy..., Chlebowski [/bib_ref]. In hysterectomised women receiving conjugated oestrogen alone, there was also a significant increase in stroke, but not in CHD and breast cancer, suggesting a deleterious effect of medroxyprogesterone acetate [bib_ref] Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's..., Anderson [/bib_ref]. Whether the benefits of HRT would outweigh the risks with other oestrogen and progestin and in younger postmenopausal women is debated, but so far there has been no placebo-controlled study showing the long-term safety of such alternatives. In most countries, HRT is only recommended for climacteric symptoms, at a dose as small as possible and for a limited period of time. Thus, HRT is no longer recommended as a first-line treatment for the prevention and treatment of osteoporosis.
## Etidronate
Etidronate is a weak bisphosphonate that has been shown to reduce vertebral fractures over 2 years, but not subsequently, with no significant effect on non-vertebral fractures [bib_ref] Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis:..., Mccloskey [/bib_ref]. Thus, etidronate is not recommended as a first-line therapy for osteoporosis in most European countries.
## Vitamin d derivatives
Alfacalcidol is a synthetic analogue of the vitamin D metabolite calcitriol (1,25-dihydroxyvitamin D 3 ) and it is metabolised to calcitriol by its 25-hydroxylation in the liver. It is somewhat less potent than calcitriol. Both alfacalcidol and calcitriol are used in some countries for the treatment of osteoporosis. Several but not all studies show decreases in vertebral fracture risk [bib_ref] Efficacy of alfacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis..., Richy [/bib_ref] [bib_ref] Vitamin D analogs versus native vitamin D in preventing bone loss and..., Richy [/bib_ref] [bib_ref] Treatment of postmenopausal osteoporosis with calcitriol or calcium, Tilyard [/bib_ref]. The effects on BMD have been less extensively studied.
A few reports have suggested that alfacalcidol and calcitriol exert a direct action on muscle strength and decrease the likelihood of falling in elderly subjects [bib_ref] Age related decrease in creatinine clearance is associated with an increase in..., Gallagher [/bib_ref].
The major problem with the use of the vitamin D derivatives is the risk of hypercalcaemia and hypercalciuria. Adverse effects of prolonged hypercalcaemia include impairment of renal function and nephrocalcinosis. The narrow therapeutic window demands the frequent surveillance of serum and possibly urine calcium in patients exposed to these agents. Calcium supplementation of the diet should be avoided or used with care.
## Clodronate
Clodronate is a relatively weak bisphosphonate, but has been shown to decrease the risk of vertebral and nonvertebral fractures in randomised controlled studies [bib_ref] Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis:..., Mccloskey [/bib_ref] [bib_ref] Clodronate reduces the incidence of fractures in community dwelling elderly women unselected..., Mccloskey [/bib_ref]. It is widely available for the treatment of neoplastic bone disease, but licensed for use in osteoporosis in only a few countries.
## Adherence and monitoring of treatment
Adherence to treatment When discussing adherence there is a need to define the terminology [bib_ref] Adherence to treatment of osteoporosis: a need for study, Lekkerkerker [/bib_ref] , since a wide variety of definitions are used in the literature.
## 1.
Adherence is a general term encompassing the aspects mentioned below. 2. Persistence describes for how long the medication is taken. Persistence could be expressed as number of days until drop-out or the proportion of the cohort still on the medication after a given time since first prescription. Non-persistence is assumed to be the same as discontinuation if a treatment gap is longer than a set number of days. 3. Compliance denotes the proximity to the treatment recommendation as given in the official product information (SPC). It is often simplified to mean the number of doses taken divided by the number of prescribed doses. This simplification does not include some important aspects of compliance, such as taking medication with food (for the oral bisphosphonates), at the correct time of the day, too large doses to compensate for forgotten doses, pill dumping, etc. 4. Primary non-adherence is when the patient is prescribed a drug and then never fills the prescription.
Non-adherence to medical therapy is a widespread public health problem. It is estimated that only half of the patients comply with long-term therapy, of whom a substantial minority do not even redeem their prescription.
Poor adherence to treatment is common in osteopenia and osteoporosis. Overcoming non-adherence presents particular challenges in asymptomatic bone diseases and other chronic, asymptomatic conditions. In such settings, the level of perceived threat to health does not motivate the patient to adhere to therapy. In addition, risk of nonadherence with any therapy increases with increased duration of treatment [bib_ref] Compliance with osteoporosis medications, Solomon [/bib_ref].
Poor adherence to medication is associated with adverse effects on outcomes in osteoporosis or osteopenia, and nonadherent patients have smaller decreases in rates of bone turnover, smaller gains in BMD and a significantly greater risk of fracture [bib_ref] Adherence to anti-osteoporotic treatment: does it really matter?, Reginster [/bib_ref].
Improving adherence to osteoporosis therapy requires effective patient/provider communication and close patient monitoring for the early identification of declining adherence. Patients' belief in a medication contributes to better adherence and can be improved by firmly associating treatment with expected benefits such as reduced risk of fracture and thereby an improved quality of life. Patients may be encouraged to adhere when presented with measurements of biochemical markers of bone turnover or their BMD results together with an explanation of how these measures relate to risk reduction. Another primary component of improving adherence is to use simplified or user-friendly treatment programs [bib_ref] The impact of compliance with osteoporosis therapy on fracture rates in actual..., Caro [/bib_ref].
It should be noted that inadequate adherence can also take the form of improper drug administration, even when doses are not missed. An example is the malabsorption of oral bisphosphonates when taken with food. Such nonadherence poses the potential problems of decreased drug absorption and increased risk of adverse effects [bib_ref] Factors associated with adherence and persistence to bisphosphonate therapy in osteoporosis: a..., Carr [/bib_ref].
## Monitoring of treatment with densitometry
The goal of drug therapy in a patient with osteoporosis is to significantly increase bone strength, in order to decrease the risk of fracture. In untreated men and women, BMD is one of the major determinants of bone strength, and low BMD is an important predictor of fracture. Whether the long-term anti-fracture efficacy of anti-osteoporotic drugs will depend on the extent to which treatment can increase or maintain BMD is controversial. Meta-regressions, based on summary statistics demonstrate a stronger correlation between the change in BMD and fracture risk reduction than results based on the individual patient data [bib_ref] Changes in bone density and turnover explain the reductions in incidence of..., Hochberg [/bib_ref] [bib_ref] Relationship between changes in bone mineral density and fracture risk reduction with..., Delmas [/bib_ref].
Whereas 16% of vertebral fracture risk reduction after treatment with alendronate was attributed to an increase in BMD at the lumbar spine [bib_ref] Improvement in spine bone density and reduction in risk of vertebral fractures..., Cummings [/bib_ref] , larger increases in BMD at both the spine and hip, observed with alendronate were associated with greater reductions in the risk of non-vertebral fractures. However, for patients treated with risedronate or raloxifene, changes in BMD predict even more poorly the degree of reduction in vertebral (raloxifene) or non-vertebral (risedronate) fractures. Twelve percent and 7% of the effects of risedronate to reduce non-vertebral fractures were attributed to changes in the spine and femoral neck BMD respectively [bib_ref] Relationship between changes in BMD and non-vertebral fracture incidence associated with risedronate:..., Watts [/bib_ref]. For raloxifene, the percentage changes in BMD accounted for 4% of the observed vertebral fracture risk reduction [bib_ref] Relationships between bone mineral density and incident vertebral fracture risk with raloxifene..., Sarkar [/bib_ref].
For bone-forming agents, increases in BMD account for approximately one-third of the vertebral fracture risk reduction with teriparatide [bib_ref] Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide..., Chen [/bib_ref]. Preliminary data suggest that a larger proportion (up to 74%) of the anti-fracture efficacy of strontium ranelate might be explained by changes in total hip or femoral neck BMD [bib_ref] Relation between bone mineral density changes and fracture risk reduction in patients..., Bruyère [/bib_ref]. Further data are needed on the role of BMD monitoring patients treated with bone-forming agents, but appears to be of greater value than their use with inhibitors of bone resorption.
## Monitoring of treatment with biochemical markers of bone turnover
Several markers have been developed over the past 20 years that reflect the overall rate of bone formation and/or bone resorption. Most are immunoassays using antibodies that recognise specifically a component of bone matrix (i.e. type I collagen or non-collagenous proteins) that is released in the bloodstream during the process of either osteoblastic bone formation or osteoclastic resorption. Other assays recognise enzymatic activity associated with the osteoblast (bone alkaline phosphatase) or the osteoclast (tartrateresistant acid phosphatase). The most informative ones for the investigation of osteoporosis are osteocalcin and procollagen I N-terminal extension peptide (P1NP) for assessing bone formation, and type I collagenand Ctelopeptide breakdown products (especially serum CTX) to assess bone resorption [bib_ref] The use of biochemical markers of bone turnover in osteoporosis. Committee of..., Delmas [/bib_ref].
Antiresorptive therapies such as calcitonin, oestrogen, SERMs and bisphosphonates induce a significant decrease in bone markers that return to the premenopausal range within 3-6 months for the resorption markers and within 6-9 months for markers of formation. The decrease in markers of bone turnover seen with alendronate or oestrogen is dose-related and correlates with the long-term increase in BMD at the spine and hip [bib_ref] Monitoring of alendronate treatment and prediction of effect on bone mass by..., Ravn [/bib_ref]. More importantly, a significant association has been reported between the short-term decrease and the absolute level of markers of bone turnover with the use of antiresorptive agents (raloxifene and bisphosphonates) on the one hand, and the magnitude of the reduction of the risk of vertebral and non-vertebral fractures on the other hand [bib_ref] Six and twelve month changes in bone turnover are related to reduction..., Bjarnason [/bib_ref] [bib_ref] Relationship of early changes in bone resorption to the reduction in fracture..., Eastell [/bib_ref] [bib_ref] Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated..., Bauer [/bib_ref]. In addition, a large prospective study suggests that the use of markers of bone turnover in the monitoring of bisphosphonate therapy is associated with a greater persistence with therapy than in those not monitored [bib_ref] Effect of monitoring bone turnover markers on persistence with risedronate treatment of..., Delmas [/bib_ref]. Thus, measurement of markers of bone turnover after a few months of treatment may provide useful information on efficacy and improve persistence. During bone-forming therapy with teriparatide, serum P1NP increases 2-to 3-fold within 1-3 months, a change that correlates with the subsequent increase in BMD [bib_ref] Short-term changes in bone turnover markers and bone mineral density response to..., Bauer [/bib_ref] [bib_ref] Early changes in biochemical markers of bone formation predict BMD response to..., Chen [/bib_ref]. There are no data relating changes in bone turnover induced with teriparatide to the subsequent reduction of fracture risk. Changes in markers of bone turnover with strontium ranelate are of small magnitude and are unlikely to be clinically useful for the monitoring of treatment [bib_ref] The effects of strontium ranelate on the risk of vertebral fracture in..., Meunier [/bib_ref].
## Assessment of fracture risk
The increasing prevalence and awareness of osteoporosis, together with the development of treatments of proven efficacy, will increase the demand for the management of patients with osteoporosis. This in turn will require widespread facilities for the assessment of osteoporosis. Measurements of bone mineral are a central component of any provision, since osteoporosis is defined in terms of BMD and micro-architectural deterioration of bone tissue. Presently, there are no satisfactory clinical tools available to assess bone quality independently of bone density, so that for practical purposes, the assessment of osteoporosis depends upon the measurement of skeletal mass, as assessed by measurements of BMD.
The clinical significance of osteoporosis is the fractures that arise with their attendant morbidity and mortality. For this reason attention has focussed on the identification of patients at high risk of fracture rather than the identification of men and women with osteoporosis [bib_ref] A new approach to the development of assessment guidelines for osteoporosis, Kanis [/bib_ref]. Although bone mass is an important component of the risk of fracture, other abnormalities occur in the skeleton that contribute to fragility. In addition, a variety of non-skeletal factors, such as the liability to fall and force of impact, contribute to fracture risk. Since BMD forms but one component of fracture risk, accurate assessment of fracture risk should ideally take into account other readily measured indices of fracture risk that add information to that provided by BMD.
## Bone mineral density
The use of bone mass measurements for prognosis depends upon accuracy. Accuracy in this context is the ability of the measurement to predict fracture. In general, all absorptiometric techniques have high specificity but low sensitivity, which varies with the cut-off chosen to designate high risk. Many cross-sectional prospective population studies indicate that the risk of fracture increases by a factor of 1.5 to 3.0 for each standard deviation decrease in BMD (see [fig_ref] Table 3: Age-adjusted increase in risk of fracture [/fig_ref] [bib_ref] Meta-analysis of how well measures of bone mineral density predict occurrence of..., Marshall [/bib_ref]. The ability of BMD to predict fracture is comparable to the use of blood pressure to predict stroke, and significantly better than serum cholesterol to predict myocardial infarction.
Despite these performance characteristics, it should be recognised that, just because BMD is normal, there is no guarantee that a fracture will not occur-only that the risk is decreased. Conversely, if BMD is within the osteoporotic range, then fractures are more likely, but not invariable. At the age of 50 years, the proportion of women with osteoporosis who will fracture their hip, spine or forearm or proximal humerus in the next 10 years (i.e. positive predictive value) is approximately 45%. The detection rate for these fractures (sensitivity) is, however, low and 96% of fractures at the spine, hip, forearm or proximal humerus would occur in women without osteoporosis [bib_ref] Ten year risk of osteoporotic fracture and the effect of risk factors..., Kanis [/bib_ref]. The low sensitivity is one of the reasons why widespread population-based screening with BMD is not widely recommended in women at the time of the menopause.
## Age
The performance characteristics of the test can, however, be improved by the concurrent consideration of risk factors that operate independently of BMD. Perhaps the best example is age. The same T-score with the same technique at any one site has a different significance at different ages. For any BMD, fracture risk is much higher in the elderly than in the young [bib_ref] Age and bone mass as predictors of fracture in a prospective study, Hui [/bib_ref]. This is because age contributes to risk independently of BMD. At the threshold for osteoporosis (T-score = −2.5 SD), the probability of hip fracture ranges from 1.4 to 10.5% in men and women from Sweden depending on age [bib_ref] Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds, Kanis [/bib_ref]. Thus, the consideration of age and BMD together increases the range of risk that can be identified.
There are, however, a large number of additional risk factors that provide information on fracture risk independently of both age and BMD.
## Other clinical risk factors
A large number of additional risk factors for fracture have been identified [bib_ref] Risk factors for hip fracture in white women, Cummings [/bib_ref] [bib_ref] Assessment of the risk of postmenopausal osteoporosis using clinical risk factors, Ribot [/bib_ref] [bib_ref] Predictors of hip fractures in elderly men, Poor [/bib_ref]. For the purposes of risk assessment, interest lies in those factors that contribute significantly to fracture risk over and above that provided by BMD measurements or age [bib_ref] Diagnosis of osteoporosis and assessment of fracture risk, Kanis [/bib_ref]. A caveat is that some risk factors identify a risk that is not amenable to particular treatments, so that the relationship between absolute probability of fracture and reversible risk is important. Liability to falls is an appropriate example where the risk of fracture is high, but treatment with agents affecting bone metabolism may arguably have little or no effect on risk.
Over the past few years a series of meta-analyses has been undertaken to identify clinical risk factors that could be used in case finding strategies with or without the use of BMD. These are summarised below and their predictive value for hip fracture risk shown in[126].
## Low body mass index (bmi). a low bmi is a
significant risk factor for hip fracture. Thus, the risk is nearly two-fold increased comparing individuals with a BMI of 25 kg/m 2 and 20 kg/m 2 (see. It is important to note that the comparison of 25 versus 30 kg/m 2 is not associated with a halving of risk, i.e. leanness is more of a risk factor rather than obesity being a protective factor. It is also important to note that the value of BMI in predicting fractures is very much diminished when adjusted for BMD [bib_ref] Body mass index as a predictor of fracture risk: a meta-analysis, Laet [/bib_ref]. 2. Many studies indicate that a history of fragility fracture is an important risk factor for further fracture [bib_ref] Predictive value of bone mineral density for hip and other fractures, Johnell [/bib_ref] [bib_ref] Patients with prior fractures have increased risk of future fractures: a summary..., Klotzbuecher [/bib_ref]. Fracture risk is approximately doubled in the presence of a prior fracture. The increase in risk is even more marked for a vertebral fracture following a previous spine fracture. The risks are in part independent of BMD. In general, adjustment for BMD would decrease the relative risk by 10-20% (see [fig_ref] Table 3: Age-adjusted increase in risk of fracture [/fig_ref].
## A family history of fragility fractures is a significant
risk factor that is largely independent of BMD [bib_ref] A family history of fracture and fracture risk: a meta-analysis, Kanis [/bib_ref]. A family history of hip fracture is a stronger risk factor than a family history of other osteoporotic fractures and is independent of BMD. 4. Cigarette smoking is a risk factor that is in part dependent on BMD [bib_ref] Smoking and fracture risk: a meta-analysis, Kanis [/bib_ref]. 5. Glucocorticoids are an important cause of osteoporosis and fractures [bib_ref] The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis, Van Staa [/bib_ref]. The fracture risk conferred by the use of glucocorticoids is, however, not solely dependent upon bone loss and BMD independent risks have been identified [bib_ref] A meta-analysis of prior corticosteroid use and fracture risk, Kanis [/bib_ref]. 6. Alcohol. The relationship between alcohol intake and fracture risk is dose-dependent. Where alcohol intake is on average two units or less daily there is no increase in risk. Indeed, some studies suggest that BMD and fracture risk may be reduced. Intakes of 3 or more units daily are associated with a dose-dependent increase in risk [bib_ref] Alcohol intake as a risk factor for fracture, Kanis [/bib_ref]. 7. Rheumatoid arthritis. There are many secondary causes of osteoporosis associated with an increase in fracture risk (e.g. inflammatory bowel disease, endocrine disorders), but in most instances it is uncertain to what extent the high fracture risk is dependent on low BMD or other risk factors (e.g. the use of glucocorticoids). By contrast, rheumatoid arthritis causes a fracture risk independently of BMD and the use of glucocorticoids [bib_ref] A meta-analysis of prior corticosteroid use and fracture risk, Kanis [/bib_ref].
Biochemical assessment of fracture risk Bone markers are increased after the menopause, and in several studies the rate of bone loss varies according to the marker value [bib_ref] The use of biochemical markers of bone turnover in osteoporosis. Committee of..., Delmas [/bib_ref]. Thus, a potential clinical application of biochemical indices of skeletal metabolism is in assessing fracture risk. Several prospective studies have shown that the serum levels and urinary excretion of markers of bone turnover correlate with subsequent risk of fractures in postmenopausal women [bib_ref] The use of biochemical markers of bone turnover in osteoporosis. Committee of..., Delmas [/bib_ref] [bib_ref] Biochemical indices of bone turnover and the assessment of fracture probability, Johnell [/bib_ref]. Thus, women who have marker values of bone turnover above the premenopausal range (25-40% of postmenopausal women) have been shown in several-but not all-studies to have approximately a two-fold increased risk of vertebral and non-vertebral fractures, including those at the hip, independently of age and of BMD.
## Case-finding
At present there is no universally accepted policy for population screening in Europe to identify patients with osteoporosis or those at high risk of fracture. With the increasing development of effective agents and price reductions, this view may change, particularly in the case of elderly people. In the absence of such policies, patients are identified opportunistically using a case-finding strategy on the finding of a previous fragility fracture or the presence of significant risk factors. The risk factors that are used for clinical assessment are summarised in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref]. Markers of bone turnover are not included since they have not been validated in enough cohorts worldwide to be readily incorporated into the algorithms.
To date, treatment of osteoporosis has largely been directed at women with clinical risk factors determined by a set BMD. The finding that the presence of clinical risk factors and age modulate risk (and therefore cost-effectiveness), reinforces the view that treatment should be directed on the basis of fracture probability, rather than on a single BMD threshold [bib_ref] A new approach to the development of assessment guidelines for osteoporosis, Kanis [/bib_ref] [bib_ref] Diagnosis of osteoporosis and assessment of fracture risk, Kanis [/bib_ref]. The preferred metric is the probability of fracture, but practising physicians are not yet familiar with the assessment of fracture probability, although algorithms will shortly be available to assess these.
A possible algorithm for case-finding is shown in [fig_ref] Figure 3: Management algorithm in postmenopausal women based on an health economic analysis for... [/fig_ref] [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref]. It is based on knowledge of the interactions of the clinical risk factors, age and BMD and is applied to the UK. Its rationale is reviewed later (see Health economics). The management algorithm provides for the treatment of patients with a previous fragility fracture without the need for a BMD test, since a prior fracture is a very strong risk factor that is largely independent of BMD. For the other risk factors treatment can be delivered cost-effectively in women aged 65 years or more, but in women below this age, further stratification of risk is indicated with a BMD test. For women with a parental history of hip fracture, treatment becomes worthwhile with a BMD T-score of −1 SD or less at the femoral neck or total hip. For women taking long-term glucocorticoids, a T-score threshold of −2.0 SD is appropriate, whereas for the weaker risk factors (secondary causes of osteoporosis, current smoking and alcohol consumption of 3 or more units daily), an appropriate threshold would be a T-score of −2.5 SD. The schema illustrates the advantage to patients in not using a single T-score value to judge suitability for treatment as has been widely practised in Europe. Although treatment can be given cost-effectively in many patients without the need for a BMD test, it is a commonly held view that treatment should not be undertaken in women without recourse to a BMD test except in women with prior fragility fractures. The adoption of such a strategy would not adversely affect estimates of cost-effectiveness, since BMD testing was included in all scenarios. Rather, the avoidance of BMD testing would make treatment even more cost-effective.
Whereas this schema can be justified from a health economic perspective in the UK, other factors will determine whether similar thresholds for age and BMD are appropriate for individual countries.
## Comparison of case-finding strategies
The utility of a bone densitometry service has been previously evaluated for the UK following the guidelines of the European Foundation for Osteoporosis (now the International Osteoporosis Foundation). The use of bone densitometry was considered to be justifiable in terms of the cost per averted fracture and more cost-effective than the treatment of patients with risk factors in whom BMD was not known .
The effectiveness of the case-finding strategy previously used in Europe (EUR) proposed in the present guideline (WHO) [bib_ref] Comparison of European and WHO strategies for the identification of women at..., Mccloskey [/bib_ref]. The comparisons were derived from simulations based on the data of ten prospective population-based cohorts with a follow-up of approximately 250,000 person-years. For this comparison, modelled on the UK, the same risk factors and the same number of BMD tests were used in each approach. The EUR strategy selected candidates for BMD tests on the basis of the presence of clinical risk factors and treatment recommended where the T-score for BMD was ≤−2.5 SD.
For the purpose of this study, the risk factors used comprised a prior history of a fragility fracture, a BMI <19 kg/m 2 , a parental history of hip fracture, long-term use of oral glucocorticoids, rheumatoid arthritis, current smoking and an average intake of alcohol of 3 or more units daily as given in the present guidelines. The number of BMD tests modelled for both strategies was determined, therefore, by the age-specific prevalence of the clinical risk factors. Assuming a treatment efficacy of 35%, the numbers of hip fractures avoided by the two strategies are shown in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] [bib_ref] Comparison of European and WHO strategies for the identification of women at..., Mccloskey [/bib_ref].
Compared with the EUR strategy, the WHO approach identifies more patients at high risk of hip fracture and thus makes more effective use of BMD tests. At each age, the cost per averted hip fracture is lower with the WHO approach.
## Integrating risk factors
The use of clinical risk factors in conjunction with BMD and age improves sensitivity of fracture prediction without adverse effects on specificity. The multiplicity of these risk factors poses problems in the units of risk to be used. The T-score becomes of little value in that different T-score thresholds for treatment would be required for each combination of risk factors. Although the use of relative risks is feasible, the metric of risk best suited for clinicians is the absolute risk (or probability) of fracture.
## Fracture probability
The absolute risk of fracture depends upon age and life expectancy as well as the current relative risk. In general, the remaining lifetime risk of fracture decreases with age, especially after the age of 70 years or so since the risk of death with age outstrips the increasing incidence of fracture with age. Estimates of lifetime risk are of value in considering the burden of osteoporosis in the community, and the societal effects of intervention strategies. For several reasons they are less relevant for assessing risk in individuals in whom treatment might be envisaged [bib_ref] Ten year risk of osteoporotic fracture and the effect of risk factors..., Kanis [/bib_ref] ; therefore, the IOF and the WHO recommend that risk of fracture should be expressed as a short-term absolute risk, i.e. probability over a 10-year interval [bib_ref] A new approach to the development of assessment guidelines for osteoporosis, Kanis [/bib_ref]. The period of 10 years covers the likely duration of treatment and the benefits that may continue once treatment is stopped.
The major advantage of using absolute fracture probability is that it standardises the output from the multiple techniques and sites used for assessment and incorporates the additional information derived from age and the clinical risk factors. The estimated probability will of course depend upon the performance characteristics (gradient of risk) provided by any technique at any one site.
The general relationship between relative risk and 10-year probability of hip fracture is shown in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] [bib_ref] Ten year risk of osteoporotic fracture and the effect of risk factors..., Kanis [/bib_ref]. For example, a woman at the age of 60 years has on average a 10-year probability of hip fracture of 2.4%. In the presence of a prior fragility fracture this risk is increased approximately 2-fold and the probability increases to 4.8%. The integration of risk factors is not new and has been successfully applied in the management of coronary heart disease. [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] , categorised for different levels of risk [bib_ref] International variations in hip fracture probability: implications for risk assessment, Kanis [/bib_ref]. Where a country is not represented (because of the lack of epidemiological data) a surrogate should be chosen. Where computer access is limited, paper charts can be downloaded that give fracture probabilities for each index country http://www.shef.ac.uk/FRAX) according to the number of clinical risk factors. An example is given in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] for women aged 60 years in the UK. Thus, a woman from the UK aged 60 years with a body mass index (BMI) of 20 kg/m 2 with a prior forearm fracture and ulcerative colitis (i.e. two clinical risk factors) has a 10-year fracture probability of 15% (9-24%). The range is not a confidence interval, but, because the weight of different risk factors varies, it is a true range.
Measurement of BMD is indicated in individuals who have a high fracture probability, provided that it will influence the management decision. This is preferred to blind treatment, because not all patients with clinical risk factors will have low BMD. In some instances, treatment will be justified without measurement of BMD, for example in patients with fragility fractures and other strong risk factors. In other instances, the low cost and absence of side effects justify the use of some agents without BMD measurements in populations (e.g. calcium with vitamin D in the institutionalised elderly). In other patients, the fracture probability may be so low that a management decision will not be changed by information on BMD. An example is a woman at the time of natural menopause without symptoms and with none of the clinical risk factors. This does not preclude the measurement of BMD in people without risk factors in patients who would take treatment if their BMD were low. The general approach is shown in . The size of the intermediate group in in whom a BMD test would be recommended will vary by region and country. In countries with very limited or no access to central DXA, the size of this segment will be very small. In those countries where screening is recommended (e.g. in women at the age of 65 years or older) this segment will include the majority of women.
The measurement of BMD provides the opportunity to reassess fracture probability in the light of the test result and the clinical risk factors. Probabilities can be computed for the index European countries shown in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref]. Where computer access is limited, FRAX™ charts can be downloaded that give fracture probabilities for each index country according to femoral neck BMD and the number of clinical risk factors. An example is given in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] for women in the UK at the age of 60 years. Such a woman [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] year probability (%) of a major osteoporotic fracture (clinical spine, hip, forearm or humerus fracture) according to body mass index (BMI), the number of clinical risk factors (CRFs) for women aged 60 years in the UK. The range is not a confidence interval but, because the weight of different risk factors varies, it is a true range. (Reprinted from, with permission) with a T-score for femoral neck BMD of −3.0 SD with rheumatoid arthritis and taking oral glucocorticoids (i.e. two clinical risk factors) has a 10-year fracture probability of 25% (19-34%). As before, the range is not a confidence interval, but, because the weight of different risk factors varies, it is a true range. Note that a secondary cause of osteoporosis, with the exception of rheumatoid arthritis, does not add weight to the fracture risk assessment where BMD is known. Thus, a woman from the UK aged 60 years with a T-score for femoral neck BMD of −3.0 SD a prior forearm fracture and ulcerative colitis (i.e. one relevant clinical risk factor) has a 10-year fracture probability of 18% (15-21%). The relationship between fracture probability and intervention thresholds is reviewed later (see Health economics).
# Limitations
The assessment takes no account of dose-responses for several risk factors. For example, two prior fractures carry a much higher risk than a single prior fracture. Dose-responses are also evident for glucocorticoid use. An example is given in [bib_ref] The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis, Van Staa [/bib_ref]. A prior clinical vertebral fracture carries an approximately two-fold higher risk than other prior fractures. Since it is not possible to model all such scenarios with the FRAX™ algorithm, these limitations should temper clinical judgement. A further limitation is that the FRAX™ algorithm uses T-scores for femoral neck BMD. Whereas the performance characteristics of BMD at this site are as good as or better than other sites, the question arises whether T-scores from other sites and technologies can be used. Unfortunately, the T-score and Z-score vary according to the technology used and the site measured. In the case of total hip BMD, however, this can be used interchangeably with femoral neck BMD in women, but not in men. Where the performance characteristics are known (i.e. gradient of risk or risk ratios) probabilities can be determined from tables in development.
## Investigation of patients with osteoporosis
Diagnostic work-up
The same diagnostic approach should be undertaken in all patients with osteoporosis irrespective of the presence or absence of fragility fractures. However, the range of clinical and biological tests will depend on the severity of the disease, the age at presentation and the presence or absence of vertebral fractures. The aims of the clinical history, physical examination and clinical tests are:
1. To exclude a disease that can mimic osteoporosis (e.g. osteomalacia, myelomatosis) 2. To elucidate the causes of osteoporosis and contributory factors 3. To assess the severity of osteoporosis to determine the prognosis of the disease, i.e. the risk of subsequent fractures 4. To select the most appropriate form of treatment [fig_ref] Table 1: Remaining lifetime probability [/fig_ref] year probability (%) of a major osteoporotic fracture (clinical spine, hip, forearm or humerus fracture) according to BMD, the number of clinical risk factors (CRFs) for women aged 60 years in the UK. THE range is not a confidence interval, but, because the weight of different risk factors varies, it is a true range. (Reprinted fromwith permission)
## Number of crfs
BMD T-score (femoral neck) Algorithm for the assessment of fracture probability. (Reprinted from [bib_ref] Prevalence of low femoral bone density in older US adults from NHANES..., Looker [/bib_ref] , with permission)
## To perform baseline measurements for the subsequent monitoring of treatment
The procedures that may be relevant to the investigation of osteoporosis are shown in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref]. These investigations may be used to:
1. Establish the diagnosis of osteoporosis (e.g. DXA or X-rays 2. Establish the cause (e.g. thyroid function tests for hyperthyroidism, and urinary free cortisol for Cushing syndrome) 3. Establish differential diagnosis (e.g. protein electrophoresis for myeloma, and serum calcium and alkaline phosphatase for osteomalacia)
Investigations commonly reserved for specialist centres include measurement of the biochemical indices of bone turnover, serum parathyroid hormone, serum 25-hydroxyvitamin D, serum or urine protein electrophoresis, fasting and 24-h urinary calcium, urinary free cortisol, thyroid function tests and transiliac bone biopsy. Free testosterone, gonadotrophin and prolactin measurements may be of value in men. Assessment is guided by the clinical findings, and some patients who apparently have primary osteoporosis, are subsequently found to have mild hyperparathyroidism or hyperthyroidism, systemic mastocytosis, the late appearance of osteogenesis imperfecta or osteomalacia.
## Differential diagnosis of osteoporosis
Specific underlying causes of bone loss are more commonly found in men than in women. In a high proportion of men presenting with symptomatic vertebral crush fractures an underlying cause of osteoporosis is identified, such as hypogonadism, oral steroid therapy or alcoholism. Casecontrol studies have shown a significantly increased risk of vertebral fractures with smoking, alcohol consumption and alcoholism, oral glucocorticoid therapy, anticonvulsant treatment, hypogonadism and underlying causes of osteoporosis. For hip fractures, the risk factors in men are similar to those found in women.
Osteomalacia and malignancy commonly induce bone loss and fractures. Osteomalacia is characterised by a defect of mineralisation of bone matrix most commonly attributable to impaired intake, production or metabolism of vitamin D. Other causes include impaired phosphate transport or the chronic use of some drugs such as aluminium salts (and other phosphate-binding antacids), high doses of fluoride or etidronate, and the chronic use of anticonvulsants. In most cases, the diagnosis of osteomalacia is suspected by the clinical history and by abnormalities in biochemical tests such as low values of serum and urinary calcium, serum phosphate and 25-hydroxyvitamin D, and high values for alkaline phosphatase and parathyroid hormone. A transiliac bone biopsy after tetracycline labelling may be necessary to demonstrate unequivocally a defect in mineralisation.
Diffuse osteoporosis with or without pathological fracture is common in patients with multiple myeloma, a condition suspected by the severity of bone pain, increased sedimen-
## Health economics
There is an increasing need for management strategies to be placed in an appropriate health economic perspective for guideline development and for reimbursement.
## Types of evaluation
A widely used measure is the "number needed to treat" (NNT) to prevent a fracture. For example, if a treatment reduces the incidence of vertebral fracture from 10% to 5% during the conduct of a trial, then 5 fractures are saved for each 100 patients treated, which gives an NNT of 20. There are several limitations in the use of NNT. First, it does not take into account the cost of intervention. Second, its use is only relevant to one population setting. In the example above, the effectiveness of the intervention is 50%. If the same efficacy is found in other populations but at a different absolute risk, the NNT changes. Thus, if the background fracture risk is, say, 5% and treatment reduces this by half, then the NNT = 40. A further feature of the use of NNT is that it does not take into account the offset of effect of therapeutic intervention.
In the context of treatments, the most straightforward pharmaco-economic evaluation is cost-minimisation analysis. This approach can be used when two strategies or interventions have identical effects, for example where both agents decrease fracture rates by a fixed percentage, and neither has adverse effects. The advantage of one over the other will then relate only to differences in cost. In practice, the benefits and risks of different strategies are rarely equal. Cost-effectiveness analyses take this into account. In this approach, outcomes are converted into a common currency. Examples include the cost per life-year saved, and the cost per fracture averted. A limitation of using these outcomes is that comparisons across diseases are difficult. Difficulties also arise within the same disease area. The cost per fracture averted has, for example, a different significance where the outcome is a hip fracture rather than a forearm fracture.
These considerations have led to the increasing use of costutility analysis as a measure of cost-effectiveness. In the context of evaluating treatments, this takes into account not only fractures avoided, but also any change in morbidity and mortality from both beneficial and unwanted effects. Qualityadjusted life-years (QALYs) are the accepted unit of measurement in health economic assessment of interventions using cost-utility analysis. In order to estimate QALYs, each year of life is valued according to its utility to the patient. Values range from 0, the least desirable health state, to 1, or perfect health. The decrement in utility associated with fractures is the cumulative loss of utility over time. A comparable approach favoured by WHO is the use of disability-adjusted life-years (DALYs). This has been extensively used to characterise the burden of disease worldwide.
## Willingness to pay
There is at present little information as to when treatment can be considered to be cost-effective in the majority of countries. One method of estimating the societal value of a QALY is based on the value of a statistical life. Using this approach, the value of a QALY has been estimated at about SEK 655,000 (about €71,000all currency conversions as of October 2007) in Sweden [bib_ref] Health services need knowledge of how the public values health, Persson [/bib_ref]. Another way of inferring threshold values is based on past reimbursement decisions and guidelines made by national government agencies, such as in the UK (€23,000 -34,000/QALY), Australia (€20,000-36,000/life year gained) and New Zealand (€7,700/QALY) [bib_ref] Use of costeffectiveness analysis in health-care resource allocation decisionmaking: how are cost-effectiveness..., Eichler [/bib_ref]. Other threshold values that can be derived from the literature vary substantially (from €13,000 to €460,000), depending on the country, perspective, outcome measure (e.g. life-year or a QALY) and methodology [bib_ref] Economic evaluation of interventions for osteoporosis, Kanis [/bib_ref]. Yet another approach is to base the threshold value on a measure of a country's economic performance. For example, the WHO Commission on Macroeconomics and Health has suggested that interventions with a cost-effectiveness ratio lower than 3 times the gross domestic product (GDP) per capita for each averted disability-adjusted life-year (DALY) could be considered good value for money in developing countries. Assuming that the value for a DALY and a QALY are reasonably comparable, then a cost-effective threshold for the UK would be €54,000. It is not specified in the report of the WHO Commission what costs should be included, but if all costs are included (all direct and indirect costs regardless of payer), then the threshold value should be set at a lower level when a health-care perspective (only costs related to the health-care sector considered) is taken. Using the 0.6 ratio for adjustment as suggested by Kanis and Jönsson [bib_ref] Economic evaluation of interventions for osteoporosis, Kanis [/bib_ref] , the threshold values would be about €32,000 in the UK, close to the recommendation of the National Institute for Health and Clinical Excellence (NICE), and about €9,000 in Turkey. Although the GDP per capita provides an index of affordability, there is also a marked heterogeneity in the proportion of GDP that countries are willing to devote to health care, and in the proportion of the population at risk of osteoporotic fracture (i.e. elderly people). These factors will also affect what is an acceptable price to pay, which needs to be defined on a country by country basis.
## Studies of intervention
There has been a rapid expansion of research on the costutility of interventions in osteoporosis, which has recently been reviewed [bib_ref] Economic evaluations of interventions for the prevention and treatment of osteoporosis: a..., Fleurence [/bib_ref] [bib_ref] Models for assessing the cost-effectiveness of the treatment and prevention of osteoporosis, Zethraeus [/bib_ref]. Attention was originally focussed on hormone replacement treatment, but is now more commonly directed at bone-specific agents. Despite the use of different models, different settings and payer perspectives, analyses suggest that there are cost-effective scenarios that can be found in the context of the management of osteoporosis for all but the most expensive interventions illustrated below in a UK setting.
The cost-effectiveness of the base case treatment (£350) and efficacy (35% effectiveness) is shown in for different ages and clinical scenarios [bib_ref] Intervention thresholds for osteoporosis in the UK, Kanis [/bib_ref]. As expected, costeffectiveness improved at any age with increasing fracture probability, because of the higher risk of fracture and thus the greater number of fractures avoided.
In women with a prior fragility fracture, and without knowledge of BMD, it was cost-effective to intervene from the age of 65 years. In women at the threshold of osteoporosis (i.e. a T-score at the femoral neck equal to −2.5 SD and no prior fracture), it was cost-effective to intervene from the age of 60 years. In women at the threshold of osteoporosis with a T-score of −2.5 SD, it was cost-effective to intervene if there was a history of a prior fracture, irrespective of age. In women with a T-score of less than −2.5 SD it was, therefore, also cost-effective to intervene, irrespective of the presence or absence of a prior fragility fracture and irrespective of age. These observations illustrate the important effect of combining independent risk indicators.
## A reference model
A reference health economic model is available for the evaluation of intervention in osteoporosis [bib_ref] Jönsson B on behalf of the Committee of Scientific Advisors of the..., Zethraeus [/bib_ref]. The model, constructed in a Swedish setting, can be used for analysing different populations: female or male, high-risk populations, and different ages. The model produces the change in costs and effectiveness (in terms of QALYs) for intervention compared with no intervention. The model uses a societal perspective where direct and indirect costs related to intervention, morbidity and mortality are included. As an option, mortality costs (costs in added life-years) may be excluded. The model also provides an opportunity to incorporate negative (side effects) or positive effects during therapy. An interface version and a description of the model are available on the internet http://www.iofbonehealth.org/ health-professionals/health-economics/cost-effectivenessmodel.html). The model permits the estimation of the costeffectiveness over different ranges for a selected number of parameters (e.g. age, fracture risk, cost of intervention).
There are several reasons why a reference model is needed. First, it may be used as a common reference for the assessment of new therapies. If every new technology is accompanied by a new model it may be difficult to conclude whether the costeffectiveness results are a consequence of the model or of the new technology. Second, new models can be validated against the reference model based on a given set of data. Such a validation provides an opportunity to discuss and compare results and clarify the reasons for discrepancies. Third, it will provide an opportunity to use a well-validated model to investigate the effect of new data for a specific population (country) or for a new technology.
## Intervention thresholds
Intervention thresholds can be defined as the fracture probability at which an intervention becomes acceptable. Decisions about the need for treatment depend not only upon the fracture probability, but also the efficacy, costs and side effects of treatment and the willingness to pay. All these differ between countries, so that intervention threshold will differ accordingly. In Europe, intervention thresholds have been estimated for Austria, Germany, Spain, Sweden and the UK [bib_ref] Intervention thresholds for osteoporosis in the UK, Kanis [/bib_ref] [bib_ref] Intervention thresholds for osteoporosis in men and women: a study based on..., Kanis [/bib_ref] [bib_ref] Intervention thresholds for osteoporosis, Kanis [/bib_ref] [bib_ref] Economic evaluation of osteoporosis prevention, Johannesson [/bib_ref] [bib_ref] At what hip fracture risk is it cost-effective to treat? International intervention..., Borgstrom [/bib_ref] using a cost-effectiveness analysis to determine the hip fracture probability at which intervention with a bisphosphonate becomes cost-effective.
Developments in the ability to assess fracture probability in individuals rather than in populations pose new chal- lenges for the health economic evaluation of interventions.
In addition, the cost of intervention has decreased with the introduction of generic alendronate in some European countries. These developments mean that previous estimates of intervention thresholds based on cost-effectiveness need to be revised using models that integrate the weights of the different clinical risk factors on the risk of fracture and death [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref] [bib_ref] Individual fracture risk and the cost-effectiveness of bisphosphonates in patients using oral..., Van Staa [/bib_ref].
## Setting intervention thresholds
For the purposes of this guidance, the cost-effectiveness of a 5-year treatment with alendronate is compared with no intervention in a UK setting by simulating costs and outcomes in cohorts of women from the age of 50 years with different combinations of clinical risk factors for fracture [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref]. Other interventions were examined in a sensitivity analysis in women aged 70 years at the BMD threshold for osteoporosis, at the BMD threshold for osteoporosis with a prior fragility fracture, and in women with a prior fragility fracture but no BMD test. The relative risks of fracture with treatments were taken from a meta-analysis . In the case of raloxifene, an effect of the agent on breast cancer was also incorporated (RR = 0.38; 95% confidence interval = 0.24-0.58) [bib_ref] Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year..., Cauley [/bib_ref]. For strontium ranelate, an additional scenario was modelled that included a post hoc analysis, accepted by the Committee of Human Medicinal Products of the European Medicines Evaluation Agency, showing a marked effect on hip fracture risk [bib_ref] Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month..., Deal [/bib_ref]. Oral ibandronate was also modelled, based on a study using 2.5 mg daily or an intermittent regimen of 20 mg on alternate days for 12 doses every 3 months [58]. Other assumptions are given elsewhere.
## Thresholds in the uk
The cost-effectiveness of alendronate directed at women at the threshold of osteoporosis is shown in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref]. In women with osteoporosis (i.e. a femoral neck T-score equal to −2.5 SD) the ICER was stable up to the age of 60 years and, thereafter, decreased progressively with increasing age. Treatment was cost-effective from the age of 60 years assuming a willingness to pay of £30,000/QALY. Treatment was also cost-effective at all ages in women who had previously sustained a fragility fracture with a BMD set at the threshold of osteoporosis. A prior fragility fracture was a sufficiently strong risk factor that treatment was costeffective even in women without other risk factors in whom BMD was not known (see [fig_ref] Table 1: Remaining lifetime probability [/fig_ref]. Indeed, treatment was cost saving at the age of 80 years. With a low BMI, treatment was cost saving from the age of 70 years.
The effect of different clinical risk factors at different T-scores for BMD is shown in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref]. Prior fractures and a parental history of hip fracture were the strongest risk factors and treatment was cost-effective across all ages with a T-score of −1.5 SD or less. The use of glucocorticoids had a lesser impact on cost-effectiveness, but across all ages the ICER lay below a £30,000 threshold in women with a T-score of −2.0 SD or below. The presence of rheumatoid arthritis had a lesser impact on cost-effectiveness, but across all ages the ICER lay below a £30,000 threshold of cost-effectiveness with T-scores in the range for osteoporosis. Current smoking and excessive alcohol intake were the weakest of the clinical risk factors and, cost-effectiveness was confined to the lower T-scores and higher ages using a £30,000 threshold.
In women with a prior fracture, treatment was cost-effective at all ages after the age of 50 years, even in the absence of a BMD test [fig_ref] Table 1: Remaining lifetime probability [/fig_ref]. With a parental history of hip fracture, treatment was cost-effective at all ages after the age of 55 years even in the absence of a BMD test. For the other clinical risk factors the ICER lay above the cost-effectiveness threshold at younger ages, but treatment was cost-effective from the age of 65 years with any single risk factor.
These analyses form the basis of the recommendations given for case-finding (see [fig_ref] Figure 3: Management algorithm in postmenopausal women based on an health economic analysis for... [/fig_ref] in that each of the man- In the presence of more than one clinical risk factor the ICER depends on the weight of the clinical risk factor. In the absence of information on BMD, the combination of any two risk factors gives an ICER of less than £30,000 from the age of 65 years. Below the age of 65 years, treatment is costeffective with a T-score of −2.5 SD with the weakest risk factors. With three clinical risk factors, treatment is costeffective at the age of 50 years with a T-score of −2.0 SD and at the age of 60 years with a T-score of −1.5 SD. T-score thresholds would, however, be less stringent in the presence of the stronger risk factors.
## Other treatments
The analysis above focuses on the cost-effectiveness of alendronate (70 mg weekly), but some other interventions compared with no treatment were examined in sensitivity analysis (etidronate, strontium ranelate, raloxifene, ibandronate and risedronate) [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref]. As expected, other treatments were less cost-effective than alendronate [fig_ref] Table 2: Principal causes of death from selected diseases in Swedish men and women... [/fig_ref] , but the ICER fell below a £30,000/QALY threshold for all treatments with the exception of intermittent ibandronate in women with a BMD T-score of −2.5 SD and no prior fracture. As might be expected, raloxifene became less costeffective when the effects on breast cancer were ignored.
Despite differences in apparent cost-effectiveness, there is, however, no proven difference in efficacy among the majority of treatmentsand head-to-head comparisons of interventions with fracture outcomes are not available. For these reasons, the value of an incremental analysis between the individual treatments is questionable, since any resulting hierarchy of treatments is dependent largely on price, but otherwise meaningless in clinical terms. In addition, the large number of untreated patients makes "no treatment" a relevant comparator. Notwithstanding, alendronate can be considered as a first-line intervention. The view arises, not because of apparent differences in efficacy between treatments, but because of cost. The cost-effectiveness of alendronate was greater than that of etidronate, strontium, raloxifene, ibandronate and risedronate in sensitivity analysis. Nevertheless, cost-effective scenarios were found for treatments other than alendronate, providing credible options for patients unable to take alendronate. There are differences, however, in the spectrum of proven efficacy of these alternatives across different fracture sites that will determine their suitability in the clinical management of individuals.
Comparison with the National Institute for Health and Clinical Excellence
The finding of cost-effectiveness for the treatment of osteoporosis is not surprising, given that many treatments in osteoporosis or established osteoporosis, including alendronate, have been shown to be cost-effective in a UK setting [bib_ref] Costeffectiveness of risedronate for the treatment of osteoporosis and prevention of fractures..., Kanis [/bib_ref] [bib_ref] Cost-effectiveness of raloxifene in the UK. An economic evaluation based on the..., Kanis [/bib_ref] [bib_ref] Cost-effectiveness of alendronate in the treatment of postmenopausal women in 9 European..., Strom [/bib_ref] and that the price of alendronate has decreased in most countries in Europe by about one-third of its former price. These findings, however, contrast markedly with those of the National Institute for Health and Clinical Excellence (NICE) , which suggest that the reduction in price, which in the UK had decreased to less than one-third of its former price, had little if any beneficial effect on costeffectiveness. The lack of impact of the price reduction of alendronate on its cost-effectiveness in the technology appraisal of NICE is explained in part by a number of changes in the assumptions contained within the economic model detailed elsewhere [bib_ref] NICE recommendations for the prevention of osteoporotic fractures in postmenopausal women, Delmas [/bib_ref]. A major difference between the majority of studies and that of NICE is that the latter appraisal used a 10-year rather than a life-time horizon, contrary to its own recommendations. It is unusual to provide 10-year time horizons in chronic diseases. The 10-year horizon captures all the costs of treatment (identification of patients and cost of treatment), but loses a component of the benefit. For example, an individual who dies after 9 years is dead for life, and not for 1 year, as would be assumed in the model. Similar considerations pertain to other consequences of fracture. The penalties for ignoring future costs and effectiveness have been previously shown in the context of osteoporosis [bib_ref] The cost-effectiveness of alendronate in the management of osteoporosis, Kanis [/bib_ref] [bib_ref] Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis, Kanis [/bib_ref].
## Comparing osteoporosis with other chronic diseases
Information from the literature on the cost-effectiveness of interventions in different diseases is difficult to compare, because of differences in perspectives, data, and model structure. Ideally, a common modelling framework should be adopted to compare the cost-effectiveness of different interventions within and between disease areas.
The cost-effectiveness has been estimated for a female population aged 50-80 years with osteoporosis, hyperlipidaemia and hypertension alone or in combination with risk factors such as diabetes and smoking using the same model construct set in Sweden [bib_ref] The cost-effectiveness of the treatment of osteoporosis, hypertension and hyperlipidaemia in Sweden, Zethraeus [/bib_ref]. Patient groups were defined by age and risk profile. At each age, four different levels of risk were chosen for each disease. For the osteoporosis group, patients were defined according to the T-score for BMD (T-score −2.5 and −3.0 SD) with or without a history of a previous fragility fracture. In the hypertension group, women were defined according to systolic blood pressure (140 and 160 mm Hg, equivalent to stage I and stage II-IV hypertension), with or without type II diabetes and smoking. In the hyperlipidaemia group, women were categorised according to the serum level of total cholesterol (TC) and high density lipoprotein (HDL) cholesterol in combination with diabetes and smoking as shown in [fig_ref] Table 1: Remaining lifetime probability [/fig_ref].
The treatments comprised alendronate (70 mg weekly), hydrochlorothiazide (25 mg daily), and simvastatin (20 mg daily). These were chosen since they were the cheapest within one class of first-line drugs. Intervention was compared with no intervention. The expected risk reductions were taken from meta-analyses. A 5-year cholesterol lowering and antihypertensive treatment was cost-effective in all the defined patient groups [fig_ref] Table 2: Principal causes of death from selected diseases in Swedish men and women... [/fig_ref] using a value of SEK 600,000 per QALY gained as a threshold for costeffectiveness (approximately 63,000 Euros), derived from the value that the Swedish authorities put on a statistical life. Treatment of osteoporosis was cost-effective in all populations, except for 50-year old women without a previous vertebral fracture, since the average fracture risks are relatively low in this age group. However, in all other cases the cost per QALY gained was below 63,000 Euros.
[fig] Figure 2, Figure 1: Burden of diseases estimated as disability-adjusted life-years (DALYs) lost due to a selection of neoplastic diseases in Europe. (Reprinted from [3Burden of diseases estimated as disability-adjusted life-years (DALYs) lost due to a selection of non-communicable diseases in Europe. (Reprinted from [/fig]
[fig] Figure 3: Management algorithm in postmenopausal women based on an health economic analysis for the UK. (Adapted from [137]) [/fig]
[table] Table 1: Remaining lifetime probability (%) of common osteoporotic fractures in Swedish men and women aged 50 years. (Reprinted from[2], with kind permission from Springer Science + Business Media) [/table]
[table] Table 2: Principal causes of death from selected diseases in Swedish men and women in 1998. (Reprinted from[6], with permission from Elsevier) [/table]
[table] Table 3: Age-adjusted increase in risk of fracture (with 95% confidence interval) in women for every 1 SD decrease in bone mineral density (BMD; by absorptiometry) below the mean value for age. (Amended with permission from the BMJ Publishing Group[14]) [/table]
[table] Table 4: Prevalence of osteoporosis at the age intervals shown in Sweden using female-derived reference ranges at the femoral neck. (Reprinted from[24], with permission from Elsevier) [/table]
[table] Table 5 [: 33]. Modifiable factors such as the correcting decreased visual acuity, reducing consumption of medication that alters alertness and balance, and improvement of the home environment (slippery floors, obstacles, insufficient light-ing, handrails) are important measures aimed at preventing falls. Although large trials have shown that it is possible to reduce falls [34, 35], randomised studies have not shown any significant decrease in fracture risk. Some randomised trials have shown that wearing hip protectors can markedly reduce hip fracture risk, particularly in the elderly living in nursing homes. A recent meta-analysis of well-conducted randomised controlled trials has, however, cast some doubt on the antifracture efficacy of this preventive measure [36-38]. [/table]
[table] Table 6: Antifracture efficacy of the most frequently used treatments for postmenopausal osteoporosis when given with calcium and vitamin D, as [/table]
[table] Table 7: Study details and antifracture efficacy (relative risk [RR] and 95% confidence intervals [CI]) of the major pharmacological treatments used for postmenopausal osteoporosis when given with calcium and vitamin D, as derived from randomised controlled trials [/table]
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Recommendations from workshops of the second international feline coronavirus/feline infectious peritonitis symposium
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Recommendations from workshops of the second international feline coronavirus/feline infectious peritonitis symposium
In August 2002, scientists and veterinarians from all over the world met in Scotland to discuss feline coronavirus (FCoV) and feline infectious peritonitis (FIP). The conference ended with delegates dividing into three workshops to draw up recommendations for FCoV control, diagnosis and treatment and future research. The workshops were chaired by the three authors and the recommendations are presented in this paper.
Due to time limits, the working group decided to concentrate on breeding and rescue catteries rather than veterinary practices, shows or boarding catteries as recommendations for the former would apply to the latter. We are using the generic term 'feline coronavirus' for a common RNA-containing virus in accordance with the guidelines set out in the Fifth International Symposium on Coronaviruses [bib_ref] Advances in experimental medicine and biology: molecular biology and virus-host interactions: coronaviruses, Laude [/bib_ref]. Feline coronavirus (FCoV) is comprised of two closely related biotypes: (1) a ubiquitous form present in virtually all large multi-cat environments which leads to seroconversion and causes very little disease, known as feline enteric coronavirus (FECV) and (2) a much less common mutant form of FECV that has gained the ability to replicate in macrophages, and causes feline infectious peritonitis known as FIP virus (FIPV). Both biotypes exist in at least two strains (types I and II) with large numbers of genetic variants.
FIP is the major consequence of feline coronavirus infection, and because FIPV occurs as a mutant of the common FCoV, control of FIP must be directed first at control of its parent virus, and should that fail, at the FIPV itself.
## Early weaning and isolation
Isolation of queens 2-3 weeks prior to parturition, strict quarantine of queen and kittens, and early weaning at 4-6 weeks of age is one means to prevent FCoV infection. This procedure is based on the findings that some queens do not shed the virus, some queens will stop shedding after several weeks if not re-exposed, and that even if they do shed, very young kittens have maternal resistance to the virus [bib_ref] A study of naturally occurring feline coronavirus infection in kittens, Addie [/bib_ref]. Therefore, if you can prevent outside infection, you should be able to remove the kittens from the queen before they can be infected and then continue to raise them clear of the infection. Early weaning and isolation is not just a good idea for the control of FCoV, but also for the control of feline calicivirus, feline herpesvirus, Bordetella bronchiseptica, Microsporum spp. and the many enteric infections to which kittens are susceptible.
Although straightforward in concept, isolation of queens and early weaning is not as simple as it may seem. The procedure requires quarantine rooms and procedures that absolutely ensure that new virus does not enter. It also works best when the isolated queens are not shedding FCoV, when they are shedding low levels, or when they can clear the infection early after being isolated. The single factor that most assures these conditions is the number of animals. The success of early weaning and isolation in FCoV control depends on effective quarantine and low numbers of cats in the household, preferably under 5 or 6. If there are less than 5 or 6 cats, the chances of there being high or persistent shedders is low. Also, human abodes do not easily allow for adequate quarantine space for large numbers of queens and kittens and the time and money required to maintain quarantine goes up in proportion to the number of queens and litters under quarantine. As examples of environment and cat numbers, all kittens under 8 weeks old submitted to a USA shelter were FCoV negative . These were kittens that largely came from one-queen homes. In contrast, a Swiss study in large catteries demonstrated viral infection of kittens as young as 2 weeks old [bib_ref] Kinetics of FCoV infection in kittens born in catteries of high risk..., Lutz [/bib_ref]. It is clear that low FCoV exposure will delay infection, while high exposure can overcome maternally derived immunity at an early age.
There are two essential downsides of isolation and early weaning. The first is that it is not easy to do and will fail if conditions are not proper. Second, some breeders believe that early weaning exacts a social price on the kittens. In recognition of both concerns, the group recommended that early weaning not be undertaken without careful consideration. FCoV-free households would not be required to undertake routine isolation and early weaning. Where kittens are isolated with their queen, extra care must be taken during the 2-7 weeks-of-age period to socialise the kittens. The success of early weaning should also be measured, and not continued in situations where it is not working. Kittens that have been successfully reared free of the FCoV should be antibody negative at 12 weeks of age. If they are antibody positive, it means that they have been infected with the virus.
Even if kittens can be raised free of FCoV, it is clear that they may become infected sooner or later. The virus is very widespread, even among outdoor cats, and it is easily carried on clothes, hair, hands, shoes, etc. [bib_ref] An enteric coronavirus infection of cats and its relationship to feline infectious..., Pedersen [/bib_ref]. Therefore, the objective of isolation and early weaning should not be to prevent infection forever, but to delay it. It is known that immunity to FIPV does not develop until around 16 weeks of age (based on experience with Primucell ® vaccine (Pfizer) (reviewed by [bib_ref] Recommendations from working groups of the international feline enteric coronavirus and feline..., Pedersen [/bib_ref]. We also have anecdotal evidence that FIPV infection in shelter and cattery kittens occurs in the first 2 months or so of life, even though the actual disease may not appear outwardly for many weeks, months, and sometimes years.
## Measurement of antibody titres and viral load
FCoV serology (also known as FIP serology) can be of some value, but only if it is performed accurately and expressed as an endpoint titre [bib_ref] Kinetics of FCoV infection in kittens born in catteries of high risk..., Lutz [/bib_ref] , For instance cats with very low titres (1:25 or below) are often shedding no or low levels of virus [bib_ref] Use of a reverse-transcriptase polymerase chain reaction for monitoring feline coronavirus shedding..., Addie [/bib_ref] , and will frequently stop shedding when isolated. Cats with high titres (1:400) are almost always shedding high levels of virus. Some of these cats will stop shedding upon isolation, and this will be demonstrated by a decrease in their titre to low or negligible levels. If a cat is persistently shedding virus, the titre will always remain high. If laboratories cannot offer accurate antibody testing, than the alternative is for commercial laboratories to make available quantitative RT-PCR to measure viral load. PCR based tests would be a direct measure of virus shedding. Veterinarians would be supplied with a faecal swab in a tube and a bar code. This would allow for accurate submission of samples.
## Genetic markers in the cat
We know that three groups of FCoV shedders exist:
(1) those that shed high levels of virus all of the time (about 10-15%), (2) those that seem to be immune to the virus and never shed (less than 5%), and (3) those that continuously lose and re-acquire the infection (about 70-80%) [bib_ref] Use of a reverse-transcriptase polymerase chain reaction for monitoring feline coronavirus shedding..., Addie [/bib_ref] [bib_ref] Patterns of feline coronavirus infection and fecal shedding from cats in multiple-cat..., Foley [/bib_ref]. Do high shedders or resistant cats have genetic markers for either state? Susceptibility to FCoV infection is likely to be different to susceptibility to the mutant FIPV. We know that the heritability of FIP is about 50%; susceptible cats being approximately twice as likely to develop FIP as other cats [bib_ref] The inheritance of susceptibility to feline infectious peritonitis in purebred catteries, Foley [/bib_ref]. That is why we do not recommend breeding cats that have thrown kittens that later developed FIP. This would be especially true of toms, which can sire so many more kittens and therefore have a greater genetic influence on the bloodline.
## Genetic markers of the virus
Are some FCoV strains more likely to mutate and thus cause FIP? We see some households without any cat deaths, despite endemic FCoV, while other households suffer many cases of FIP.
## Vaccination
A FCoV vaccine may well be different from an FIPV vaccine, just as immunity to the two biotypes of the virus may differ. However, doubt was expressed about the possibility of ever developing a successful vaccine to the non-mutated form of FCoV (or FECV), because no vaccine can work better than natural infection. Most infected cats develop immunity, but the immunity disappears when the virus is controlled and the cats are then reinfected. Most cats are repeatedly infected with the same strain of FCoV, as well as by different strains [bib_ref] The persistence and transmission of type I feline coronavirus in natural infections, Addie [/bib_ref]. Panleucopenia vaccines work well because most cats in nature recover from the infection. Where hosts do not have good immunity, we often do not have good vaccines, e.g. feline calicivirus.
## Shelters
Forty percent of young cats in the USA are now coming from shelters. Previously people acquired kittens from newspaper advertisements and word of mouth. [bib_ref] Common virus infections in cats, before and after being placed in shelters,..., Pedersen [/bib_ref] found that admission into a rescue cattery resulted in high levels of shedding of feline calicivirus, herpesvirus and coronavirus. All of these viruses can cause long term consequences in an infected cat. Shelters need to optimise facilities and husbandry so they can be cleaned easily and minimise virus spread. It is essential to decrease viral load and stress levels in shelters.
## Recommendations for diagnosing fip (especially with regard to rt-pcr tests) and treatment (paltrinieri) serology and rt-pcr
At the present time, FIP cannot be diagnosed solely by serology or on a positive RT-PCR test. In particular, no specific data regarding the pathogenic role of some mutated genes or proteins, detectable by RT-PCR or serology, have been published in independent peer reviewed scientific journals. The diagnosis of FIP is based on the history of the animal, the history of the disease signs, on gross clinical abnormalities, and a number of suggestive (but not specific) abnormal laboratory findings. Immunohistochemistry to identify viral proteins in macrophages within lesions can be used on tissues taken at biopsy or necropsy. Positive immunohistochemical staining of macrophages within lesions is considered the most definitive test for FIP. However, the possibility of detecting replicating FCoVs within circulating monocytes by RT-PCR was presented at this meeting and looks promising [bib_ref] Detection of replicating Feline Coronavirus in Peripheral Blood Mononuclear Cells as a..., Simons [/bib_ref]. Based on the assumption that only mutated FCoV can replicate within monocytes, this test or other future tests based on biologic behaviour of mutated FCoVs, might have a high diagnostic significance. More detailed descriptions of diagnostic tests are given below.
## Recommended tests for diagnosing fip
The most important tests for FIP are not laboratory, but rather historical. Most cats with FIP are from 6 months to 3 years of age, come from shelters or catteries, and show signs of cyclical antibiotic resistant fevers and specific physical manifestations depending on the form of the disease and location of lesions. A second tier of test findings include characteristic analysis of peritoneal or pleural effusions, elevated white blood cell counts with neutrophilia and lymphopenia, elevated globulin levels, and non-regenerative anaemia of chronic disease and hypoalbuminemia, and elevated fibrinogen. Laboratory tests, such as the serology and RT-PCR should comprise a third tier of diagnostics. Because a wide range of tests is quite expensive, it is prudent to start with basic tests first and add additional procedures only if preliminary testing justifies them. For these reasons we recommend starting with a laboratory approach only when the clinical signs are strongly suggestive of FIP and keeping in mind a list of possible differential diagnoses. This might help to choose the best panel of tests to apply to your case.
## Analysis of the effusion
In the case of suspect effusive FIP, the analysis of the effusions remain the best diagnostic method, although it can be supported by other clinicopathological changes. In particular, protein and globulin determination, cytology and bacterial cultures should be performed. These tests might strongly support the diagnosis of FIP, when high proteins and/or globulin concentrations are found in a sterile effusion with cytologic signs of a nonspecific inflammatory process. In any case, they will rule out septic effusions and neoplasia (mainly lymphomas), but might not be enough to differentiate FIP from, for example, cholangiohepatitis. The detection of FCoVs in the effusion is the only conclusive test in these cases. To do this, immunocytologic techniques (immunofluorescence, immunohistochemistry) are preferable to the detection of FCoV genome by RT-PCR: although RT-PCR might easily detect FCoV in the effusions, as previously stated, it is a very sensitive technique and can detect any small amount of virus that might extravasate from blood to the effusion during every inflammatory process in cats with circulating FCoVs. In contrast, immunocytology detects only large amounts of virus and, moreover, allows identification of macrophages as the cells carrying the FCoVs. A positive result using these techniques can thus confirm the diagnosis of FIP, while an eventual negative result does not exclude the disease . In these cases, as in dry forms, the detection of other clinico-pathological changes is needed to support the clinical diagnosis of FIP.
## Non-effusive fip
In dry forms, a list of possible differential diagnoses must also be considered to suggest the best diagnostic approach. It is not possible in this report, to list all possible differential diagnoses, due to the extreme variability in clinical signs detectable in dry forms. This list, however, should include any possible cause of fever of unknown origin (FUO), uveitis, neurological alterations, hepatic or renal failure. The panel of tests to be used should be decided based on these symptoms and should always include a complete CBC (non-regenerative anaemia, neutrophilic leukocytosis and in particular, lymphopenia might have a high diagnostic value for FIP), the determination of the albumin/globulin ratio, eventually followed by a serum protein electrophoresis in the case of high globulins ( 2 and -globulins are expected to be elevated during FIP), and the measurement of 1 -acid glycoprotein levels (high concentrations of this protein, although not specific, might be strongly suggestive of FIP; [bib_ref] Value of 1-acid glycoprotein in the diagnosis of feline infectious peritonitis, Duthie [/bib_ref]. Although none of the above mentioned changes is per se suggestive of FIP, the presence of multiple alterations in cats with symptoms suggestive of FIP might highly increase the probability of correctly diagnosing the disease. Other tests might also be considered: in pure neurologic forms, for example, diagnostic imaging can exclude the presence of intracranial tumours, and antibody titre in CSF can be evaluated and compared to those in blood; a high CSF/blood ratio might be detected during FIP, based on the assumption that antibodies are produced within the CNS but the results of this test must be carefully considered, since alterations of the blood-brain barrier (BBB) are often present during FIP. The presence of a BBB damage can be excluded by measuring the serum:CSF ratio of antibodies against other infectious agents (e.g. herpesviruses). The cost/benefit ratio of such a complicated panel of tests, however, strongly reduces its practical use. The detection of histologic lesions consistent with FIP has been considered the only conclusive test for FIP for a long time [bib_ref] Cats and coronaviruses, Barlough [/bib_ref] and the finding of viral antigen in the lesions using immunofluorescence or immunohistochemistry (again, RT-PCR, is too sensitive) allows further confirmation of the diagnosis. Unfortunately, surgical biopsies cannot be taken frequently during FIP, due to the poor general conditions of the affected cats. The probability of detecting histologic lesions or positive macrophages in ultrasound-guided tru-cut biopsies (TCB) or in fine needle aspiration biopsies (FNA) is very low and negatively correlated with the extension of the pyogranulomatous foci (Paltrinieri, manuscript in preparation). Based on the general health status, the clinician should then decide among the following three diagnostic approaches: expose the cat to the risk of anaesthesia and laparoscopy/ laparotomy to obtain surgical biopsies and gather a conclusive diagnosis of FIP; perform a non-invasive bioptic technique (TCB, FNA) with the possibility of a false negative result; obtain only a presumptive diagnosis based on clinico-pathological changes. A presumptive diagnosis, however, would be not enough to subject the cat to any treatment.
In conclusion, the only conclusive diagnosis of FIP must be obtained by the detection of FCoVs within macrophages in the effusions or within the lesions detected in surgical biopsies. If such an approach cannot be followed, the presence of multiple clinico-pathological changes might support the clinical diagnosis of FIP in both wet and dry forms. Serology and RT-PCR are much more useful in the cattery management than in the diagnosis of the disease.
## Recommendations on treatment of fip
No therapies have been proved to be effective for FIP, and the use of alternative treatments and so-called immunosuppressive or immunomodulating drugs should be suspect. Although encouraging results obtained using feline recombinant feline interferon have been presented at this meeting [bib_ref] Use of recombinant feline interferon and glucocorticoid in the treatment of feline..., Ishida [/bib_ref] further data are needed before recommendation of extensive use of this treatment. The best treatment at the present time is to stage the disease and treat symptomatically. As long as the cat is eating, feeling relatively well, and not losing weight, affected animals should be fed a high quality diet and kept as stress free as possible. In contrast, if the cat is losing condition, is suffering from specific debilitating signs of the disease, and has a poor quality of life, treatment should be counselled against. Severely affected animals should then be euthanased, due to short survival expectation. Even in cats with mild initial disease signs, the ultimate mortality is over 95%. However, miracle cures do happen from time to time, and miracles cannot happen unless they are allowed time to happen.
## Recommendations for priority areas of future fcov research (addie)
1. In the absence of an effective vaccine, it was considered a priority to prevent cats becoming infected with FCoV at all. It was considered important to look at ways of minimising virus dose. Existing cat litters need to be checked for their ability to limit FCoV transmission by biocidal action and/or good clumping. The effect of flushing litter trays on FCoV spread needs to be investigated. 2. The ideal vaccine should protect against FIP, give good mucosal immunity to prevent infection and reduce virus shedding. Development of a therapeutic vaccine should also be considered, both to treat cats with FIP and to attempt to stop carrier cats from shedding. For the latter, it is essential to establish where the virus is in carrier cats (the ileum and colon are the most likely areas) so that immune clearance of virus from this area is taken into consideration in vaccine development. 3. The group was concerned about antibody dependent enhancement (ADE) being a laboratory artefact [bib_ref] Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses, Vennema [/bib_ref]. Studies have shown that 40% or more of cats with FIP shed FCoV from their gut, but that the virus is of the intestinal type and will not cause FIP when given to susceptible kittens . In contrast, virus taken from internal lesions readily induces FIP. The FIP causing virus is only present within macrophages in internal lesions, where it has no access to the outside. However, some investigators have seen 'outbreaks' of FIP, which can best be explained by an FIPV carrier. Although there are alternative explanations for such mini-epidemics, it is theoretically possible for cats with lesions in their kidneys or intestinal wall to shed FIPV in urine or feces. 5. More molecular work needs to be undertaken on the exact mutations that cause FCoVs to become FIPVs and how these mutations change the behavior of the virus:
- to establish whether all FIPVs have 3c deletions - to define the functions of non-structural proteins 3a, b, c and 7a and b - to do a worldwide phylogenetic study so that future vaccines will cover as many natural FCoV strains as possible.
6. More work needs to be undertaken to grow the type I FCoV in cell culture. Different cell lines should be tried, and if that fails, the type I receptor needs to be found and cloned into a cell line. 7. More work is required to understand exactly what FIPV does in the infected macrophage. In addition, the cytokine profiles of naturally infected cats needs to be determined. 8. The phenomenon of resistant cats requires further investigation. Might it be possible to breed cats resistant to FCoV infection? Could resistant cats simply have been exposed very early in life (e.g. in the first week) and therefore have become immune tolerant? 9. Since the research community in FCoV is small, it is important that we exchange ideas more often and work together. An email newslist will be established and the www.felinecoronavirus. com website will continue as a place where researchers can list available reagents.
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Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT
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Metabolic syndrome and cardiovascular disease following hematopoietic cell transplantation: screening and preventive practice recommendations from CIBMTR and EBMT
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% amongst HCT recipients. While MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors. DeFilipp et al.
# Introduction
Advances in hematopoietic cell transplantation (HCT) and supportive care have led to substantial improvements in transplant outcomes and an increased number of long-term HCT survivors [bib_ref] Prevalence of hematopoietic cell transplant survivors in the United States, Majhail [/bib_ref]. Transplant survivors are at considerable risk for developing significant late effects and experience mortality rates higher than the general population [bib_ref] Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term..., Bhatia [/bib_ref] [bib_ref] Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone..., Bhatia [/bib_ref]. One challenge faced in the post-HCT setting is the development of metabolic syndrome (MetS), with reported prevalence rates of 31-49% [bib_ref] High prevalence of metabolic syndrome after allogeneic hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] Prevalence of metabolic syndrome in long-term survivors of hematopoietic stem cell transplantation, Annaloro [/bib_ref] [bib_ref] Metabolic syndrome appears early after hematopoietic cell transplantation, Mcmillen [/bib_ref] [bib_ref] Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute..., Oudin [/bib_ref]. HCT recipients are predisposed to develop MetS through several mechanisms, including conditioning regimen-mediated damage to the neurohormonal system and vascular endothelium, as well as the immunological and inflammatory effects of allografting (including subsequent graft-versus-host disease (GVHD) and its therapy) [bib_ref] High prevalence of metabolic syndrome after allogeneic hematopoietic cell transplantation, Majhail [/bib_ref]. Individuals in the general population with MetS are twice as likely to develop cardiovascular disease than those without MetS [bib_ref] Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart,..., Grundy [/bib_ref]. A better understanding of MetS following HCT may prove to be significant, as HCT survivors are known to be at increased risk for cardiovascular morbidity and mortality. In the Bone Marrow Transplant Survivor Study (BMTSS), the risk of premature cardiovascular-related death following HCT was found to be increased 2.3-fold compared to the general population [bib_ref] Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term..., Bhatia [/bib_ref] [bib_ref] Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone..., Bhatia [/bib_ref]. Similarly, others have reported the risk of cardiovascular hospitalizations and mortality to be increased by 3.6-fold in HCT recipients compared to the general popuation [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref].
Intensive chemotherapy and radiation have been associated with MetS and contribute to the development of this syndrome post-HCT, especially in heavily pre-treated populations [bib_ref] Prevalence and risk factors of the metabolic syndrome in adult survivors of..., Oudin [/bib_ref] [bib_ref] Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute..., Gurney [/bib_ref]. has not yet been proven to impact cardiovascular risk after HCT. However, an understanding of the incidence and risk factors for MetS and cardiovascular disease following HCT provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. Therefore, a collaboration was established between the Center for International Blood and Marrow Transplant Research (CIBMTR) Late Effects and Quality of Life Working Committee and the European Group for Blood and Marrow Transplantation (EBMT) Complications and Quality of Life Working Party with the goal to review literature, including previously published guidelines for screening and preventive practices for HCT survivors [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation:..., Rizzo [/bib_ref] [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. We subsequently provide specific screening and preventive practice recommendations for MetS and cardiovascular disease appropriate to HCT recipients based on published evidence and expert opinion.
## Metabolic syndrome
MetS is a cluster of interrelated factors that increases the risk of cardiovascular disease, diabetes mellitus (DM), and all cause mortality . The International Diabetes Foundation (IDF) estimates that 25% of the world's adult population has MetS . The four core clinical measures are increased body weight/visceral adiposity, elevated lipids, raised blood pressure (BP), and hyperglycemia/insulin resistance (IR) . The individual diagnostic criteria of MetS have varied over time according to the different definitions applied. The diagnostic criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) [bib_ref] Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart,..., Grundy [/bib_ref] , the IDF and the American Heart Association (AHA) and the World Health Organization (WHO) are shown in . A comparison of various definitions in terms of their predictive value established that the prevalence of MetS was significantly greater when using the criteria of the AHA and IDF compared with the NCEP ATPIII definition . However, the risks of cardiovascular events and death were markedly greater for participants who satisfied any of the criteria for diagnosis of MetS compared with healthy individuals. This supports other reports that found agreement between MetS components and cardiovascular risk factors in the general population [24, 25].
## Abdominal obesity
Obesity, defined as a body mass index (BMI) ≥30 kg/m 2 , affects 35% of adults in the United States [26] and 10-30% of adults in Europe . Obese persons have a higher risk of developing serious medical conditions, including hypertension (HTN), dyslipidemia, type 2 DM, coronary heart disease (CHD), and ischemic stroke, and have a higher mortality than the non-obese population . However, BMI is an insufficient measure of abdominal obesity. Waist circumference, which emphasizes visceral adipose deposits, is preferentially used in the evaluation of abdominal obesity when defining MetS (see as this distribution of fat accumulation independently confers cardiometabolic risk . Yet, as studies reporting waist circumference at the time of and following HCT are limited, BMI may act as a possible surrogate.
BMI ≥35 kg/m 2 (severely obese) is part of the HCT-specific Comorbidity Index since 2005, as this was determined to be a risk factor for increased non-relapse mortality (NRM) [bib_ref] Impact of pretransplant body mass index on the clinical outcome after allogeneic..., Fuji [/bib_ref]. While pre-transplant obesity can influence body composition following HCT, changes in waist circumference can be seen independent of pre-existing obesity. Despite what may be a normal BMI, HCT survivors are at an increased risk to develop sarcopenic obesity (increase in percent fat mass, decrease in lean body mass), which can significantly contribute to IR [bib_ref] Metabolic syndrome and cardiovascular risk in survivors after hematopoietic cell transplantation, Baker [/bib_ref] [bib_ref] Sarcopenia: characteristics, mechanisms and functional significance, Narici [/bib_ref]. A longitudinal study using dual X-ray absorptiometry (DXA) to calculate body fat mass index (BFMI) in 82 patients found the prevalence of a high BFMI was greater at 2-3 years following allo-HCT than in healthy controls [bib_ref] Longitudinal follow-up of body composition in hematopoietic stem cell transplant patients, Kyle [/bib_ref]. Corticosteroids, which remain the first line treatment of GVHD, contribute to sarcopenic obesity by promoting muscle atrophy and may contribute to obesity in the early post-HCT period [bib_ref] Metabolic syndrome in hematologic malignancies survivors: a meta-analysis, Li [/bib_ref]. Robust data on the changes in abdominal obesity following autologous HCT (auto-HCT) are lacking. One study evaluated metabolic and body composition changes in 32 patients with multiple myeloma who had received three lines of intensive treatment, including at least one HCT. At a median duration of 6 years from diagnosis, DXA identified sarcopenic obesity in 65% of patients [bib_ref] Endocrine, metabolic, nutritional and body composition abnormalities are common in advanced intensively-treated..., Greenfield [/bib_ref]. Importantly, the development of sarcopenic obesity following HCT has yet to be independently associated with increased cardiovascular mortality. In the pediatric population, a cross-sectional study evaluating 54 allo-HCT survivors and 894 healthy participants found a deficiency in lean mass (as identified by DXA) as compared to fat mass in HCT survivors [bib_ref] Body composition abnormalities in long-term survivors of pediatric hematopoietic stem cell transplantation, Mostoufi-Moab [/bib_ref]. A prospective, descriptive, cross-sectional study evaluating children and adolescents for the development of MetS post-HCT found that 73% of individuals with this diagnosis had a characteristic of abdominal obesity (abdominal circumference >75 th percentile by age and gender).
## Screening and preventive recommendations
The United States Preventive Services Task Force (USPSTF) and the National Heart, Lung, Blood Institute (NHLBI) recommend screening for obesity in all adults and children >2 years of age, though no recommendation is made regarding appropriate intervals for screening. Current guidelines for HCT recipients do not provide specific screening recommendations for abdominal obesity, though education and counseling regarding regular exercise, healthy weight, and dietary counseling are encouraged [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. Given the increase in abdominal obesity that can occur after HCT, clinicians should consider monitoring body composition at each visit, with regular measurement of height, weight, and waist circumference (at least yearly). Based on what is known in other populations, we recommend that patients with a BMI ≥30 kg/m 2 , waist circumference >102 cm (>40 inches) in men or >88 cm (>35 inches) in women, or significant increases in either of these measurements should be considered for intensive, multicomponent behavioral interventions. DXA may be used to assist evaluation and monitoring of changes in body composition in survivors of HCT.
## Dyslipidemia
Dyslipidemia, defined as elevated levels of total cholesterol, low-density lipoprotein (LDL) cholesterol or triglycerides, or low levels of high-density lipoprotein (HDL) cholesterol, is an important risk factor for CHD and ischemic stroke [bib_ref] Hypertriglyceridemia and its pharmacologic treatment among US adults--invited commentary, Thompson [/bib_ref]. The prevalence of dyslipidemia is high in the general population: in 2000, approximately 25% of adults in the United States had total cholesterol greater than ≥240 mg/dL (≥6.2 mmol/L) or were taking lipid-lowering medication [bib_ref] Primary prevention of CVD: treating dyslipidaemia, Fodor [/bib_ref]. A high prevalence of dyslipidemia has also been reported in European countries. Of the various dyslipidemias, low HDL (<40-50 mg/dL, <1.0-1.3 mmol/L) and hypertriglyceridemia (>150 mg/dL, >1.7 mmol/L) have been incorporated into the diagnostic criteria of MetS (see .
Survivors of allo-HCT are at an increased risk of post-transplant dyslipidemia. In a retrospective cohort study comparing incidence and risk factors for cardiovascular events, allo-HCT recipients had significantly higher risk of new-onset dyslipidemia (RR: 2.31; 95% CI, 1.15 to 4.65) compared to auto-HCT recipients [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref]. Single institution studies have estimated the incidence of hypercholesterolemia and/or hypertriglyceridemia following allo-HCT to be 43-73% [bib_ref] Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on..., Kagoya [/bib_ref] [bib_ref] Hyperlipidemia and statin use after allogeneic hematopoietic stem cell transplantation, Blaser [/bib_ref]. The onset of dyslipidemia post-HCT can be rapid, with the median interval to development of hypertriglyceridemia and hypercholesterolemia being 8 and 11 months following allo-HCT, respectively, in one single center experience [bib_ref] Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on..., Kagoya [/bib_ref]. Factors predicting development of post-HCT dyslipidemia include family history of hyperlipidemia, obesity, high-dose total body irradiation (TBI), grade II-IV acute GVHD, chronic GVHD, and chronic liver disease [bib_ref] Metabolic syndrome in adults who received hematopoietic stem cell transplantation for acute..., Oudin [/bib_ref] [bib_ref] Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on..., Kagoya [/bib_ref] [bib_ref] Hyperlipidemia and statin use after allogeneic hematopoietic stem cell transplantation, Blaser [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref]. In addition, immunosuppressant medications (e.g., sirolimus, calcineurin inhibitors, corticosteroids) not only increase lipid levels but also lead to significant drug-drug interactions with 3-hydroxy-3-methyl-gutaryl (HMG)-CoA reductase inhibitors (statins) via the cytochrome p450 pathway [bib_ref] Dyslipidemia after allogeneic hematopoietic stem cell transplantation: evaluation and management, Griffith [/bib_ref] [bib_ref] Treatment of dyslipidemia in allogeneic hematopoietic stem cell transplant patients, Marini [/bib_ref]. Data regarding the incidence of dyslipidemia following auto-HCT are limited. In a single center analysis evaluating late post-HCT cardiovascular complications in 1379 patients, which included both auto-and allo-HCT recipients, 1-year post-HCT dyslipidemia requiring treatment was associated with an increased risk for stroke (HR 7.4; 95% CI, 1.2-47) [bib_ref] Late cardiovascular complications after hematopoietic cell transplantation, Chow [/bib_ref]. In the pediatric population, the risk of hypercholesterolemia is high in childhood cancer survivors who underwent auto-HCT (HR = 3.2; CI 1.7-5.9) [bib_ref] Prevalence of cardiovascular risk factors in long-term survivors of childhood cancer: 16..., Felicetti [/bib_ref].
## Screening and preventive recommendations
The USPSTF strongly recommends screening for lipid disorders every 5 years in men ≥35 years, women ≥45 years, and persons ≥20 years at increased risk for CHD, while the NHLBI recommends screening in children between the ages of 9-11 years or earlier in those with family history. Current guidelines for HCT recipients recommend similar screening practice for dyslipidemia amongst the general population [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. We recommend standard-risk patients (including auto-HCT recipients without personal risk factors) should follow these guidelines. However, early onset of dyslipidemia following allo-HCT is not uncommon, especially in high-risk patients. Thus, we propose early assessment of exposures and risk factors in all HCT patients. For recipients of allo-HCT, we suggest an initial lipid profile 3 months after HCT. For high-risk patients with ongoing risk factors (including those on sirolimus, calcineurin inhibitors, corticosteroids), we suggest repeat evaluation every 3-6 months. In recipients without ongoing risk factors, we suggest repeat evaluation according recommendations for the general population. Non-pharmacologic management of dyslipidemia primarily involves lifestyle modifications such as diet (low saturated fat and low cholesterol), exercise (or other regular physical activities), weight reduction, smoking cessation, and limiting alcohol intake. Although not validated amongst HCT survivors, we recommend use of the Framingham risk score (http://cvdrisk.nhlbi.nih.gov) to assess cardiovascular risk and guide therapy decisions. The safety of lipid-lowering agents must be considered in the pediatric population, as the AHA recommends considering drug therapy for high-risk lipid abnormalities in boys ≥10 years of age and after onset of menses in girls, preferably after a 6 to 12 month trial of saturated fat-and cholesterol-restricted dietary management [bib_ref] Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific..., Mccrindle [/bib_ref].
## Hypertension
HTN, defined as a systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, is a worldwide epidemic affecting approximately ~25% of adults [bib_ref] Global burden of hypertension: analysis of worldwide data, Kearney [/bib_ref]. Of note, the blood pressure criteria used in most definitions of MetS is systolic BP ≥135 mmHg or diastolic BP ≥85 mmHg (or drug treatment for HTN) (see , which is classified as pre-hypertension according to the report from the Eighth Joint National Committee (JNC 8) [bib_ref] evidence-based guideline for the management of high blood pressure in adults: report..., James [/bib_ref].
An analysis of the BMTSS showed that after adjustment for age, sex, race, and BMI, allo-HCT recipient were 2.06 times (95% CI, 1.39-3.04) more likely to report HTN as compared to sibling donors or auto-HCT recipients, who had a similar risk (OR, 0.96; 95% CI, 0.65-1.44) [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. Similarly, a retrospective, single-institution evaluation of 265 long-term transplant survivors reported that allo-HCT recipients have an increased risk of HTN (RR: 2.50; 95% CI, 1.19 to 5.27) compared to auto-HCT patients [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref]. A direct cause and effect relationship of conditioning regimen, acute or chronic GVHD and HTN was not established [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. Two large retrospective studies did not show a significant difference in the incidence of HTN in allo-HCT recipients with or without GVHD [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref] [bib_ref] Male survivors of allogeneic hematopoietic stem cell transplantation have a long term..., Pophali [/bib_ref]. It appears that HTN is related to use of certain GVHD therapies (e.g., calcineurin inhibitors, steroids) rather than GVHD induced pro-inflammatory cytokine response and endothelial damage. Although pediatric patients are less likely than adults to have pre-transplant HTN as well as any risk factors for HTN, an analysis of 1-year survivors of allo-HCT found a similar incidence of post-HCT HTN in adult (68%) and pediatric (73%) HCT survivors [bib_ref] Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic..., Majhail [/bib_ref]. In multivariate analyses, exposure to cyclosporine increased the risk of HTN post-HCT (RR: 1.6; 95% CI, 1.1-2.5), but only within the first 2 years, suggesting this may revert once medications are stopped.
## Screening and preventive recommendations
The USPSTF recommends BP assessment every 3 to 5 years in adults aged 18-39 years with normal BP (<130/85 mm Hg) who do not have other risk factors and annually in adults aged ≥40 years and for those who are at increased risk for high BP. In children, the NHLBI recommends BP assessment yearly after the age of 3 years, interpreted for age, sex, and height. Current guidelines for HCT recipients recommend at least annual BP assessment in children and BP assessment every other year in adults [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref]. We recommend BP assessment for HCT recipients at every clinic visit (at least yearly). The JNC 8 report recommends initiating pharmacologic treatment for BP of ≥150/≥90 mmHg in persons ≥60 years of age (to a BP goal of <150/<90 mmHg) and for BP of ≥140/≥90 in persons 30-59 years of age (to a BP goal of <140/<90) [bib_ref] evidence-based guideline for the management of high blood pressure in adults: report..., James [/bib_ref]. In the absence of HCT-specific evidence, these goals can be used to guide management of HCT recipients, but other factors such as end organ compromise (cardiac or renal failure) and therapy with calcineurin inhibitors also need to be taken into account.
## Insulin resistance/diabetes mellitus
DM, which affects almost 10% of the adult population worldwide, is characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of DM is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. The American Diabetes Association (ADA) defines DM as a fasting plasma glucose ≥126 mg/dl (≥7 mmol/L), a hemoglobin A1C (HbA1C) ≥6.5%, a 2-hour plasma glucose ≥200 mg/dl (≥11.1 mmol/L) during an oral glucose tolerance test, or a random glucose ≥200 mg/dl (≥11.1 mmol/L) in a patient with classic symptoms or hyperglycemia or hyperglycemic crisis. Impaired fasting glucose (IFG, fasting glucose 100-126 mg/dL (5.6-7 mmol/L)) or DM are used in most definitions of MetS . The treatment of DM may reduce the progression of microvascular and cardiovascular disease [bib_ref] Lifestyle interventions for patients with and at risk for type 2 diabetes:..., Schellenberg [/bib_ref] [bib_ref] Effect of regression from prediabetes to normal glucose regulation on long-term reduction..., Perreault [/bib_ref]. Although randomized trials have failed to demonstrate an unequivocal benefit, the identification of patients by screening allows for earlier intervention with potential reduction in complications [bib_ref] Screening for type 2 diabetes mellitus: a systematic review for the U.S...., Selph [/bib_ref] [bib_ref] Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge):..., Simmons [/bib_ref].
While hyperglycemia and impaired glucose tolerance (IGT) are well-recognized complications of cancer and GVHD treatment (corticosteroids), data regarding the long-term risk of DM in HCT survivors are limited [bib_ref] Diabetes mellitus after hematopoietic stem cell transplantation, Griffith [/bib_ref]. In the BMTSS, both allo-HCT (OR, 3.65; 95% CI, 1.82-7.32) and auto-HCT (OR: 2.03; 95% CI, 0.98-4.21) recipients were more likely to report DM than sibling donors [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. The incidence of post-HCT DM was 30% among 1-year allo-HCT recipients in both adult and pediatric populations [bib_ref] Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic..., Majhail [/bib_ref]. In this study, exposure to high-dose corticosteroids (cumulative prednisone dose of > 0.25 mg/kg/day) increased the likelihood of developing DM (RR, 3.6; 95% CI, 1.7-7.5) and for having persistent DM at 2 years post-HCT (RR, 4.1; 95% CI, 1.0-18.2). While data regarding the incidence of IR in survivors of adult HCT are lacking, the incidence of IR for pediatric HCT survivors has been estimated to be 10-52% in single center studies [bib_ref] Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in..., Taskinen [/bib_ref] [bib_ref] Early and progressive insulin resistance in young, non-obese cancer survivors treated with..., Bizzarri [/bib_ref] [bib_ref] Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and..., Mostoufi-Moab [/bib_ref]. These reports suggest an increased risk for IR/DM in survivors of both allo-and auto-HCT compared to patients treated with chemotherapy alone or untreated siblings, even when off immunosuppressive treatments. Preliminary data from a cross sectional study including 151 HCT survivors (76.8% allo-HCT) and 92 sibling controls found HCT survivors who had received TBI conditioning to be significantly more likely to have IR than their sibling controls, but there was no increased risk of IR for those patients who had a history of acute or chronic GVHD (personal communication, Baker KS). Multiple studies found high-dose TBI as a risk factor for IR and IGT, in addition to older age and lipodystropic body type [bib_ref] Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and..., Mostoufi-Moab [/bib_ref] [bib_ref] Risk factors for diabetes mellitus and impaired glucose tolerance following allogeneic hematopoietic..., Hirabayashi [/bib_ref] [bib_ref] Disorders of glucose homeostasis in young adults treated with total body irradiation..., Chemaitilly [/bib_ref]. While data have not demonstrated an increased risk of diabetes to be directly associated with history of GVHD, further study is warranted.
## Screening and preventive recommendations
The most common tests to screen for diabetes are fasting plasma glucose, two-hour plasma glucose during an oral glucose tolerance test, and HbA1C. The USPSTF recommends screening for abnormal blood glucose (HbA1C, fasting plasma glucose or oral glucose tolerance test (OGTT)) every 3 years in adults aged 40-70 years who are overweight or obese. The NHLBI recommends screening with a fasting glucose every 2 years after the age of 10 years in overweight children with other risk factors. Current guidelines for HCT recipients recommend screening for type 2 DM every 3 years in adults aged ≥45 years or in those with sustained higher BP (>135/80 mm Hg) and fasting glucose at least every 5 years pediatric survivors [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref] [bib_ref] National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow..., Pulsipher [/bib_ref] , which should be appropriate for standard-risk patients. For highrisk patients with ongoing risk factors (including those on systemic corticosteroids), we recommend screening for abnormal blood glucose (HbA1C or fasting plasma glucose) 3 months after HCT with repeat evaluation every 3-6 months. For patients with IFG, we encourage weight reduction and increased physical activity while patients with type 2 DM should implement lifestyle therapy and pharmacotherapy, if necessary, to achieve nearnormal HbA1C (<7%).
## Coronary heart disease
More people die from cardiovascular disease each year than from any other cause. Cardiovascular disease is caused by disorders of blood vessels and is closely related to atherosclerosis, where endothelial lesions occur up to decades before clinical manifestations [bib_ref] Inflammation, atherosclerosis, and coronary artery disease, Hansson [/bib_ref] [bib_ref] Inflammation and atherosclerosis: novel insights into plaque formation and destabilization, Stoll [/bib_ref]. Risk factors for arteriosclerosis in the general population are well established and include smoking, arterial HTN, obesity, DM, dyslipidemia, familial history of CHD, physical inactivity, male gender and elevated C-reactive protein [bib_ref] Prediction of lifetime risk for cardiovascular disease by risk factor burden at..., Leip [/bib_ref].
Several studies have attempted to assess the incidence of cardiovascular disease after HCT, with or without a comparison to a control population. A retrospective multicenter EBMT analysis showed that 3.6% of long-term allo-HCT survivors transplanted between 1990 and 1995 had a cardiovascular event in at least one arterial territory observed [bib_ref] Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter..., Tichelli [/bib_ref]. The cumulative incidence of a first cardiovascular event 15 years after HCT was 6% (95% CI, 3%-10%). One study reported a cumulative incidence of 7.5% for the first cardiovascular event at 15 years post allo-HCT, as compared with 2.3% post auto-HCT [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref]. In multivariate analysis, allo-HCT, in addition to at least 2 of 4 cardiovascular risk factors (HTN, dyslipidemia, DM, and obesity) was associated with a higher incidence of cardiovascular events (RR: 12.4; P=.02). In a retrospective cohort study, ≥2-year HCT survivors experienced an increased incidence of cardiovascular death (adjusted incidence rate difference, 3.6 per 1000 person-years (95% CI, 1.7 to 5.5) when compared with the general population [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref]. In this study, an increased cumulative incidence was also found for ischemic heart disease, cardiomyopathy or heart failure, stroke, vascular diseases, and rhythm disorders and an increased incidence of related conditions that predispose toward more serious cardiovascular disease (HTN, renal disease, dyslipidemia, and DM). In another study, HCT recipients had significantly higher rates of cardiomyopathy (4.0% vs. 2.6%), stroke (4.8% vs. 3.3%), dyslipidemia (33.9% vs. 22.3%) and DM (14.3% vs. 11.7%) (P<.05 for all comparisons) than the general population, though lower rates of ischemic heart disease (6.1% vs. 8.9%; P<.01) [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref]. In the BMTSS, survivors of both allo-and auto-HCT were not more likely to report arterial disease, myocardial infarction or stroke than sibling donors [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. One series, which included 42.7% allo-HCT recipients, reported an incremental increase in 10-year incidence of cardiovascular disease by number of cardiovascular risk factors (4.7% (no factor), 7.0% (one risk factor), 11.2% (≥2 risk factors), P<.01); the risk was especially high (15.0%) in patients with multiple risk factors and pre-HCT exposure to anthracyclines or chest radiation [bib_ref] Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of..., Armenian [/bib_ref]. In the adult population, it is important to acknowledge that an increasing number of older patients are undergoing allo-HCT with reduced intensity conditioning and that future studies are needed to assess the incidence of cardiovascular complications in this population.
In children with acute lymphoblastic leukemia, high-dose TBI and cranial irradiation correlated with multiple adverse cardiovascular factors including central adiposity, HTN, IR and dyslipidemia [bib_ref] Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with..., Chow [/bib_ref] [bib_ref] Hyperinsulinemia in children and adolescents after bone marrow transplantation, Lorini [/bib_ref]. Some studies have analyzed the correlation with GVHD and either found a correlation [bib_ref] Late altered organ function in very long-term survivors after allogeneic hematopoietic stem..., Rovó [/bib_ref] or not [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref] [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref] and if so, more likely with acute than chronic GVHD [bib_ref] Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter..., Tichelli [/bib_ref] [bib_ref] Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of..., Armenian [/bib_ref].
## Screening and preventive recommendations
In the general population, a person's 10-year risk for CHD is determined based on age, gender, and conventional CHD risk factors such as smoking, HTN, and dyslipidemia (Framingham risk score, http://cvdrisk.nhlbi.nih.gov)) [bib_ref] Forecasting the Future of Cardiovascular Disease in the United States: A Policy..., Heidenreich [/bib_ref]. Overall, the benefits of screening with resting or exercise electrocardiography (ECG) or for non-traditional risk factors, including coronary artery calcification on electron-beam computerized tomography (EBCT), have not been clearly demonstrated to outweigh harms. The USPSTF recommends against screening with ECG in asymptomatic adults with low risk for CHD and concludes that there is insufficient evidence to assess the balance of benefits and harms of screening with resting or exercise ECG in asymptomatic adults at intermediate-or high-risk for CHD events. Similarly, the USPSTF finds insufficient evidence to assess the balance of benefits and harms of using non-traditional risk factors to screen asymptomatic men and women with no history of CHD to prevent CHD events. Current guidelines for HCT recipients do not provide specific screening recommendations for coronary heart disease [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref]. Decisions about screening in adults at increased risk should be made on a case-by-case basis and after careful discussion with the patient about the risks and benefits of screening. Although little data are available about specific interventions in the HCT populations, we recommend a similar approach.
## Ischemic stroke
Stroke is the fourth leading cause of death in the United States, whereas globally it is the second most common cause of mortality and the third most common cause of disability [bib_ref] Deaths: leading causes for, Heron [/bib_ref] [bib_ref] Global and regional mortality from 235 causes of death for 20 age..., Lozano [/bib_ref]. Globally, stroke incidence from ischemia is 68% and 32% from hemorrhagic stroke (intracerebral and subarachnoid combined) [bib_ref] Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010:..., Krishnamurthi [/bib_ref]. Pediatric stroke is a top ten cause of death in children, occurring at 11 per 100,000 children per year, with acute ischemic stroke accounting for half of all cases [bib_ref] Heart disease and stroke statistics-2009 update: a report from the American Heart..., Carnethon [/bib_ref] [bib_ref] Management of stroke in infants and children: a scientific statement from a..., Roach [/bib_ref] [bib_ref] Etiology of stroke in children, Riela [/bib_ref].
The cumulative incidence of stroke after adult HCT has been reported in single center series to be 1-5% at a median of 4-10 years following HCT [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref] [bib_ref] Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation, Tichelli [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] [bib_ref] Increased cardiometabolic traits in pediatric survivors of acute lymphoblastic leukemia treated with..., Chow [/bib_ref] [bib_ref] Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a..., Sun [/bib_ref]. In one study of 3833 HCT survivors of ≥1 year (71.3% allo-HCT), the prevalence of stroke at a median of 10.8 years since HCT was slightly higher than in a matched general population sample (4.8% vs 3.3%) [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref]. Reported risk factors for stroke include hyperlipidemia, suboptimal physical activity, HTN treatment before HCT, BMI ≥ 30 kg/m 2 at HCT, and recurrence of the original disease [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] [bib_ref] Late cardiovascular complications after hematopoietic cell transplantation, Chow [/bib_ref]. The risk of stroke did not differ statistically between autoor allo-HCT, gender, age at HCT, TBI dose, smoking history, donor type, stem cell source, fruit or vegetable intake, and prior cranial radiation [bib_ref] Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation, Chow [/bib_ref] [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] [bib_ref] Late cardiovascular complications after hematopoietic cell transplantation, Chow [/bib_ref] [bib_ref] Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a..., Baker [/bib_ref]. A history of chronic GVHD was associated with an increased risk of stroke among ≥5-year HCT survivors (OR, 2.0; 95% CI, 1.1-3.6) in one study [bib_ref] Influence of conventional cardiovascular risk factors and lifestyle characteristics on cardiovascular disease..., Chow [/bib_ref] , while it was not statistically associated with risk of stroke in the other studies. Although ischemic stroke is an indication for HCT in sickle cell disease (SCD), reports indicate that there is no increased risk post-HCT in this population. In one report of pediatric SCD patients, 2 had TIAs after allo-HCT but not stroke [bib_ref] Cerebral vascular abnormalities in pediatric patients with sickle cell disease after hematopoietic..., Bodas [/bib_ref]. Similarly, another study of pediatric SCD matched related allo-HCT patients did not report stroke in those with successful engraftment [bib_ref] Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for..., Walters [/bib_ref]. Adult SCD may have a higher risk of stroke and allo-HCT studies in the adult population are ongoing.
While the reported incidence of stroke in HCT survivors is low, it may be under recognized due to under reporting. Central nervous system complications -such as stroke, posterior reversible encephalopathy syndrome (PRES) and seizures -also occur frequently in the early post-HCT follow-up with significant impact on patient survival [bib_ref] Central Nervous System Complications and Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation, Bhatt [/bib_ref]. Beside the well-known PRES, calcineurin inhibitors may cause a reversible cerebral vasoconstriction syndrome that can progress to cerebral infarction [bib_ref] Reversible cerebral vasoconstriction syndrome resulted in cerebral infarction after allogeneic stem cell..., Imataki [/bib_ref]. Furthermore neurovascular complication -including stroke and transient ischemic attacks (TIA) -occur commonly upon initial presentation of thrombotic microangiopathies presentation and cryptogenic stroke may develop before the onset of alarming hematologic abnormalities [bib_ref] Pearls and oy-sters: acute ischemic stroke caused by atypical thrombotic thrombocytopenic purpura, Rojas [/bib_ref] [bib_ref] Progressive multifocal cerebral infarction in a young kidney transplant recipient due to..., Haghikia [/bib_ref].
## Screening and preventive recommendations
The risk of a first stroke can be assessed by a global risk assessment tool such as the American Heart Association/American College of Cardiology Cardiovascular Risk Calculation online tool for adults (http://my.americanheart.org/cvriskcalculator), which has also been endorsed by the American Academy of Neurology [bib_ref] Guidelines for the primary prevention of stroke: a statement for healthcare professionals..., Meschia [/bib_ref]. The USPSTF recommends against screening for asymptomatic carotid artery stenosis in the general adult population. Preventive practice includes performing moderate to vigorous aerobic physical activity for at least 40 minutes 3-4 times a week, statin therapy according to 10 year calculated cardiovascular risk, implementation of a Mediterranean diet, HTN therapy, and weight loss in overweight and obese patients. Current guidelines for HCT recipients do not provide specific screening recommendations for stroke [bib_ref] Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation, Majhail [/bib_ref]. In the absence of HCT-specific evidence, these goals represent appropriate guidelines for HCT recipients.
## Recommendations for screening and preventive practices
While evidence demonstrating the benefits of screening and preventive practices in HCT survivors is lacking, this review of MetS and cardiovascular disease emphasizes the high incidence of cardiovascular risk factors and the related morbidity and mortality experienced by HCT recipients. Based on this data, we present published guidelines for general population and HCT survivors [fig_ref] Table 2: Screening guidelines for metabolic syndrome and cardiovascular risk factors for adult and... [/fig_ref] as well as our consensus recommendations on the screening and preventive practices [fig_ref] Table 4: CIBMTR/EBMT screening guidelines and preventive practice recommendations for metabolic syndrome and cardiovascular... [/fig_ref] for MetS and cardiovascular disease. We also present risk factors to consider when screening for components of metabolic syndrome in transplant recipients [fig_ref] Table 5: Risk factors to consider when screening for components of metabolic syndrome in... [/fig_ref]. HCT survivors with no identifiable risk factors should be counseled to have a healthy lifestyle and to follow the well-established screening recommendations for the healthy population. However, high-risk patients with ongoing risk factors should be more closely monitored.
Although not addressed formally in this manuscript, endocrine abnormalities, such as male hypogonadism, premature menopause, and hypothyroidism can occur following HCT and may contribute to MetS cardiovascular risk. Health care providers should be aware of these risks and evaluate for these conditions in HCT survivors, especially in the presence of MetS or those with risk factors.
A number of online tools are available to help providers assess risk in patients. In addition to the Framingham risk score (http://cvdrisk.nhlbi.nih.gov), the AHA released a mobile application in 2013 (http://tools.acc.org/ASCVD-Risk-Estimator) to estimate 10-year and lifetime risks for atherosclerotic cardiovascular disease in healthy subjects considering age, ethnicity, gender, systolic BP, history of smoking and DM, total and HDL cholesterol. However, these calculators were designed for the general population and have limitation by age, ethnicity, and/or comorbid conditions. Furthermore, it is important to acknowledge that these tools have not been validated in HCT survivors and thus potentially underestimate risk in this population.
# Conclusion
We provide a consensus recommendations for screening and preventive measures for MetS and cardiovascular disease in recipients of HCT. Such effort by the CIBMTR and EBMT Late Effects Working Groups is intended to raise awareness of the cardiovascular risk in HCT survivors and lead to practices that will decrease related mortality. This document does not discuss strategies to achieve these practices (e.g. survivorship clinics, rehabilitation or exercise programs) given the differences in health care environments between different countries, but efforts to facilitate such strategies to be developed at the local or national level are needed.
[table] Table 2: Screening guidelines for metabolic syndrome and cardiovascular risk factors for adult and pediatric patients amongst the general population and HCT survivorsBiol Blood Marrow Transplant. Author manuscript; available in PMC 2016 November 14. [/table]
[table] Table 3: Preventive practice recommendations for metabolic syndrome and cardiovascular risk factors for adult and pediatric patients amongst the general population and HCT survivors * [/table]
[table] Table 4: CIBMTR/EBMT screening guidelines and preventive practice recommendations for metabolic syndrome and cardiovascular risk factors for adult and pediatric patients amongst the general population and HCT survivors Weight, height, and BMI assessment at every clinic visit (at least yearly) Waist circumference measurement yearly Consider DXA to assess sarcopenia Provide advice regarding intensive, multicomponent behavioral interventions focused on achieving and maintaining healthy weight by reducing caloric intake and increasing physical activityDyslipidemiaFor all allo-HCT recipientes, initial lipid profile 3 months after HCT. For high-risk patients with ongoing risk factors (including those on sirolimus, calcineurin inhibitors, corticosteroids), repeat evaluation every 3-6 months.For standard-risk patients, lipid profile assessment every 5 years in males aged ≥35 years and females aged ≥45 years. The interval for screening should be shorter for people who have lipid levels close to those warranting therapy.Lifestyle modifications and lipid lowering therapies to achieve relative reductions in LDL is the primary goal In adults, the decision to initiate lipid lowering therapy should include assessment of overall risk of heart disease (http://cvdrisk.nhlbi.nih.gov).Non-pharmacologic treatments may also be tried for mild hypertension and include moderate dietary sodium restriction, weight reduction in the obese, avoidance of excess alcohol intake, and regular aerobic exercise. Treatment is indicated for readings >140/90 in adults on two separate visits at least 1 week apart, unless hypertension is mild or can be attributed to a temporary condition or medication (eg, cyclosporine). Hyperglycemia For high-risk patients with ongoing risk factors (including those on systemic corticosteroids), screen for abnormal blood glucose (HbA1C or fasting plasma glucose) 3 months after HCT with repeat evaluation every 3-6 months. For standard-risk adult patients, screening for abnormal blood glucose every 3 years in adults aged ≥45 years or in those with sustained higher blood pressure (>135/80 mm Hg) For standard-risk pediatric patients, fasting glucose at least every 5 years; if abnormal, screen annually For IFG, encourage weight reduction and increased physical activity. For type 2 DM, lifestyle therapy, and pharmacotherapy, if necessary, should be used to achieve near-normal HbA1C (<7%). Abbreviations: BMI: body mass index; CIBMTR: Center for International Blood and Marrow Transplant Research; DM: diabetes mellitus; DXA: dual X-ray absorptiometry; EBMT: European Group for Blood and Marrow Transplantation; HbA1C: hemoglobin A1C; HCT: hematopoietic cell transplantation; IFG: impaired fasting glucose; LDL: low-density lipoprotein; TG: triglycerides [/table]
[table] Table 5: Risk factors to consider when screening for components of metabolic syndrome in transplant recipients• TBI as part of pre-transplant conditioning • Development of acute or chronic GVHD [/table]
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Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines
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Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines
[bib_ref] The effect of perioperative anemia on clinical and functional outcomes in patients..., Halm [/bib_ref] [bib_ref] Higher Hb level is associated with better early functional recovery after hip..., Lawrence [/bib_ref] [bib_ref] Postoperative anemia and quality of life after primary hip arthroplasty in patients..., Conlon [/bib_ref] [bib_ref] The influence of preclinical anaemia on outcome following total hip replacement, Myers [/bib_ref] [bib_ref] Mortality and morbidity in patients with very low postoperative Hb levels who..., Carson [/bib_ref] [bib_ref] Human cardiovascular and metabolic response to acute, severe isovolemic anemia, Weiskopf [/bib_ref] [bib_ref] Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip..., Carson [/bib_ref] [bib_ref] Perioperative myocardial ischemic episodes are related to hematocrit level in patients undergoing..., Hogue [/bib_ref] [bib_ref] Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in..., Nelson [/bib_ref] [bib_ref] The influence of preclinical anaemia on outcome following total hip replacement, Myers [/bib_ref] [bib_ref] Silent myocardial ischaemia and haemoglobin concentration: a randomized controlled trial of transfusion..., Grover [/bib_ref] [bib_ref] Silent myocardial ischaemia and haemoglobin concentration: a randomized controlled trial of transfusion..., Grover [/bib_ref] [bib_ref] The effect of perioperative anemia on clinical and functional outcomes in patients..., Halm [/bib_ref] [bib_ref] A pilot randomized trial comparing symptomatic vs. hemoglobin-level-driven red blood cell transfusions..., Carson [/bib_ref] [bib_ref] The influence of preclinical anaemia on outcome following total hip replacement, Myers [/bib_ref] [bib_ref] The effects of liberal versus restrictive transfusion thresholds on ambulation after hip..., Foss [/bib_ref] [bib_ref] Transfusion trigger trial for functional outcomes in cardiovascular patients undergoing surgical hip..., Carson [/bib_ref] [bib_ref] A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care...., Hébert [/bib_ref] [bib_ref] Detection, evaluation, and management of anemia in the elective surgical patient, Goodnough [/bib_ref] [bib_ref] Management of preoperative anaemia in patients undergoing elective surgery, Goodnough [/bib_ref] [bib_ref] Detection, evaluation, and management of iron-restricted erythropoiesis, Goodnough [/bib_ref] [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] [fig_ref] Fig 1: quality evidence=A [/fig_ref] [bib_ref] Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based..., Guyatt [/bib_ref]
## Recommendations
## Detection of anaemia
Recommendation 1: We recommend that elective surgical patients have an Hb level determination as close to 28 days before the scheduled surgical procedure as possible (Grade 1C).
The Circular of Information for Blood and Blood Products 33 has recommended that iron, vitamin B 12, folic acid, and erythropoietin be used instead of blood transfusion, 'if the clinical condition of the patient permits sufficient time for those agents to promote erythropoiesis . . .' The key phrase relevant to this recommendation is, 'sufficient time . . . to promote erythropoiesis.' Detection of anaemia as close to 28 days before surgery is recommended for sufficient time for evaluation and management.
Recommendation 2: We suggest that the patient's target Hb before elective surgery be within the normal range (female ≥12 g dl 21 , male ≥13 g dl 21 ), according to the WHO criteria (Grade 2C).
This recommendation is a suggestion, indicating a lack of panel consensus and evidence on whether elective surgical procedures should be cancelled, representing best practices, for patients who are identified to be anaemic. Delay of elective scheduled surgery for definitive evaluation of newly detected anaemia and associated clinical conditions (nutritional deficiency, chronic renal disease, etc.) will benefit patients and reduce harm, including likelihood of exposure to blood transfusions.
## Evaluation of anaemia
Recommendation 3: We recommend that laboratory testing be performed to further evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C).
Unexplained anaemia should be considered as secondary to some other process, 2 9 and the cause of the anaemia must be evaluated. Laboratory testing must be performed to further evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease and the cause of the anaemia must be evaluated. If a screening blood count detects anaemia, evaluation should begin with an assessment of iron status. The assessment of iron-restricted erythropoiesis needs to distinguish between absolute iron deficiency, iron sequestration due to inflammation, and/or functional iron deficiency due to erythropoietin stimulation. [bib_ref] Use of erythropoietin to increase the volume of autologous blood donated by..., Mercuriali [/bib_ref] The accurate differentiation of these is difficult using traditional biochemical markers of iron status, such as serum iron, percentage saturation of transferrin, and serum ferritin. 9 As ferritin is an acute-phase reactant, traditional laboratory thresholds of ,12 mg litre 21 may be suitable for identifying absolute iron deficiency in normal individuals, but not in patients with any evidence of an inflammatory process. [bib_ref] Detection, evaluation, and management of iron-restricted erythropoiesis, Goodnough [/bib_ref] Correlation of iron stores with ferritin values has demonstrated that ferritin levels must exceed 30 mg litre 21 to achieve a 92% sensitivity for exclusion of absolute iron deficiency. [bib_ref] Clinical utility of the soluble transferrin receptor and comparison with serum ferritin..., Mast [/bib_ref] For patients without chronic renal disease, ferritin levels .100 mg litre 21 confirm the presence of stored iron. When absolute iron deficiency is detected, referral to a gastroenterologist to rule out a gastrointestinal malignancy as a source of chronic blood loss is indicated. [bib_ref] Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based..., Guyatt [/bib_ref] If laboratory evaluation or a diagnostic trial of iron therapy rules out absolute iron deficiency, measurement of serum creatinine and glomerular filtration rate (GFR) may indicate CKD and the need for referral to a nephrologist. If ferritin, iron saturation values, or both or other markers of iron-restricted erythropoiesis are inconclusive, further evaluation to rule out iron deficiency or iron sequestration due to inflammation/ chronic disease is necessary. A therapeutic trial of oral iron therapy would confirm absolute iron deficiency. No response to iron therapy may not rule out absolute iron deficiency because of patient non-compliance, [bib_ref] Use of erythropoietin to increase the volume of autologous blood donated by..., Mercuriali [/bib_ref] ongoing blood (iron) losses in excess of oral iron absorption, [bib_ref] Clinical utility of the soluble transferrin receptor and comparison with serum ferritin..., Mast [/bib_ref] and/or diminished gastrointestinal absorption of iron due to inflammation. 9 Additionally, iron-restricted erythropoiesis due to iron sequestration, functional deficiency, or both must be considered. In these instances, management strategies that include i.v. iron, with or without erythropoiesis-stimulating agents (ESA) therapy, should be considered. 41
## Management of anaemia
## Treatment of nutritional deficiencies
Recommendation 4: We recommend that nutritional deficiencies be treated (Grade 1C).
Nutritional deficiencies must be treated. Iron supplementation is indicated in the presence of confirmed iron deficiency anaemia. The effectiveness of oral iron in the management of preoperative anaemia has been demonstrated in patients undergoing orthopaedic and colorectal cancer surgery. In the absence of preoperative iron supplementation, postoperative iron supplementation has not been shown to be effective. Three small series of orthopaedic surgery patients, undergoing repair of hip fracture or joint replacement and back surgery, 52 demonstrated the feasibility of parenteral iron supplementation in the preoperative management of irondeficiency anaemia, particularly if there was a short interval before surgery. An expert panel recently reviewed the role of i.v. iron in the management of perioperative anaemia and concluded that patients with preoperative anaemia due to iron deficiency or chronic disease should receive preoperative treatment with oral or i.v. iron, depending on the timescale before surgery, tolerance of oral iron, and iron status. [bib_ref] Perioperative anaemia management: consensus statement on the role of intravenous iron, Beris [/bib_ref]
## Stimulation of erythropoiesis
Recommendation 5: We suggest that ESA be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A).
The use of ESA therapy in patients undergoing major, elective surgery is well established on the basis of controlled, randomized trials and is approved for use in this setting. However, recent concerns regarding the RR/benefit of these agents and their appropriate use in patients with chronic renal disease, in patients with anaemia related to cancer or chemotherapy, and in patients undergoing elective surgery [bib_ref] An open-label, randomized study to compare the safety and efficacy of perioperative..., Stowell [/bib_ref] have resulted in a Grade 2 or 'suggested' recommendation.
The use of ESAs in patients with anaemia undergoing elective orthopaedic (hip, knee, and spine) surgery was reviewed under the auspices of NATA.A meta-analysis of 41 published studies [eight studies of ESA alone, studies of ESA augmented with preoperative autologous blood donation (PABD), seven studies of ESA compared with PABD, and four studies of ESA and other comparators] 106 -109 was performed. Pooled estimates of transfusion exposure demonstrated clinically important benefit for both rHuEPO alone (RR, 0.44; 95% CI, 0.31 -0.64) and rHuEPO augmented by PABD (RR, 0.61; 95% CI, 0.49 -0.75). Although sufficient data were available for patients undergoing hip surgery, a large number of studies performed in patients undergoing a mixture of surgical procedures, and a failure to report indication-specific associations with the intervention, limit the ability to make judgement on the effectiveness of rHuEPO in patients undergoing non-hip procedures such as knee and spinal surgery. Taking account of all the studies, the risk of deep vein thrombosis was increased with the use of rHuEPO [Peto OR of 1.66 (95% CI 1.10 -2.48)] but was inconclusive on the risk of mortality, myocardial infarction, and cerebrovascular accidents due to their low incidence.
Anaemia of chronic disease is a diagnosis of exclusion. 7 However, the following are considered evidence of anaemia of chronic disease: anaemia with no evidence of nutritional deficiencies or chronic renal disease, and the presence of an associated chronic disease. In the presence of a low Hb and normal mean corpuscular volume, a reticulocyte count and serum creatinine level should be measured and GFR calculated. A nephrology consultation is appropriate if an abnormal creatinine level or GFR is present to evaluate for possible haemolysis, blood loss, or chronic renal disease.
Patients should receive iron supplementation throughout the course of ESA therapy, to optimize the dose -response relationship for ESA therapy and red blood cell production in the pre-surgical setting. [bib_ref] Erythropoietin, iron, and erythropoiesis, Goodnough [/bib_ref] ESA therapy with iron supplementation is effective in reducing subsequent need for allogeneic transfusion.Detection, evaluation, and management of preoperative of anaemia: an algorithm
We propose an algorithm for the detection, evaluation, and management of preoperative anaemia based on the above recommendations [fig_ref] Fig 2: Proposed algorithm for the detection, evaluation, and management of preoperative anaemia [/fig_ref].
If anaemia is detected on a screening sample, evaluation is necessary and begins with an assessment of iron status. If serum ferritin, transferrin saturation levels, or both indicate absolute iron deficiency, referral to a gastroenterologist to rule out a gastrointestinal malignancy as a source of chronic blood loss may be indicated.
If serum ferritin, transferrin saturation values, or both rule out absolute iron deficiency, serum creatinine and GFR determination may indicate CKD and the need for referral to a nephrologist.
When serum ferritin, transferrin saturation values, or both are inconclusive, further evaluation to rule out absolute iron deficiency or inflammation/chronic disease is necessary. A therapeutic trial of iron would confirm absolute iron deficiency. No response to iron therapy would indicate the anaemia of chronic disease, suggesting that ESA therapy be initiated.
These recommendations are intended to provide guidance for preoperative evaluation in the elective surgical patient. Limiting preadmission testing to a few days before the scheduled operative procedure precludes the opportunity to evaluate and manage the patient with unexplained anaemia. The recommended time frame of testing 4 weeks before the scheduled elective procedure ensures that anaemia can be detected, evaluated, and managed appropriately before elective surgery.
Anaemia should be viewed as a serious and treatable medical condition, rather than as simply an abnormal laboratory value. Anaemia is a common condition in surgical patients and is independently associated with increased mortality. The diagnosis of an unexpected anaemia in patients undergoing elective surgery in which significant blood loss is anticipated should be considered an indication for rescheduling surgery until the evaluation is completed. The presence of preoperative anaemia is significantly associated with morbidity and mortality after surgery, thus warranting this recommendation. Treatment of postoperative anaemia should be the focus of investigations for the reduction of perioperative risk. We conclude that implementation of anaemia management in the elective surgery setting will improve patient outcome.
# Supplementary material
Supplementary material is available at British Journal of Anaesthesia online.
## Conflict of interest
[fig] Fig 1: quality evidence=A (meta-analyses, randomized controlled trials)Moderate-quality evidence=B (randomized controlled trials with limitations, observational studies with large effects) Low-or very low-quality evidence=C (obervational studies, randomized controlled tried with major limitationsThe grading system used for assessment. [/fig]
[fig] Fig 2: Proposed algorithm for the detection, evaluation, and management of preoperative anaemia. SF, serum ferritin; TSAT, transferrin saturation. [/fig]
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http://bjanaesthesia.org/article/S0007091217333561/pdf
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Previously undiagnosed anaemia is common in elective orthopaedic surgical patients and is associated with increased likelihood of blood transfusion and increased perioperative morbidity and mortality. A standardized approach for the detection, evaluation, and management of anaemia in this setting has been identified as an unmet medical need. A multidisciplinary panel of physicians was convened by the Network for Advancement of Transfusion Alternatives (NATA) with the aim of developing practice guidelines for the detection, evaluation, and management of preoperative anaemia in elective orthopaedic surgery. A systematic literature review and critical evaluation of the evidence was performed, and recommendations were formulated according to the method proposed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. We recommend that elective orthopaedic surgical patients have a haemoglobin (Hb) level determination 28 days before the scheduled surgical procedure if possible (Grade 1C). We suggest that the patient's target Hb before elective surgery be within the normal range, according to the World Health Organization criteria (Grade 2C). We recommend further laboratory testing to evaluate anaemia for nutritional deficiencies, chronic renal insufficiency, and/or chronic inflammatory disease (Grade 1C). We recommend that nutritional deficiencies be treated (Grade 1C). We suggest that erythropoiesis-stimulating agents be used for anaemic patients in whom nutritional deficiencies have been ruled out, corrected, or both (Grade 2A). Anaemia should be viewed as a serious and treatable medical condition, rather than simply an abnormal laboratory value. Implementation of anaemia management in the elective orthopaedic surgery setting will improve patient outcomes.
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Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline
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Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline
Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited.Target Audience: Patients with COPD, clinicians who care for them, and policy makers.Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework.Recommendations: 1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of Pa CO 2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.
## Summary of recommendations
For patients with chronic (FEV 1 /FVC , 0.70; resting Pa CO 2 . 45 mm Hg; not during exacerbation) hypercapnic respiratory failure due to chronic obstructive pulmonary disease (COPD):
1. We suggest the use of nocturnal noninvasive ventilation (NIV) in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty). 2. We suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty). 3. We suggest not initiating long-term NIV during an admission for acuteon-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty). 4. We suggest not using an in-laboratory overnight polysomnogram (PSG) to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty). 5. We suggest NIV with targeted normalization of Pa CO 2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).
# Introduction
COPD is a major cause of morbidity and mortality in the world and is the fourth leading cause of death in the United States [bib_ref] GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality..., Roth [/bib_ref]. Despite progress in the treatment of symptoms and prevention of acute exacerbations, few advances have been made to ameliorate disease progression or decrease mortality [bib_ref] Chronic obstructive pulmonary disease, Rabe [/bib_ref]. To date, the only therapeutic interventions known to reduce mortality in COPD are smoking cessation and long-term treatment with continuous supplemental oxygen for patients who have severe hypoxemia at rest [bib_ref] Long-Term Oxygen Treatment Trial Research Group. A randomized trial of long-term oxygen..., Albert [/bib_ref].
Since the development of NIV, there has been interest in its use for the treatment of patients with COPD and chronic stable hypercapnia. During acute exacerbations with ventilatory failure, NIV is frequently used because it has been shown to improve survival (reviewed in . However, there have been fewer studies addressing the use of chronic domiciliary, nocturnal NIV for stable hypercapnic COPD. Most older studies were small and/or used modest driving pressures [bib_ref] Australian trial of non-invasive Ventilation in Chronic Airflow Limitation (AVCAL) Study Group...., Mcevoy [/bib_ref] in an attempt to normalize gas exchange, improve symptoms, and reduce morbidity and mortality. More recently, however, interest in the use of NIV in chronic hypercapnic COPD has been renewed with studies of so-called "high-intensity" NIV, which refers to inspiratory pressures higher than those used in most previous randomized controlled trials (RCTs) as well as controlled ventilation with higher-than-baseline respiratory rates to maximally reduce the Pa CO 2 [bib_ref] High-intensity non-invasive positive pressure ventilation for stable hypercapnic COPD, Windisch [/bib_ref] [bib_ref] Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive..., Köhnlein [/bib_ref] [bib_ref] Nocturnal non-invasive positive pressure ventilation for COPD, Windisch [/bib_ref].
Thus, in stable patients with COPD and chronic hypercapnia (defined as FEV 1 /FVC , 0.70; resting Pa CO 2 . 45 mm Hg; not during exacerbation), long-term NIV has the potential to improve physiological parameters (e.g., lung function or gas exchange), clinical symptoms (e.g., functional capacity, dyspnea, quality of life , and sleep quality) and patient-centered outcomes (e.g., hospital readmission and survival).
The purpose of this clinical practice guideline is to summarize the available evidence and provide actionable recommendations addressing 1) patients with COPD, especially potential subgroups who might benefit from NIV therapy; 2) the ideal timing and location (e.g., hospital or sleep laboratory vs. home) for NIV initiation; and 3) the identification of optimal modes and settings for chronic NIV therapy.
# Methods
## Panel composition
The project was proposed by the chair and co-chairs (M.M., M.B.D., and R.L.O.) through the American Thoracic Society (ATS) Sleep and Respiratory Neurobiology Assembly and was approved by the ATS Board of Directors. The chair and co-chairs identified potential panelists on the basis of their expertise in sleep-disordered breathing and COPD. The panel consisted of 12 physicians and 2 respiratory therapists with expertise in the field of domiciliary NIV and/or COPD and 2 clinician-methodologists with experience in evidence synthesis and guideline development using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. The ATS also recruited two patient partners who did not participate in further development of the recommendations to participate in question selection and outcome prioritization. The panel met regularly through conference calls and met in person at the yearly ATS International Conferences.
## Conflict-of-interest policy
Industry relationships and other potential conflicts of interest were disclosed and managed in accordance with the policies and procedures of the ATS (available at https://www.thoracic.org/about/ governance/ethics-and-coi/coiprinciples.php). Briefly, all potential panelists disclosed their conflicts of interest to the ATS. Panelists determined to have no substantial conflicts of interest were "approved without limitation," whereas those with potential conflicts of interest that were considered manageable were "approved with management," allowing participation in discussions about the evidence but not in the formulation of recommendations related to their conflicts of interest. Potential panelists whose conflicts of interest were deemed not manageable were disqualified.
## Question generation
The panel chairs developed an initial list of questions, which was discussed in detail by panel members considering the importance, availability of evidence, and patient perspectives before final selection and wording of questions. The panel prioritized five PICO (patients, intervention, comparator, and outcome) questions for the guideline to address.
## Prioritization of outcomes
Following the standard GRADE guidance, the panel rated each outcome for their perceived importance to a patient with COPD on a scale of 1-9, with mean scores of 7-9 indicating a "critical" outcome, mean scores of 4-6 indicating an "important but not critical" outcome, and scores of 1-3 indicating an outcome that was "not important." [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref] In general, outcomes deemed critical should be most informative to the panel in generating recommendations. The panel identified 11 key outcomes that would take priority in guideline decision-making for all PICO questions: dyspnea, hospitalizations, mortality, 6-minute-walk distance (6MWD), serum CO 2 and O 2 , QOL, FEV 1 , FVC, sleep efficiency, and minor side effects.
## Literature search and study selection
With the assistance of a medical librarian, the two methodologists conducted literature searches for each PICO question. We searched Medline, Embase, Cochrane CENTRAL (Central Register of Controlled Trials), CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Web of Science from inception to April 2019 for English-language observational studies and RCTs addressing the PICO questions of interest. If existing systematic reviews addressing the PICO questions were available, these searches and reviews were updated to include the latest evidence [bib_ref] The effect of domiciliary noninvasive ventilation on clinical outcomes in stable and..., Dretzke [/bib_ref] [bib_ref] Nocturnal noninvasive positive pressure ventilation in stable COPD: a systematic review and..., Struik [/bib_ref] [bib_ref] Effects of long-term non-invasive ventilation in stable chronic obstructive pulmonary disease: a..., Shen [/bib_ref]. The two methodologists screened all potential citations identified by the search independently in duplicate to identify all relevant studies to include in the quantitative evidence summaries.
## Evidence summary and critical appraisal of included studies
The methodologists extracted data and imported them into RevMan version 5.3 software (Cochrane) for meta-analysis. We used DerSimonian and Laird randomeffects models to conduct all meta-analyses [bib_ref] Meta-analysis in clinical trials, Dersimonian [/bib_ref]. Study weights were generated using the inverse-variance method. We present results of all analyses using relative risks (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, both with 95% confidence intervals (CIs). We assessed risk of bias (RoB) independently and in duplicate for each outcome of individual studies using the Cochrane RoB tool that classifies RoB as "low," "high," or "unclear" for each of the following domains: sequence generation, allocation sequence concealment, blinding, selective outcome reporting, and other bias. We rated the overall RoB as the highest risk attributed to any criterion.
With input from the panel chairs, the methodologists developed an evidence profile for each PICO. Following GRADE principles, the certainty of evidence for each outcome was judged to be "high," "moderate," "low," or "very low." In accordance with GRADE, the certainty of evidence for each outcome was originally set as high if it originated from RCTs and low if it originated from observational data. We subsequently downgraded the quality of the evidence by one or two degrees if results from individual studies had a serious or very serious RoB [bib_ref] GRADE guidelines: 4. Rating the quality of evidence: study limitations (risk of..., Guyatt [/bib_ref] , there were serious inconsistencies in the results across studies [bib_ref] GRADE guidelines: 7. Rating the quality of evidence: inconsistency, Guyatt [/bib_ref] , the evidence was indirect [bib_ref] GRADE guidelines: 8. Rating the quality of evidence: indirectness, Guyatt [/bib_ref] , the data were imprecise [bib_ref] GRADE guidelines 6. Rating the quality of evidence: imprecision, Guyatt [/bib_ref] , or publication bias was believed to be likely.
## Generation of clinical recommendations for pico questions
The direction and strength of recommendations was decided by consensus at an in-person panel meeting. With the assistance of the methodologists, the chairs led the panel in developing recommendations for each PICO question by working through the GRADE Evidenceto-Decision (EtD) framework, which considers the quality of evidence, balance of desirable and undesirable effects, assumptions of patient values and preferences, resource use, health equity, acceptability of an intervention, and feasibility of implementation [bib_ref] GRADE Working Group. GRADE evidence to decision (EtD) frameworks: a systematic and..., Alonso-Coello [/bib_ref]. For question 2 (obstructive sleep apnea [OSA] screening), we used the GRADE EtD framework for diagnostic tests [bib_ref] GRADE Working Group. GRADE guidelines: 16. GRADE evidence to decision frameworks for..., Schünemann [/bib_ref]. Following GRADE guidance, each recommendation was designated as "strong" or "conditional," using the phrasing "we recommend" for strong recommendations and "we suggest" for conditional recommendations [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref].
## Manuscript preparation
After the generation of recommendations, the panel divided up into working groups for manuscript preparation. For each PICO question, we summarized the recommendation, provided a narrative summary of the evidence (highlighting the largest and most relevant clinical trials for each PICO question), discussed issues raised as part of the EtD framework, and provided a justification for the final recommendation considering the above, together with implementation considerations and future research directions. Each PICO summary was reviewed by the individual working group and then synthesized by the chairs and methodologists.
Editing and feedback on the manuscript were conducted electronically and were coordinated by the panel chairs. The final wording of all recommendations and justifications was agreed on by the entire panel and submitted to ATS for review and approval. The guideline underwent anonymous peer review by content experts and a methodologist. After multiple cycles of review and revision, the guideline was reviewed and approved by a multidisciplinary board of directors.
## How to use these guidelines
Patient preferences, available resources, technical expertise, and clinical circumstances vary widely across clinical practice settings. Thus, alongside each recommendation, we also summarize evidence limitations, panel judgments made when moving from evidence to decisions, subgroup considerations, and implementation concerns. These summaries will allow patients, clinicians, policy makers, and other healthcare stakeholders to make rational, evidence-based decisions with regard to the use of long-term NIV in COPD, which are relevant to their local setting. In [fig_ref] Table 1: to 1 [/fig_ref] , we provide a high-level summary of how these guidelines can be applied [bib_ref] GRADE Working Group. Going from evidence to recommendations, Guyatt [/bib_ref] [bib_ref] Clinical meaning of the GRADE rules, Rochwerg [/bib_ref]. For additional information, including the complete evidence summaries and EtD frameworks, see the online supplement. The guideline will be reviewed by the ATS 3 years after publication, and whether an update is necessary will be determined.
For evidence summaries (including forest plots from meta-analyses) and EtD tables for each PICO question, see the online supplement.
# Results
Question 1: Should long-term nocturnal NIV versus usual care be used for chronic stable outpatients with hypercapnic COPD?
Recommendation. We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty).
Background. Currently, COPD has been diagnosed in over 15 million adults in the United States. The most severe of these have hypercapnia, which has been associated with increased dyspnea, decreased QOL, more frequent hospitalizations, and increased mortality [bib_ref] Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory..., Costello [/bib_ref] [bib_ref] Is hypercapnia associated with poor prognosis in chronic obstructive pulmonary disease? A..., Yang [/bib_ref]. Despite progress in the treatment of symptoms and prevention of acute exacerbations, few advances have been made to ameliorate disease progression or reduce mortality in this population. Since the development of positive-pressure NIV, there has been interest in its use for the treatment of patients with COPD and hypercapnia. However, clinical heterogeneity and variability in NIV protocols employed in available studies have led to a lack of consensus, variable practice, and no clear direction related to its use in this population with COPD.
Summary of the evidence. Thirteen RCTs from the search were included in the analysis for this question. Follow-up for these trials ranged from 3 to 12 months. There was some variation in the standard of care provided to the control group in the included studies. Although most trials compared NIV as an addition to oxygen therapy, two compared nocturnal NIV with exercise training with exercise training alone [bib_ref] Nocturnal non-invasive ventilation in addition to rehabilitation in hypercapnic patients with COPD, Duiverman [/bib_ref] [bib_ref] Randomized controlled trial of domiciliary noninvasive positive pressure ventilation and physical training..., Garrod [/bib_ref] , and in one study, not all patients received oxygen therapy in the control arm [bib_ref] Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive..., Köhnlein [/bib_ref].
All 13 studies reported mortality, but in 5 studies, the effect of NIV on mortality was not able to be estimated because of an absence of events in either group. In the remaining eight studies, mortality risk was reduced by 14% in the NIV group compared with those receiving usual care (RR, 0.86; 95% CI, 0. [bib_ref] The influence of co-morbidity on health-related quality of life in asthma and..., Wijnhoven [/bib_ref]
## For policy makers
The recommendation can be adapted as policy in most situations, including for use as performance indicators.
Policy making will require substantial debates and involvement of many stakeholders. Policies are also more likely to vary between regions. Performance indicators would have to focus on the fact that adequate deliberation about the management options has taken place.
These guidelines were created using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) Working Group criteria [bib_ref] GRADE Working Group. Going from evidence to recommendations, Guyatt [/bib_ref]. No significant difference in lung function as measured by FEV 1 was seen between NIV and standard care (FEV 1 : SMD, 0.07; 95% CI, 20.14 to 0.27; FVC: SMD, 0.10; 95% CI, 20.06 to 0.26; both low certainty). There was also no difference in sleep efficiency between NIV and standard care (low certainty), although sleep questionnaires rather than objective measures (i.e., PSG) were used to rate sleep quality. The 6MWD was higher with NIV (MD, 32 m; 95% CI, 10.8-53.3 m; moderate certainty).
## American thoracic society documents
Four studies provided data around adverse events associated with NIV compared with usual care. One study [bib_ref] Noninvasive positive pressure ventilation in subjects with stable COPD: a randomized trial, Bhatt [/bib_ref] reported an increase in discomfort and skin breakdown with NIV, whereas two studies [bib_ref] Home noninvasive positive pressure ventilation with built-in software in stable hypercapnic COPD:..., Zhou [/bib_ref] reported skin rashes associated with the NIV mask. Overall, there was a 10-fold increase in the risk of discomfort, skin breakdown, and rash in the NIV group when compared with standard of care. No serious adverse events such as hypotension or pneumothorax were reported in any of the trials included in our analyses.
Rationale for the recommendation.
Overall, the balance between desirable and undesirable effects of NIV in this patient population probably favors NIV. Desirable effects of NIV included possible reductions in mortality and hospital admissions, improved QOL, reduced dyspnea, and improvements in functional capacity, awake blood gases, and 6MWD. The use of NIV appeared to have little impact on subjective sleep quality, and the harms reported were generally minor and related to the interface. However, the panel acknowledged that the amount of certainty around these outcomes is low because of RoB from lack of blinding and imprecision. Nevertheless, the panel was impressed with the consistency of the direction of effect in favor of improvement in dyspnea and QOL scores in the NIV group. These benefits would likely outweigh the inconveniences of using a mask overnight. However, it was recognized that attention to mask fit and comfort is paramount to minimize harms.
The severity of baseline hypercapnia and lung disease, mode of ventilation, and pressure settings used varied considerably among studies. In addition, management of the control groups also differed with respect to the use of oxygen therapy and whether the comparator included exercise training or not. This clinical heterogeneity may have contributed to the imprecision of the data.
The panel recognized that the implementation of resources and cost of NIV may be significant barriers to the widespread acceptance of NIV in patients with stable hypercapnic COPD. It was judged that the costs of treating patients with stable hypercapnic COPD with NIV were moderate. It was noted that there would likely be high upfront cost in initiating NIV, and many of the studies included frequent follow-ups with personnel who called or interacted with the study subjects weekly or biweekly. Many clinical services may not have the resources and expertise to provide such intensive followup, even in the short term, which might be important to achieving high adherence and, thus, improved outcomes.
There are also costs to the patients, as many insurers may not cover NIV or copayments may be too high for patients to afford. Overall, despite the initial costs, NIV may be cost-effective in many settings. Patients may have difficulty accepting NIV because of claustrophobia or dyssynchrony. This difficulty is reflected in the variations in adherence seen in the studies; some patients may choose to discontinue NIV, particularly if there are problems with the interface. The panel recognized that this recommendation could impact health equity. Access to experts in both pulmonary and sleep medicine is increasingly rare, especially in rural and nonacademic centers. Training in sleep medicine has also changed in recent years, with more trainees entering sleep fellowships without pulmonary training. Similarly, pulmonary training programs may not provide adequate education to trainees regarding home NIV. Access to respiratory therapists with sleep and/or home ventilation training is also necessary to ensure a patient's success with mask fittings and NIV acceptance. The panel judged, however, that if the infrastructure is in place, providing NIV in patients with stable hypercapnic COPD is feasible in many settings.
## Unanswered questions and research
priorities. The panel identified many areas for future investigation related to this question. First, research is needed into which patients (i.e., phenotypes) would be expected to benefit the most from NIV therapy. Second, the mechanism by which NIV appears to improve outcomes remains unclear, although it may include respiratory muscle rest, reduction in hyperinflation, and improvement in V : =Q : matching. A better understanding of the contribution of these components would allow clinicians to better target and titrate therapy. Third, major questions remain (although we have attempted to address these with other PICO questions) regarding how exactly (mode, settings, monitoring, and titration) to implement and follow patients on longterm NIV therapy. Finally, further data examining important patient outcomes and cost-effectiveness (in less intensive, realworld settings) are needed to improve the certainty of evidence informing the recommendation.
Question 2: Should patients with chronic stable hypercapnic COPD undergo assessment for sleep apnea (i.e., overlap syndrome) before initiation of long-term NIV?
Recommendation. We suggest that patients with chronic stable hypercapnic COPD undergo screening for OSA before initiation of long-term NIV (conditional recommendation, very low certainty).
Background. Among the populations with COPD, COPD-OSA prevalence estimates vary widely, from 0.5% in individuals with generally mild COPD (SHHS [Sleep Heart Health Study]) to 39% in a U.S. veteran population (again, with milder disease) and up to 65% in a pulmonary rehabilitation population with moderate COPD and some severe COPD (mean FEV 1 , 42%; 39% on long-term oxygen therapy) Thus, in particular, the true prevalence of COPD-OSA is not known in those with severe COPD (i.e., those most likely to qualify for NIV) [bib_ref] Sleep Heart Health Study. Sleep and sleep-disordered breathing in adults with predominantly..., Sanders [/bib_ref] [bib_ref] High prevalence of obstructive sleep apnea in patients with moderate to severe..., Soler [/bib_ref] [bib_ref] Overlap syndrome: an indication for sleep studies? A pilot study, López-Acevedo [/bib_ref]. Alternatively, in one recent single-center trial of those initiating NIV, home polygraphy (which might underestimate OSA severity) found only about 5% of subjects to have an AMERICAN THORACIC SOCIETY DOCUMENTS e78 apnea-hypopnea index . 15/h [bib_ref] Home initiation of chronic non-invasive ventilation in COPD patients with chronic hypercapnic..., Duiverman [/bib_ref]. Flenley [bib_ref] Sleep in chronic obstructive lung disease, Flenley [/bib_ref] has considered "the overlap syndrome" to have important clinical and therapeutic implications, which were different from the presentation and management of each underlying disorder. Indeed, several studies have shown that those with COPD and OSA have more profound nocturnal oxygen desaturations and sleep disturbances compared with those with either disease alone [bib_ref] Sleep Heart Health Study. Sleep and sleep-disordered breathing in adults with predominantly..., Sanders [/bib_ref]. Thus, we aimed to compare the effect of an OSA screening strategy versus no OSA screening strategy on proposed outcomes in patients with stable hypercapnic COPD.
Summary of the evidence. The panel identified several studies that suggest that identification and treatment of OSA with continuous positive airway pressure (CPAP) in patients with COPD improves outcomes. However, these data were not from RCTs, nor were they from studies of patients with hypercapnic COPD initiating or already on NIV [bib_ref] Survival benefit of CPAP favors hypercapnic patients with the overlap syndrome, Jaoude [/bib_ref] [bib_ref] Early recognition of obstructive sleep apnea in patients hospitalized with COPD exacerbation..., Konikkara [/bib_ref] [bib_ref] CPAP and survival in moderate-to-severe obstructive sleep apnoea syndrome and hypoxaemic COPD, Machado [/bib_ref] [bib_ref] Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea:..., Marin [/bib_ref] [bib_ref] Nocturnal CPAP improves walking capacity in COPD patients with obstructive sleep apnoea, Wang [/bib_ref]. We did find ongoing trials evaluating the treatment of OSA-COPD overlap syndrome, including those examining the use of CPAP (clinicaltrials.gov identifier NCT 03647462), NIV (clinicaltrials.gov identifiers NCT 03184714 and NCT 02363413), and CPAP versus NIV (clinicaltrials.gov identifier NCT 03766542); however, these results were not reported in time for inclusion in this guideline.
No trials comparing an OSA screening strategy with no OSA screening strategy in patients with stable hypercapnic COPD were identified. Similarly, there was no evidence evaluating the consequences of identifying (or failing to identify) OSA in patients who are already receiving long-term NIV for COPD. The panel noted that most trials evaluating NIV in COPD excluded patients with OSA and/or high body mass index (BMI), thus precluding subgroup analysis. Therefore, the panel chose to proceed with a GRADE-supported two-step approach to develop this recommendation, first evaluating anticipated test accuracy and second evaluating the anticipated impact of test results on patient-important outcomes [bib_ref] GRADE Working Group. GRADE guidelines: 22. The GRADE approach for tests and..., Schünemann [/bib_ref].
Two studies have evaluated the diagnostic accuracy of OSA screening tools in patients with COPD [bib_ref] Sleep apnea clinical score, Berlin questionnaire, or Epworth sleepiness scale: which is..., Faria [/bib_ref] [bib_ref] Age, gender, neck circumference, and Epworth sleepiness scale do not predict obstructive..., Soler [/bib_ref]. These two small studies have demonstrated that OSA-screening-test characteristics in patients with COPD are consistent with those seen in patients without COPD, although the estimates are imprecise because of the small sample sizes. The panel therefore chose to use indirect estimates from the population without COPD, for which there were substantially more data (and therefore more precise estimates) available, acknowledging that the indirect estimate would increase our uncertainty in the effects. These pooled estimates of screening test characteristics were adapted from Chiu and colleagues [bib_ref] Diagnostic accuracy of the Berlin questionnaire, STOP-BANG, STOP, and Epworth sleepiness scale..., Chiu [/bib_ref] , who used a random-effects bivariate analysis (49) including 108 studies and a total of 47,989 participants with suspected OSA. The panel recognized that test accuracy may vary in the population with COPD, particularly in patients with comorbidities such as congestive heart failure, who often report less daytime sleepiness [bib_ref] Sleepiness and sleep in patients with both systolic heart failure and obstructive..., Arzt [/bib_ref]. As the reported prevalence of OSA in patients with COPD varies, we evaluated the accuracy of screening tests across the low (10%), middle (30%), and high (60%) prevalences described in the literature [bib_ref] High prevalence of obstructive sleep apnea in patients with moderate to severe..., Soler [/bib_ref] [bib_ref] Sleep-disordered breathing and COPD: the overlap syndrome, Owens [/bib_ref]. As accurate identification of severe OSA (apnea-hypopnea index . 30 events/h) was identified by the panel as the clinical priority, the data below represent the screening characteristics for detecting severe OSA, with an estimated overall 10% prevalence. The overall certainty of test accuracy was judged to be low because of heterogeneity and indirectness, as the screening tests have not been extensively validated in people with COPD.
Desirable and undesirable consequences. The panel discussed the potential desirable and undesirable consequences for screening in the context of two OSA screening tools, the STOP-BANG (Snoring, Tiredness, Observed Apnea, Pressure, BMI, Age, Neck size, Gender) Questionnaire (SBQ; sensitive but not specific) and the Epworth Sleepiness Scale (ESS; less sensitive and not specific). Assuming a prevalence of severe OSA of 10%, application of these screening tools to 100 people with COPD would yield the following:
The SBQ would yield a pooled sensitivity of 0.93 (95% CI, 0.89-0.95) and a pooled specificity of 0.35 (95% CI, 0.28-0.44; low certainty) and would result in 9 true-positive screen results, 1 falsenegative screen result, 32 true-negative screen results, and 58 false-positive screen results.
The ESS would yield a pooled sensitivity of 0.58 (95% CI, 0.48-0.67; low certainty) and a pooled specificity of 0.60 (95% CI, 0.53-0.68) and would result in 6 true-positive, 4 false-negative, 54 truenegative, and 36 false-positive screen results.
Patients who screen positive and have OSA (true-positive results) will likely go on to receive further diagnostic sleep testing to evaluate for OSA. If OSA is found to be the major contributor to the patient's respiratory failure, the patient may require CPAP alone, rather than the more costly and challenging-to-implement NIV. Alternatively, knowledge of OSA diagnosis may result in better titration of NIV (e.g., higher expiratory positive airway pressure that may result in better outcomes due to fewer obstructive events. Finally, adherence to therapy might be improved if patients and clinicians were aware that they had two indications for NIV. These effects would not be seen in the absence of OSA screening. Patients who screen positive and do not have OSA (falsepositive results) may undergo unnecessary diagnostic sleep testing (a one-time event) and will still receive NIV to treat their COPD.
Patients who screen negative and do not have OSA (true-negative results) will likely receive NIV and avoid further diagnostic sleep testing. This would also occur in the absence of screening. Patients who screen negative but actually have OSA (false-negative results) may not receive diagnostic sleep testing to diagnose OSA and thus may not have their OSA fully treated using NIV alone with standard settings for hypoventilation (e.g., EPAP of 5 cm of water). However, some patients with falsenegative results may receive NIV when all they require is CPAP to treat their OSA. These effects would also occur in the absence of screening.
Rationale for the recommendation. The panel judged that the greatest benefit to screening would be in patients ultimately determined to have COPD-OSA overlap (true-positive results), as this might lead to better titration of settings to address OSA and might focus clinicians on OSA and/or obesity as contributors to hypoventilation rather than COPD alone. The panel judged that patients with true-negative or falsenegative screen results would not be AMERICAN THORACIC SOCIETY DOCUMENTS adversely or beneficially affected by screening, as a negative screen result would not change management compared with no screening being performed. False-positive screen results would have some negative effects (unnecessary costs and time of confirmatory testing of OSA using a sleep study); however, these are likely of minimal consequence, as they are part of a singular event. Furthermore, the burden of sleep testing may vary depending on whether a full in-hospital or clinic-based PSG is done (vs. a less-burdensome home sleep study).
The panel made this suggestion on the basis of the anticipated benefits of successfully identifying patients with severe OSA, as this may result in optimal management of their respiratory disease, including choice of CPAP versus NIV, better titration of EPAP, and weaning or discontinuation of inhalers if it is recognized that OSA and obesity hypoventilation syndrome contribute to hypercapnia and are treated. Use of a sensitive test such as the SBQ will pick up most of these patients (9 out of 10 per 100 patients) and may result in improved management. On the other hand, the high number of patients with false-positive results (58 out of 90 per 100 patients) will result in an increased number of diagnostic sleep tests, most of which will be negative. These were judged by the panel to be of minor consequence to patients, as described above.
Use of a specific screening instrument such as ESS would also result in falsepositive test results (36 of 90 patients) but would miss nearly half of the patients with severe OSA who would benefit from having properly diagnosed OSA (6 of 10). Weighing these considerations, together with the minimal cost and burden of screening using the SBQ, the panel judged that the benefits of screening using a highly sensitive test (e.g., the SBQ) probably outweigh the harms in a population with a severe OSA prevalence around 10%. Patients with COPD and overweight (BMI > 25 kg/m 2 ) and cardiovascular disease appear to be at particularly high risk of overlap syndrome, and these characteristics may prompt consideration of OSA screening before initiating long-term NIV, although patients without these characteristics can also have concomitant OSA [bib_ref] Age, gender, neck circumference, and Epworth sleepiness scale do not predict obstructive..., Soler [/bib_ref].
Although this recommendation may also apply to sensitive OSA screening questionnaires other than the SBQ, it should be noted that less sensitive and more specific screening tests have differing test characteristics, and the desirable and undesirable consequences of using these tests may differ from those used in the panel's deliberations. In particular, screening tests with high specificity and lower sensitivity (such as the ESS) may not perform well in patients with COPD [bib_ref] Age, gender, neck circumference, and Epworth sleepiness scale do not predict obstructive..., Soler [/bib_ref]. Similarly, this recommendation would not apply in settings where the prevalence of OSA in patients with COPD is either extremely high or extremely low.
## Unanswered questions and research
priorities. COPD-OSA overlap was identified by the panel as an area of research priority, given the increasing recognition that a high proportion of patients with severe COPD receiving longterm NIV may also have OSA. Specific research topics identified include OSAscreening-tool test characteristics, specifically in patients with COPD; effects of screening for OSA in COPD (impact of testing on management decisions, clinical effects, financial costs, cost-effectiveness, etc.); identifying which patients with COPD are most at risk of OSA and therefore most likely to benefit from screening and management of overlap syndrome; phenotypes of sleep changes in overlap syndrome (e.g., apneas vs. hypopneas) and whether or not these phenotypes require different management strategies; and the natural history of overlap syndrome, as it is currently unclear how it differs from OSA or COPD alone. Question 3: Should long-term NIV be initiated in patients hospitalized with a COPD exacerbation associated with acute-on-chronic respiratory failure?
Recommendation. We suggest not using inhospital initiation of long-term NIV after an episode of acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty).
Background. COPD exacerbations are a key cause of morbidity and mortality and place a considerable burden on healthcare systems. Unfortunately, patients often do not recover to the baseline amount of lung function or degree of symptoms, and COPD exacerbations are therefore an important contributor to worse outcomes, including lung-function decline, poorer QOL, and increased risk of death [bib_ref] Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary..., Donaldson [/bib_ref] [bib_ref] Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease, Soler-Cataluña [/bib_ref]. After discharge, 60-80% of the patients are readmitted within 1 year, and 30-49% die within this first year after their hospital admission for an acute COPD exacerbation [bib_ref] Readmission rates and life threatening events in COPD survivors treated with noninvasive..., Chu [/bib_ref]. These disappointing outcomes raised the question of whether long-term NIV should be provided to patients admitted to the hospital with an exacerbation of COPD.
Summary of the evidence. We identified four RCTs evaluating the use of long-term NIV after an episode of acute hypercapnic respiratory failure. Pooled data suggest that there are no major differences in mortality (RR, 0.92; 95% CI, 0.67 to 1.25; low certainty), exacerbations (MD, 0.3 fewer; 95% CI, 1.17 fewer to 0.57 more; low certainty), the need for hospitalization (RR, 0.61; 95% CI, 0.30 to 1.24; very low certainty), changes in dyspnea (MD, 0.8 points lower; 95% CI, 2.17 points lower to 0.58 points higher; low certainty), QOL (MD, 2.89 points higher; 95% CI, 1.03 points lower to 6.8 points higher; low certainty), or exercise tolerance measured with 6MWD (MD, 8.64 m lower; 95% CI, 209 m lower to 192 m higher; very low certainty) when using NIV. There was a significant reduction in Pa CO 2 (MD, 3.41 mm Hg lower; 95% CI, 4.09 to 2.73 mm Hg lower; moderate certainty), but there was no improvement in Pa O 2 (MD, 1.53 mm Hg lower; 95% CI, 4.24 mm Hg lower to 1.17 mm Hg higher; very low certainty) or FEV 1 (SMD, 0.36 SD; 95% CI, 20.74 to 0.03; low certainty).
As this analysis was driven by two large RCTs, the RESCUE (Respiratory Support in COPD after Acute Exacerbation) trial (Struik and colleagues [bib_ref] Nocturnal non-invasive ventilation in COPD patients with prolonged hypercapnia after ventilatory support..., Struik [/bib_ref] and the HOT-HMV (Home Oxygen Therapy-Home Mechanical Ventilation) trial (Murphy and colleagues [bib_ref] Effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone..., Murphy [/bib_ref] , some detail of these trials is important. In RESCUE, 201 patients with COPD admitted to the hospital with acute hypercapnic respiratory failure who had persistent hypercapnia more than 48 hours after ventilatory support were randomly assigned to NIV or to no NIV. At 1 year, although there was improvement in both daytime and nocturnal hypercapnia, there was no improvement in mortality, frequency of exacerbation, or time to hospital readmission or death. In HOT-HMV, 116 patients with severe COPD who received NIV during acute hypercapnic respiratory failure and who remained hypercapnic (defined as Pa randomly assigned to long-term NIV (HMV) with HOT or to HOT alone. At 1 year, there was no significant difference in 12-month mortality between the groups (28% for HOT 1 HMV vs. 32% for HOT), although there was some crossover to NIV in the HOT-only arm. However, there were fewer exacerbations (3.8 exacerbations/yr with HOT 1 HMV vs. 5.1 exacerbations/yr in HOT-only arm).
HOT-HMV and RESCUE assessed QOL with general (health-related QOL) and respiratory-specific (Severe Respiratory Insufficiency Questionnaire, St. George's Respiratory Questionnaire [SGRQ]) assessment tools. In both the HOT-HMV and the RESCUE study, there was a minimal and temporary impact of NIV intervention on general QOL assessment. Similarly, there was no sustained impact on respiratory-specific QOL scores. The limited available data from these studies make a definitive conclusion regarding the impact of NIV on QOL metrics difficult to assess when initiated after a severe COPD exacerbation. The minimal impact of NIV in these studies may reflect prior observations that respiratory-specific health-related QOL questionnaires are driven so substantially by COPD factors (FEV 1 and exacerbations) that improvements in comorbid disease control (such as through interventions like NIV) may not be sufficient to impact respiratoryspecific QOL outcomes. This is supported by other studies showing that comorbidities like congestive heart failure, diabetes mellitus, and venous thromboembolism do not contribute to SGRQ scores, and improving comorbidity control is therefore not expected to substantially impact SGRQ scores [bib_ref] INITIATIVES BPCO Scientific Committee. Impact of comorbidities on COPD-specific health-related quality of..., Burgel [/bib_ref] [bib_ref] The influence of co-morbidity on health-related quality of life in asthma and..., Wijnhoven [/bib_ref]. Moreover, additional multidisciplinary management after COPD exacerbation may influence the impact of NIV initiation on QOL metrics. It is also possible that the side effects or burdens of NIV offset potential improvements in QOL. The current data in this area limit meaningful conclusions on the impact of NIV on QOL outcomes after COPD exacerbations.
Rationale for the recommendation.
Patients with COPD and frequent hospitalizations might be expected to benefit from NIV, and inpatient hospitalization might provide a convenient clinical pathway to initiate NIV. Although the pooled evidence might suggest a possible benefit in starting NIV in patients who remain hypercapnic after an episode of acute hypercapnic respiratory failure, the RESCUE trial, the largest of the included trials, suggests that initiation of NIV in the hospital directly after termination of NIV for acute hypercapnic respiratory failure does not improve patient-important outcomes. Indeed, these trials are complementary in that many (nearly 21%, and the largest reason for exclusion) potential HOT-HMV patients who were hypercapnic at hospital discharge were no longer hypercapnic 2-4 weeks later. These data suggest that initiation too early may result in many patients receiving long-term NIV unnecessarily. The panel also noted that the theoretical benefits of starting NIV earlier (reducing early readmission or recurrent exacerbation) were not supported by the data from the HOT-HMV trial, which demonstrated a larger effect size than the trials that initiated long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure. Lastly, there might be potential convenience to initiating NIV during an admission for acute-on-chronic hypercapnic respiratory failure, including availability of trained staff and equipment, but it might further prolong hospitalization to acclimatize to NIV. In fact, more recent data suggest that home initiation of NIV leads to similar outcomes yet is less costly [bib_ref] Home initiation of chronic non-invasive ventilation in COPD patients with chronic hypercapnic..., Duiverman [/bib_ref]. Given all of the above concerns, the panel made a conditional recommendation against inhospital initiation of long-term NIV after an episode of acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution.
Patients with known or suspected OSA were excluded from many of these studies and should be considered separately, as reviewed above in PICO question 2. These recommendations would not apply to those who remain persistently hypercapnic and cannot be "weaned" from NIV in the hospital. In such patients, in-hospital continuation and transition to long-term NIV may be required.
## Unanswered questions and research
priorities. There are no studies examining which hospitalized patients will have resolution of hypercapnia versus those who will not, nor has the time course of resolution after an acute exacerbation of COPD been thoroughly examined. Thus, the ideal time to evaluate (or reassess) appropriateness of NIV is not known. Long-term studies with extended follow-up are needed to see whether differential outcomes are maintained after prolonged outpatient therapy, including outcomes such as exacerbations, rehospitalizations, and QOL. Finally, there are no data regarding costeffectiveness in the United States, although on the basis of costs in the United Kingdom, the use of long-term NIV is likely to be commensurate with other therapies considered to be cost-effective [bib_ref] Costeffectiveness of home oxygen therapy-home mechanical ventilation (HOT-HMV) for treatment of COPD..., Goss [/bib_ref].
Question 4: Should long-term NIV settings be determined by an inlaboratory overnight PSG in patients with chronic stable hypercapnic COPD?
Recommendation. We suggest not using an in-laboratory overnight PSG to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty).
Background. There is little guidance about how to initiate NIV in patients with COPD. Trials outside the United States sometimes adjust settings over time (e.g., 1-2 wk) while patients are hospitalized [bib_ref] High-intensity non-invasive positive pressure ventilation for stable hypercapnic COPD, Windisch [/bib_ref]. Initiation in a sleep laboratory might allow for acclimatization to equipment and might provide additional education from sleep technicians. Conversely, PSG and real-time Pa CO 2 measurement tools constitute a limited resource in most settings.
Summary of the evidence. Two RCTs have examined the initiation of NIV using in-laboratory PSG titration versus an alternative method. Hannan and colleagues (60) predominantly included patients with neuromuscular disease being initiated on NIV using daytime titration followed by a sham PSG comparator. Patout and colleagues (61) examined patients with COPD and OSA, using a nurse-led titration protocol as the comparator, but there were only seven patients in each arm. The study by Hannan and colleagues (60) demonstrated no effect on mortality (RR, 0.32; 95% CI, 0.01 to 27.61), NIV asynchrony as measured by the patient-ventilator asynchrony index (MD, 215.3; 95% CI, 259 to 28 points), or adverse effects as measured with a sleep apnea QOL questionnaire (MD, 0.5; 95% CI, 21.75 to 2.8 points). Pooled data from both studies showed no difference in NIV adherence (245 min; 95% CI, 2202 to 112 min; very low certainty), QOL at 3 months
## American thoracic society documents
as measured with the Severe Respiratory Insufficiency Questionnaire (MD, 0.6 points higher with in-laboratory titration; 95% CI, 24.2 to 5.4 points; very low certainty), or Pa CO 2 amounts at 3 months (MD, 1.39 mm Hg; 95% CI, 24.3 to 7.1; very low certainty).
Rationale for the recommendation. In theory, in-laboratory overnight titration might be useful to optimize NIV settings and/or provide a setting to introduce patients to NIV. For example, higher amounts of EPAP may be adjusted to maintain upper-airway patency and minimize patient-ventilator asynchrony. Some laboratories also have the ability to monitor transcutaneous CO 2 concentrations, so that titration could occur over the night and target near-normal CO 2 concentrations. Or, CO 2 measurements taken at night or during sleep may be more sensitive for nocturnal hypoventilation than daytime arterial blood gases and could be used to assess the efficacy of ventilation over time [bib_ref] Diagnostic accuracy of simple tools in monitoring patients with chronic hypoventilation treated..., Aarrestad [/bib_ref]. The presence of a registered polysomnographic technician could also introduce NIV and the interface to the patient, possibly resulting in higher adherence.
However, possible concerns include the cost of in-laboratory testing and the delay in therapy that such testing would entail. Although measurement of CO 2 concentrations might have value in these patients (see question 5 below), few sleep laboratories currently measure CO 2 concentrations or have developed clear titration protocols for NIV on the basis of the overnight concentrations. Furthermore, it is not clear if it is desirable, or even safe, to achieve normocapnia in a single night, and aggressive titration can result in glottic closure rather than increased ventilation [bib_ref] Life-threatening hypokalemia following rapid correction of respiratory acidosis, Hammond [/bib_ref] [bib_ref] Nasal two-level positive-pressure ventilation in normal subjects: effects of the glottis and..., Parreira [/bib_ref]. Substantial education and training would be needed for sleep physicians and technicians. Multiple studies examining positive airway pressure adherence for the treatment of OSA have not demonstrated lower adherence in the absence of inlaboratory titration. The panel also noted that most NIV devices would provide information that might be used to titrate settings over time (e.g., residual apnea-hypopnea index) and that, increasingly, NIV devices incorporate algorithms for the automatic determination of EPAP [bib_ref] Treating chronic hypoventilation with automatic adjustable versus fixed EPAP intelligent volume-assured positive..., Mcardle [/bib_ref] [bib_ref] Automatic EPAP intelligent volume-assured pressure support is effective in patients with chronic..., Orr [/bib_ref]. Similarly, daytime measurements of CO 2 concentrations could be used as surrogates for nocturnal changes over time. Finally, in-laboratory titration could always be pursued later for subjects experiencing difficulties with therapy. Alternatively, in-laboratory titration could be reserved for certain patients (e.g., those with known COPD-OSA overlap).
Duiverman and colleagues [bib_ref] Home initiation of chronic non-invasive ventilation in COPD patients with chronic hypercapnic..., Duiverman [/bib_ref] recently published an RCT of home and telemedicine versus in-hospital initiation of NIV. They found no difference in CO 2 reduction or QOL at 6 months. Although there were differences in NIV settings early on, these differences were not statistically significant after 6 months, suggesting the feasibility (and need) to adjust settings over time. Finally, adherence was good in both groups but better in the home-initiation group.
## Unanswered questions and research
priorities. Many basic questions remain about the optimal mode and settings used for NIV in COPD and how such settings should be modified over time to maximize effectiveness and adherence. The ideal time course for change in CO 2 is not known (i.e., should the goal be to change Pa CO 2 in a single night or over many weeks?). Whether clinicians should attempt to decrease Pa CO 2 using a specific mode of NIV, by attempting larger VTs or with a more rapid respiratory rate, is not known. Finally, nearly all research studies of NIV in chronic stable hypercapnic COPD exclude those who are at risk for OSA or those with known OSA. Yet, in clinical practice, many patients with COPD will also have OSA and will likely need higher EPAP settings.
Question 5: Should NIV with targeted normalization of Pa CO 2 amounts versus NIV without targeting normal Pa CO 2 amounts be used for long-term NIV in patients with COPD?
Recommendation. We suggest NIV with targeted normalization of Pa CO 2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).
Background. A variety of different approaches to NIV have been used over the years in studies of patients with hypercapnic COPD, including different equipment, ventilation modes and settings, and therapeutic targets (e.g., symptoms and patient adherence). Given that stable hypercapnia is characterized by persistent elevation in Pa CO 2 , one target for NIV has been adjustment of therapy on the basis of Pa CO 2 . More recently, several studies have used so-called high-intensity NIV, which refers to high inspiratory pressures as well as higher-than-baseline respiratory rates to reduce Pa CO 2 [bib_ref] High-intensity non-invasive positive pressure ventilation for stable hypercapnic COPD, Windisch [/bib_ref] [bib_ref] Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive..., Köhnlein [/bib_ref]. However, the impact of normalization of Pa CO 2 is not known.
Summary of the evidence. There has been no direct comparison of these two similar but distinct modes of titration of NIV with regard to long-term outcomes (e.g., mortality). Nor have there been smaller homogenous studies that lend themselves to a meta-analytic approach. The available indirect data are from generally small physiological studies in which patients already on NIV were placed on settings designed to reduce Pa CO 2 for minutes to weeks at a time and then crossed over to less intense settings in random order, and outcomes that have been studied to date include change in CO 2 concentrations, patient comfort, and NIV adherence. Pooled data from these studies demonstrate greater reductions in Pa CO 2 amounts when NIV is specifically targeting CO 2 clearance (MD, 4.9 mm Hg lower; 95% CI, 7.4 to 2.4 mm Hg lower; low certainty), and Pa O 2 increased by 3.4 mm Hg (2.4 mm Hg lower to 9.2 mm Hg higher, low certainty). There were no significant differences in QOL (low certainty) or adherence (low certainty).
In addition to these physiological studies directly comparing high-versus lowintensity NIV, the panel also considered subgroup analysis of all available studies of NIV in stable hypercapnic COPD (from PICO question 1). As part of this subgroup analysis, we compared RCTs that targeted normalization of Pa CO 2 (high intensity) to studies that did not specifically target Pa CO 2 (low intensity). This analysis did not demonstrate any credible subgroup effect, with similar clinical outcomes seen in both groups. In part, this might be because the difference in Pa CO 2 between high-versus low-intensity NIV was relatively modest at 2.8 mm Hg. However, it should be noted that sleep amounts of Pa CO 2 were not always measured and might show larger differences.
Rationale for the recommendation. Our analysis did not demonstrate any effect on mortality when using targeted Pa CO 2 reduction with NIV in patients with stable hypercapnic COPD, although the certainty of evidence was low or very low for all outcomes, with no direct head-to-head trials. Pa CO 2 amounts tend to decrease only modestly with therapy; thus, the benefits of a further reduction in Pa CO 2 are unclear, and it is uncertain whether any potential benefit of NIV is mediated directly through lowered Pa CO 2 amounts or whether Pa CO 2 is a marker of other benefits from NIV (e.g., intrinsic muscle work of breathing).
In the absence of strong data favoring high-intensity NIV, the primary concerns were cost and other practical considerations related to measurement and monitoring of CO 2 . Costs associated with targeted Pa CO 2 reduction are not insignificant and would include the possible need for hospital admission to titrate initial settings, increased follow-up clinic visits, and arterial or transcutaneous blood-gas testing, all of which are potentially not needed when using low-intensity NIV that does not target Pa CO 2 amounts. Overall, the marginal "cost" to stakeholders is probably small. A commonly voiced concern with Pa CO 2targeted NIV is adherence related to higher pressures required to normalize Pa CO 2 . However, adherence to NIV has been similar to that for low-intensity settings in two studies [bib_ref] Impact of high-intensity-NIV on the heart in stable COPD: a randomised cross-over..., Duiverman [/bib_ref] [bib_ref] High pressure versus high intensity noninvasive ventilation in stable hypercapnic chronic obstructive..., Murphy [/bib_ref] and slightly greater with high-intensity NIV in one study [bib_ref] High-intensity versus low-intensity non-invasive ventilation in patients with stable hypercapnic COPD: a..., Dreher [/bib_ref]. Thus, the use of Pa CO 2 -targeted NIV is probably feasible and acceptable to key stakeholders, allowing for a clear target to guide the use and titration of NIV.
## Unanswered questions and research
priorities. Further research is needed to define optimal Pa CO 2 reduction (to normal amounts or a different threshold), define the speed at which Pa CO 2 should be reduced, and determine whether benefits of NIV occur in all patients with COPD and hypercapnia or whether there are specific subgroups that benefit most. In addition, the relationship between nighttime Pa CO 2 and daytime Pa CO 2 should be further evaluated to determine which is a better target to direct titration. As noted above, the optimal modes and settings used to reduce CO 2 need further study. In addition, titration with less invasive forms of CO 2 monitoring, such as transcutaneous or venous blood gases, should also be evaluated. Possible additional harms of NIV with targeted normalization of Pa CO 2 that require further investigation include its impact on hemodynamics, especially in patients with COPD and cardiac comorbidities. For example, Duiverman and colleagues [bib_ref] Impact of high-intensity-NIV on the heart in stable COPD: a randomised cross-over..., Duiverman [/bib_ref] reported individual reductions in Q : with high-intensity NIV in patients with heart failure.
# Discussion
What Others Are Saying
The European Respiratory Society (ERS) recently published the results of a task force examining the broad issue of home NIV for stable hypercapnic COPD [bib_ref] European Respiratory Society guidelines on long-term home non-invasive ventilation for management of..., Ergan [/bib_ref]. Several PICO questions were similar to our questions and resulted in similar conclusions (i.e., conditional recommendation for NIV and for attempts to target reductions in Pa CO 2 ). However, one notable difference was the timing of NIV initiation, with the ERS guideline suggesting initiation of NIV shortly after hospitalization for an acute exacerbation of COPD if hypercapnia persists. No specific time frame was provided, and reassessment 2-4 weeks after the initial episode "could be considered." As discussed above, we do suggest reassessment at 2-4 weeks before consideration of long-term therapy. Although the ERS task force considered various modes and settings for delivery of NIV, we remain agnostic, given the paucity of data in this regard. Another difference was our consideration of OSA before the initiation of NIV, which may reflect higher rates of obesity in the United States than in Europe (70) and thus a greater likelihood of encountering OSA. Overall, the ATS and ERS statements complement each other and provide assurance about the validity of the recommendations made in them.
## Putting it all together
Few interventions have been shown to improve morbidity and mortality in COPD. Thus, it is exciting to consider NIV as additional therapy for those with hypercapnic COPD. Nevertheless, there are many issues to consider.
First, appropriate patient selection remains critical. We emphasize that the patients in the studies reviewed here were selected because they had severe chronic stable hypercapnic COPD, and subjects with severe obesity or known OSA were excluded. In clinical practice, there are likely patients who have unrecognized concomitant OSA (so-called overlap syndrome) who might be treated with CPAP rather than NIV. Although data are lacking, have demonstrated hypercapnia with relatively preserved lung function in patients with OSA-COPD compared with patients with COPD alone, a finding that may help clinicians recognize those patients. Although use of NIV, properly titrated, for these patients will not clearly cause harm, there are additional costs with NIV, and the emphasis of treatment might differ on the basis of the underlying diagnosis. Alternatively, many clinicians do not routinely measure arterial blood gases in clinic or use other surrogate measures such as transcutaneous CO 2 monitoring. As a result, it is possible that many patients who should be considered for NIV will not be included. Our recommendations have generally tried to limit the use of NIV to patients with persistent hypercapnia from COPD alone. Unfortunately, COPD is often clinically misdiagnosed in patients with overweight and obesity; clinicians need to be aware of alternate diagnoses such as obesity hypoventilation [bib_ref] The association of weight with the detection of airflow obstruction and inhaled..., Collins [/bib_ref].
Second, there are implementation barriers to consider with these recommendations. Not all pulmonologists, nor all sleep physicians, are comfortable with NIV. Education will be needed for clinicians, respiratory therapists, and registered polysomnographic technicians who will be expected to evaluate, study, and potentially titrate NIV for subjects in the sleep laboratory. Such education should include knowledge of supplemental oxygen, measurement of transcutaneous CO 2 , positive-pressure ventilation modes, and interfaces. Furthermore, initiation of NIV in clinical practice will be very different from its initiation in research. For example, in the recent study by Duiverman and colleagues [bib_ref] Home initiation of chronic non-invasive ventilation in COPD patients with chronic hypercapnic..., Duiverman [/bib_ref] , initiation in the hospital occurred over 7 days, on average (range, 4-15 d). Finally, adherence to this therapy will require additional efforts.
Third, clearly more data are needed to guide the desired goals of therapy, specifically regarding how aggressively clinicians should target Pa CO 2 . Is a greater reduction always better? Might there be tradeoffs with adherence with increasing pressures (or improvements with adherence with more respiratory support)? What are the dangers of a too-rapid normalization of Pa CO 2 ? In addition, if Pa CO 2 is a rational target for therapy, what will be the best mode and settings to achieve such a reduction?
Fourth, the panel noted that there were several regulatory and payor considerations AMERICAN THORACIC SOCIETY DOCUMENTS (at least in the United States) related to the ability to obtain home NIV for COPD (reviewed in Reference 73). The Centers for Medicare and Medicaid Services requires the following testing and evaluation elements to consider NIV therapy: arterial blood gas, overnight oximetry, and evaluation for OSA (although formal testing is not required). Although these tests alone may be difficult to accomplish, successful completion will only confirm eligibility for a respiratory assist device that will not have a backup rate; many of the studies above, and particularly those targeting Pa CO 2 reductions, used devices capable of providing a backup rate. Paradoxically, it may be easier to qualify a patient for a more expensive home ventilator. Should more definitive evidence suggest mortality or other hard outcome benefits, an easier approval process for the needed therapy will be required.
Finally, given the cost and expertise needed to provide NIV for patients with stable hypercapnic COPD, there is potential for worsening of healthcare disparities. This is especially likely in rural and underserved regions, where important comorbidities (obesity, OSA) are likely to coexist.
The strengths of the current work include an expert panel including leaders in the field, strict conflict-of-interest management, an a priori set of questions and outcome prioritization, librarian support, a comprehensive search of the literature, and application of GRADE to assess certainty in evidence and develop recommendations using the EtD process. Thus, the panel has gathered all relevant information to comment on patient-and provider-relevant outcomes. Although the panel did include patients with COPD when considering relevant outcomes, one limitation is that we could have included more patients or maintained involvement of patients throughout the guidelinedevelopment process. Other limitations relate to the paucity of direct data for some of our PICO questions and heterogeneity in pooled analyses, which ultimately led to low or very low certainty of evidence for many of our PICO questions. Finally, there are as yet few cost-effectiveness data, particularly in the United States, and this limited our ability to include these considerations in the recommendation deliberations with any degree of certainty.
# Future research
Specific research topics are reviewed for each PICO question above. As can be seen, there are a number of questions that will require several different approaches to answer. For example, studies of relatively short duration might be useful to compare modes and settings of ventilation. A modest number of longitudinal studies of those with acute exacerbation of COPD would be useful to help address gaps in knowledge regarding resolution versus persistence of elevated Pa CO 2 . However, larger and longerduration studies will be needed to assess the efficacy of NIV both on hard outcomes and also on patient-centered metrics. A recurring theme was the need for more generalizable studies (i.e., less restrictive patient inclusion criteria, such as including concomitant OSA) and more real-world studies to better assess the impact of NIV distinct from the effects of frequent assessments and interactions with healthcare providers that take place during research.
# Conclusions
On the basis of the evidence to date, we suggest long-term nocturnal NIV for chronic stable hypercapnic COPD. Research is needed to better determine the benefits and optimal management of such patients. Barriers to implementation will require attention from physicians as well as payors and other stakeholders. n patent 10,315,002 for a ventilator with integrated oxygen production and U.S. patent 10,245,406 for a ventilator with integrated oxygen production. B.C. served on an advisory committee for Chiesi, GlaxoSmithKline, Pulmonx, and Sanofi; as a consultant for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini, and Sanofi; and as a speaker for Novartis; and received research support from AstraZeneca. D.R.H. served on an advisory committee for Ventec Life Support; served as a consultant for Philips Respironics and Ventec Life Support; received author royalties from Jones and Bartlett, McGraw-Hill, and UpToDate; received other transfers of value from American Board of Internal Medicine Pulmonary Disease Board; and served as an editor-in-chief of Respiratory Care and as such is an employee of Daedalus Enterprises. J.A.O. served on an advisory committee for AstraZeneca, Boehringer Ingelheim,
[fig] 2: 53 mm Hg) 2-4 weeks afterward were AMERICAN THORACIC SOCIETY DOCUMENTS e80 American Journal of Respiratory and Critical Care Medicine Volume 202 Number 4 | August 15 2020 [/fig]
[table] Table 1: to 1.27; low certainty). Application of Guideline Recommendations for Different Stakeholders [/table]
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https://pure.rug.nl/ws/files/132158460/Long_Term_Noninvasive_Ventilation_in_Chronic_Stable_Hypercapnic_Chronic_Obstructive_Pulmonary_Disease._An_Official_American_Thoracic_Society_Clinical_Practice_Guideline.pdf
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Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited. Target Audience: Patients with COPD, clinicians who care for them, and policy makers. Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework. Recommendations: 1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty). Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.
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468e3d05337bb939c2270d36ff4a6d14d3377d81
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pubmed
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Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition
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Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition
[bib_ref] Usefulness of a rapid faecal calprotectin test to predict relapse in Crohn's..., Ferreiro-Iglesias [/bib_ref] [bib_ref] The utility of faecal calprotectin to predict post-operative recurrence in Crohns disease, Bachiller [/bib_ref] [bib_ref] NICE referral guidelines for suspected cancer: colorectal cancer and faecal occult blood..., Benton [/bib_ref] [bib_ref] Application of NICE guideline NG12 to the initial assessment of patients with..., Quyn [/bib_ref]
## Common disoders
## Maldigestion of fructose-based carbohydrates and lactose, and polyhydric alcohols
Although the clinical utility of fructose / fructan hydrogen breath tests in this context is unproven, the expense and relative difficulty of adhering to a diet low in fermentable carbohydrates such as the 'low FODMAP diet makes desirable the ability to direct dietary management to those patients that are most likely to benefit. Recent studies have shown that the occurrence of symptoms after ingestion of a dietary challenge including 20g lactose (in IBS patients with lactase deficiency) or 25g lactulose (all IBS patients) identified a group of patients with visceral hypersensitivity; the sensitivity falls with lower doses. [bib_ref] Lactulose Challenge Determines Visceral Sensitivity and Severity of Symptoms in Patients With..., Neve [/bib_ref] Concurrent assessment of oro-caecal transit and fermentation has the potential to identify the causes of IBS symptoms in many patients. Studies are awaited that assess whether this approach identifies patients that will respond to a reduction in dietary FODMAPs or other specific interventions. [bib_ref] Dietary challenge tests: identifying food intolerance as a cause of symptoms in..., Deng [/bib_ref] 6.0 TESTS FOR MALABSORPTION
## Faecal elastase
A sensitive commercial ELISA utilising 2 monoclonal antibodies to human E1 is available.
Faecal elastase has also been compared with structural/imaging tests. measured FE in 213 patients undergoing ERCP finding that sensitivity for any ductal change was only 45% but this increased to 75% for more severe ductal abnormality. These results have been broadly confirmed by Keim et al. [bib_ref] Clinical value of a new fecal elastase test for detection of chronic..., Keim [/bib_ref] who found sensitivities of 69% and 78% for 2 FE assays with specificities of 76 and 77% for ductal changes seen at ERCP. An MRCP study of 81 patients with chronic pancreatitis showed 31/56 patients had MRI abnormalities despite normal FE emphasising the point that exocrine function is preserved long after structural change is present. [bib_ref] Magnetic resonance imaging and magnetic resonance cholangiopancreatography findings compared with fecal elastase..., Bilgin [/bib_ref] The wider availability of FE testing has led to its use in assessment of a number of conditions. Thus FE has been found to be reduced in coeliac disease, [bib_ref] Pancreatic insufficiency in adult celiac disease: do patients require long-term enzyme supplementation?, Evans [/bib_ref] , IBS, [bib_ref] Some patients with irritable bowel syndrome may have exocrine pancreatic insufficiency, Leeds [/bib_ref] senescence [bib_ref] Fecal pancreatic elastase-1 levels in older individuals without known gastrointestinal diseases or..., Herzig [/bib_ref] and in diabetes. [bib_ref] High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study..., Hardt [/bib_ref] Whether this reflects a true deficiency in pancreatic function or confounding factors due to the dilutional effects of diarrhoea remain unclear. However, care is needed in interpreting low FE results as this does not necessarily indicate pancreatic dysfunction.
Nevertheless, given the ease of use and at least comparable performance compared with other non-invasive pancreatic function tests, Faecal elastase remains the most effective initial screening test for pancreatic insufficiency.
Bristol Stool Chart (courtesy of Dr K Heaton)
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None
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https://gut.bmj.com/content/gutjnl/67/8/1380.full.pdf
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Chronic diarrhoea is a common problem, hence clear guidance on investigations is required. This is an updated guideline from 2003 for the investigations of chronic diarrhoea commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG). This document has undergone significant revision in content through input by 13 members of the Guideline Development Group (GDG) representing various institutions. The GRADE system was used to appraise the quality of evidence and grading of recommendations.
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b87b63a5eca361918661bc21b6b4baa69812ec51
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pubmed
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Measles, Mumps, Rubella Vaccine (PRIORIX): Recommendations of the Advisory Committee on Immunization Practices — United States, 2022
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Measles, Mumps, Rubella Vaccine (PRIORIX): Recommendations of the Advisory Committee on Immunization Practices — United States, 2022
[bib_ref] Recommendation of the Advisory Committee on Immunization Practices for use of a..., Marin [/bib_ref] [bib_ref] Maintenance of measles elimination status in the United States for 20 years..., Mathis [/bib_ref] [bib_ref] Recommendation of the Advisory Committee on Immunization Practices for use of a..., Marin [/bib_ref]
## Summary of key findings
SAEs related to administration of PRIORIX were assessed using findings from four randomized controlled clinical trials at the licensed U.S. potency of PRIORIX and one Cochrane review with PRIORIX at any potency [bib_ref] Immunogenicity and reactogenicity of a new measles, mumps and rubella vaccine when..., Gothefors [/bib_ref] [bib_ref] Safety and immunogenicity of human serum albumin-free MMR vaccine in US children..., Mufson [/bib_ref] [bib_ref] Vaccines for measles, mumps, rubella, and varicella in children, Pietrantonj [/bib_ref]. Four additional observational studies and one additional systematic review addressed additional adverse events of interest (i.e., rate of febrile seizures, aseptic meningitis, and ITP) [bib_ref] A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and..., Farrington [/bib_ref] [bib_ref] Vaccine Safety Datalink Team. Risk of immune thrombocytopenic purpura after measles-mumpsrubella immunization..., France [/bib_ref] [bib_ref] Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United..., Miller [/bib_ref] [bib_ref] The risk of immune thrombocytopenic purpura after vaccination in children and adolescents, O'leary [/bib_ref] [bib_ref] Enhancing global vaccine pharmacovigilance: proof-of-concept study on aseptic meningitis and immune thrombocytopenic..., Perez-Vilar [/bib_ref]. Outcomes for PRIORIX were compared with those for M-M-R II. In the four randomized controlled clinical trials at the U.S. potency of PRIORIX, safety profiles among 1,960 subjects receiving 1 or 2 doses of PRIORIX were compared with those among 933 subjects randomized to receive 1 or 2 doses of M-M-R II. The subjects ranged in age from 12 months to 12 years, with 90% aged 12-15 months. The frequency of vaccine-related SAEs was similar across the vaccine These studies included coadministration of recommended age-appropriate vaccines, and all found the differences in rates of febrile seizures between the two vaccines to be nonsignificant [bib_ref] Safety and immunogenicity of human serum albumin-free MMR vaccine in US children..., Mufson [/bib_ref] [bib_ref] Immunogenicity and safety of a measles-mumps-rubella vaccine administered as a first dose..., Klein [/bib_ref]. Similarly, the time course of fever was comparable for both vaccines across all studies, with most instances observed 5-12 days postvaccination (Remon Abu-Elyazeed, MD, PhD, GlaxoSmithKline Biologicals, personal communication, . No evidence of an association of aseptic meningitis with MMR vaccination was reported in the literature for vaccines containing Jeryl Lynn or Jeryl Lynnderived mumps strains, which are included in both M-M-R II and PRIORIX for immunization against mumps [bib_ref] Vaccines for measles, mumps, rubella, and varicella in children, Pietrantonj [/bib_ref] [bib_ref] Risks of convulsion and aseptic meningitis following measles-mumps-rubella vaccination in the United..., Miller [/bib_ref].
ITP is associated with the receipt of live attenuated measles vaccines [bib_ref] Vaccines for measles, mumps, rubella, and varicella in children, Pietrantonj [/bib_ref] [bib_ref] Vaccine Safety Datalink Team. Risk of immune thrombocytopenic purpura after measles-mumpsrubella immunization..., France [/bib_ref] [bib_ref] The risk of immune thrombocytopenic purpura after vaccination in children and adolescents, O'leary [/bib_ref] [bib_ref] Enhancing global vaccine pharmacovigilance: proof-of-concept study on aseptic meningitis and immune thrombocytopenic..., Perez-Vilar [/bib_ref]. In the four randomized controlled clinical trials at the U.S. potency of PRIORIX, one case of ITP was identified among 1,960 PRIORIX recipients and one case among 933 M-M-R II recipients. From a previous postmarketing study conducted in the United States, the rate of ITP after M-M-R II is estimated at 2.5 per 100,000 doses [bib_ref] Vaccine Safety Datalink Team. Risk of immune thrombocytopenic purpura after measles-mumpsrubella immunization..., France [/bib_ref]. However, strain-or vaccine formulation-specific data on ITP risk are sparse. Based on the clinical trials and the literature [bib_ref] Vaccines for measles, mumps, rubella, and varicella in children, Pietrantonj [/bib_ref] [bib_ref] Vaccine Safety Datalink Team. Risk of immune thrombocytopenic purpura after measles-mumpsrubella immunization..., France [/bib_ref] [bib_ref] The risk of immune thrombocytopenic purpura after vaccination in children and adolescents, O'leary [/bib_ref] [bib_ref] Enhancing global vaccine pharmacovigilance: proof-of-concept study on aseptic meningitis and immune thrombocytopenic..., Perez-Vilar [/bib_ref] , the rates of ITP after vaccination were considered similar for PRIORIX and M-M-R II.
Short-term humoral immunity was assessed using data from 13 randomized controlled trials [bib_ref] Immunogenicity and reactogenicity of a new measles, mumps and rubella vaccine when..., Gothefors [/bib_ref] [bib_ref] Safety and immunogenicity of human serum albumin-free MMR vaccine in US children..., Mufson [/bib_ref] [bib_ref] Immunogenicity and safety of a measles-mumps-rubella vaccine administered as a first dose..., Klein [/bib_ref] [bib_ref] Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered..., Abu-Elyazeed [/bib_ref] [bib_ref] A randomized comparative trial in order to assess the reactogenicity and immunogenicity..., Gatchalian [/bib_ref] [bib_ref] A new measles mumps rubella (MMR) vaccine: a randomized comparative trial for..., Lee [/bib_ref] [bib_ref] Reappraisal of MMR vaccines currently used in Korea, Lee [/bib_ref] [bib_ref] Comparative study of reactogenicity and immunogenicity of new and established measles, mumps..., Usonis [/bib_ref] [bib_ref] Neutralization activity and persistence of antibodies induced in response to vaccination with..., Usonis [/bib_ref] [bib_ref] Reactogenicity and immunogenicity of a new live attenuated combined measles, mumps and..., Usonis [/bib_ref] , four at the licensed U.S. potency of PRIORIX, and nine at a lower potency of PRIORIX used in other countries. Serologic response thresholds were achieved for all three antigens in all studies. Antibodies in all studies were more than 8.8-fold higher than the predefined seroresponse threshold for measles (200 mIU per mL; correlate of protection 120 mIU per mL) and more than 4.2-fold higher than the rubella correlate (10 IU per mL). Although an antibody correlate of protection has not been established for mumps, the anti-mumps antibody level was ≥3.3-fold higher than the mumps seroconversion threshold (10 IU per mL). The four studies conducted with PRIORIX at the U.S. potency found no significant difference in anti-measles, anti-mumps, or anti-rubella geometric mean concentrations (GMC) after the first dose between PRIORIX and M-M-R II recipients. Among the nine studies at a lower PRIORIX potency, eight showed no statistically significant difference between anti-measles or anti-rubella GMC levels, and seven showed no statistically significant difference between anti-mumps GMC levels. One study reported on persistence of the humoral immune response (2 years after vaccination) and found no difference between vaccines [bib_ref] Two-year antibody persistence in children vaccinated at 12-15 months with a measlesmumps-rubella..., Berry [/bib_ref]. None of the four studies that reported on GMC after a second dose noted a significant difference for any antigen at any potency after a second dose between PRIORIX or M-M-R II recipients [bib_ref] Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered..., Abu-Elyazeed [/bib_ref].
Additional data reviewed within the EtR framework included findings from a focus group conducted with state immunization managers and a survey of pediatric and general practitioners regarding the feasibility for use and acceptability of PRIORIX. Both the focus group and the survey findings supported the interchangeability of M-M-R II and PRIORIX and the benefit of having a second MMR vaccine option available.
## Summary
What is already known about this topic?
Since 1978, M-M-R II has been the only measles, mumps, and rubella (MMR) combination vaccine used in the United States. In June 2022, the Food and Drug Administration licensed an additional MMR vaccine, PRIORIX.
What is added by this report?
The Advisory Committee on Immunization Practices recommends PRIORIX as an additional option to prevent MMR according to existing vaccine recommendations and off-label uses.
What are the implications for public health practice?
Both vaccines are interchangeable for all indications for which MMR vaccination is recommended. Availability from multiple manufacturers safeguards U.S. vaccine supply.
## Rationale for recommendation
Given the similarities in potency and vaccine components, and evidence for similar safety and immunogenicity, as well as stakeholder support, PRIORIX and M-M-R II are considered fully interchangeable, including for all off-label recommended uses. Either vaccine may be administered in any situation in which an MMR virus-containing vaccine is indicated. Two interchangeable vaccines from different manufacturers will help safeguard vaccine supply in the United States to maintain measles and rubella elimination and mitigate mumps cases and outbreaks.
## Acip recommendation
PRIORIX is recommended according to the existing MMR recommended schedules and off-label uses [bib_ref] Recommendation of the Advisory Committee on Immunization Practices for use of a..., Marin [/bib_ref] as an option to prevent measles, mumps, and rubella.
## Clinical guidance
PRIORIX is supplied as a single-dose vial of lyophilized antigen to be reconstituted with the accompanying prefilled syringe of sterile water diluent. A single dose after reconstitution is approximately 0.5 mL. PRIORIX is formulated without preservatives and is administered as subcutaneous injection (the same as M-M-R II).
PRIORIX may be used according to the existing MMR recommendations for both on-and off-label use for prevention of measles, mumps, and rubella † † [bib_ref] Recommendation of the Advisory Committee on Immunization Practices for use of a..., Marin [/bib_ref]. For routine vaccination, 2 doses are recommended, the first at age 12-15 months, and the second at age 4-6 years. For catch-up vaccination of previously unvaccinated children and adolescents, 2 doses † † No direct evidence for PRIORIX for off-label uses; recommendation is based on existing ACIP recommendations and comparative use of M-M-R II in similar situations.
should be administered ≥4 weeks apart. Before international travel, infants aged 6-11 months should receive a single dose. Travelers aged ≥12 months who have not received 2 doses of MMR should receive 2 doses separated by ≥28 days. During a measles outbreak, infants aged 6-11 months should receive a single dose of MMR. For measles postexposure prophylaxis in unvaccinated persons, 1 dose of MMR should be administered within 72 hours of exposure to a person with infectious measles, and the 2-dose series (i.e., the second of 2 MMR doses) should be completed ≥28 days later. During mumps outbreaks, a third dose of MMR is recommended for persons identified by public health authorities as being part of a group or population at increased risk for acquiring mumps because of an outbreak.
## Interchangeability
PRIORIX and M-M-R II are fully interchangeable. ACIP General Best Practices states a preference that doses of vaccine in a series come from the same manufacturer; however, vaccination should not be deferred when the manufacturer of the previously administered vaccine is unknown or when the vaccine from the same manufacturer is unavailable. Studies have shown that PRIORIX is safe and immunogenic when administered as a second dose after M-M-R II [bib_ref] Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered..., Abu-Elyazeed [/bib_ref].
## Timing of vaccination and coadministration with other vaccines
PRIORIX can be administered concomitantly, at different anatomic sites, with other routine childhood vaccines. Concomitant administration of PRIORIX with other live and nonlive vaccines § § has been studied; results indicated no safety concerns or evidence for interference in the immune response to either [bib_ref] Safety and immunogenicity of human serum albumin-free MMR vaccine in US children..., Mufson [/bib_ref] [bib_ref] Immunogenicity and safety of a measles-mumps-rubella vaccine administered as a first dose..., Klein [/bib_ref] [bib_ref] Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered..., Abu-Elyazeed [/bib_ref]. Additional live virus vaccines not administered on the same day should be separated by ≥4 weeks.
## Precautions and contraindications
Before administering PRIORIX, health care providers should consult the package insert for precautions, warnings, and contraindications. Contraindications for PRIORIX are the same as those for M-M-R II. PRIORIX should not be administered to persons with a history of severe allergic reactions (e.g., anaphylaxis) to any component of the vaccine or after a previous dose of any measles, mumps, and rubella virus-containing vaccine (unlike M-M-R II, PRIORIX does § § Among children aged 12-15 months: with 13-valent pneumococcal conjugate vaccine (PCV13-Prevnar), Varivax (VAR), Havrix (HAV), and 7-valent pneumococcal conjugate vaccine (PCV7). Among children aged 4-6 years: with Kinrix (DTaP-IPV) and Varivax. not contain gelatin); persons with severe humoral or cellular (primary or acquired) immunodeficiency; or women who are pregnant. Pregnancy should be avoided for 1 month after receipt of MMR. Additional information on warnings and precautions can be found in the package insert and previous vaccine recommendations.
## Reporting of vaccine adverse events
Adverse events following administration of any vaccine should be reported to the Vaccine Adverse Event Reporting System (VAERS). Reports can be submitted to VAERS online, by fax, or by mail. Additional information about VAERS is available by telephone (1-800-822-7967) or online (https:// vaers.hhs.gov). Any future revisions to this ACIP recommendation will be dictated by reported adverse events and new research evidence.
[table] TABLE: Components and infectious dosage* of measles, mumps, and rubella vaccines † licensed in the United States [/table]
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None
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https://www.cdc.gov/mmwr/volumes/71/wr/pdfs/mm7146a1-H.pdf
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Vaccination is the main means for preventing measles, mumps, and rubella virus infections and their related complications (1,2). Achieving and maintaining high 2-dose measles, mumps, and rubella vaccination coverage in the United States has led to elimination of endemic measles in 2000, rubella and congenital rubella syndrome in 2004, and a sharp decrease in mumps cases. However, measles and rubella remain endemic in many countries, leading to importations of cases and occasional local transmission within the United States (3). Reported U.S. mumps cases declined >99% from the prevaccine period (4); however, mumps is endemic worldwide, and since 2006, the number of mumps cases and mumps outbreaks has increased in the United States, with wider geographic spread since 2016 (4). Given the risk for importation of measles and rubella and the resurgence of mumps, maintaining high measles, mumps, and rubella (MMR) vaccination coverage is important. Since 1978, only one MMR vaccine, M-M-R II (Merck and Co., Inc.), has been available in the United States. On June 6, 2022, the Food and Drug Administration approved a second MMR vaccine, PRIORIX (GlaxoSmithKline Biologicals), for the prevention of measles, mumps, and rubella in persons aged ≥12 months. The three live attenuated viruses contained in PRIORIX are genetically similar or identical to the corresponding components in M-M-R II (Table) (5-7). On June 23, 2022, the Advisory Committee on Immunization Practices (ACIP) unanimously recommended PRIORIX as an option to prevent measles, mumps, and rubella according to the existing recommended schedules and for off-label uses (i.e., indications not included in the package insert)* (1,2). ACIP considered PRIORIX to be safe, immunogenic, and noninferior to M-M-R II. Both PRIORIX and M-M-R II are fully interchangeable for all indications for which MMR vaccination is recommended. This report contains ACIP recommendations specific to PRIORIX and supplements the existing ACIP recommendations for MMR use (1,2).
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52317fa1262a899a26de465579fccee760925259
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pubmed
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Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines
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Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines
Purpose: To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness.Methods:We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We defined "early" EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds.Results:We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion.Conclusions:We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate >500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access.
# Introduction
Existing guidelines recommend initiating enteral nutrition (EN) within the first 24-48 h after intensive care unit (ICU) admission if patients are unable to eat, not clearly defining reasons to delay EN [bib_ref] for Parenteral and Enteral Nutrition) (2006) ESPEN guidelines on enteral nutrition: intensive..., Kreymann [/bib_ref] [bib_ref] Metabolism and Nutrition Working Group of the Spanish Society of Intensive Care..., Fernández-Ortega [/bib_ref] [bib_ref] Guidelines for the provision and assessment of nutrition support therapy in the..., Taylor [/bib_ref]. The present guideline is issued by the Working Group on Gastrointestinal Function within the Metabolism, Endocrinology and Nutrition (MEN) Section of the European Society of Intensive Care Medicine (ESICM) and is endorsed by ESICM. Our objective was to provide evidence-based guidelines for early enteral nutrition (EEN) in critically ill patients, focusing on specific clinical conditions frequently associated with delayed EN. Caloric and protein requirements, time to reach targets, type and route of EN, and timing of supplemental or full parenteral nutrition (PN) were not addressed. A full version of the introduction with references is available in Supplement 1.
# Methods
A full version of methods with references is available in Supplement 1.
We performed a systematic review of "early" EN (EEN) vs. early parenteral nutrition (PN) and EEN vs. delayed EN in adult critically ill patients. After critical appraisal of identified studies and in accordance with current guidelines [bib_ref] for Parenteral and Enteral Nutrition) (2006) ESPEN guidelines on enteral nutrition: intensive..., Kreymann [/bib_ref] [bib_ref] Metabolism and Nutrition Working Group of the Spanish Society of Intensive Care..., Fernández-Ortega [/bib_ref] [bib_ref] Guidelines for the provision and assessment of nutrition support therapy in the..., Taylor [/bib_ref] , we defined EEN as EN started within 48 h of admission independent of the type or amount.
Thereafter, we predefined conditions in which EN is frequently delayed and performed a systematic review for each of these questions.
If randomised controlled trials (RCT) were available, we gave an evidence-based recommendation; if not, our recommendations were based on expert opinion (very low quality evidence), as all observational studies evaluating EEN are intrinsically biased, because patients who are less severely ill are more likely to receive and tolerate EEN.
## General considerations
We focussed on specific conditions in which EN is frequently delayed and tolerance of EN might be impaired. Therefore, all our recommendations are based on general principles and precaution measures outlined in [bib_ref] Nutrition in the acute phase of critical illness, Casaer [/bib_ref] [bib_ref] Early high protein intake is associated with low mortality and energy overfeeding..., Weijs [/bib_ref] [bib_ref] Permissive underfeeding or standard enteral feeding in critically ill adults, Arabi [/bib_ref] [bib_ref] Editorial on the original article entitled "Permissive underfeeding of standard enteral feeding..., Casaer [/bib_ref] [bib_ref] Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of..., Blaser [/bib_ref]. All study questions and recommendations refer to adult critically ill patients.
# Results
All recommendations with the final agreed results are presented in.
A flow chart with evidence identification process (Supplement 2), number of identified abstracts and assessed full texts for each study question (Supplement 3), Pubmed search formulas (Supplement 4), evidence tables for each question with respective references (Supplement 5), evidence profiles for questions with meta-analyses [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref] , evidence profiles for additional meta-analyses for Question 1 and 11 (Supplement 6), Forest plots for meta-analyses (Figs. 1, 2 and Supplement 7) are provided.
## Question 1: should we use een in critically ill adult patients?
The methodology is described in Supplement 1. Do not increase EN in cases of intolerance or new symptoms, such as pain, abdominal distension or increasing intra-abdominal pressure. In these circumstances EN should be either continued at a slow rate or ceased depending on the severity of symptoms and suspected underlying sinister pathology (e.g. mesenteric ischaemia)
## Table 1 general principles and precautions for using een in critically ill patients at risk of intolerance
Energy target during EEN Do not aim to cover full energy target with EEN. The optimal energy and protein target in the early phase of acute critical illness is not known. EEN that exceeds actual energy expenditure appears harmful and should be avoided [bib_ref] Nutrition in the acute phase of critical illness, Casaer [/bib_ref] [bib_ref] Early high protein intake is associated with low mortality and energy overfeeding..., Weijs [/bib_ref] , whereas hypocaloric EEN may be safe [bib_ref] Permissive underfeeding or standard enteral feeding in critically ill adults, Arabi [/bib_ref] [bib_ref] Editorial on the original article entitled "Permissive underfeeding of standard enteral feeding..., Casaer [/bib_ref] Monitoring and protocolised management of GI dysfunction during EEN In case of gastric retention without other new abdominal symptoms use prokinetics and/or postpyloric feeding in a protocolised way [bib_ref] Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of..., Blaser [/bib_ref] During introduction and increasing the rate of EN, measurement of intraabdominal pressure (IAP) provides an additional numeric value to detect negative dynamics of IAP during EN in patients with severe abdominal pathology, hypoperfusion or fluid overload
Individualized approach For patients with diminished consciousness and inadequate swallowing, precautions to prevent aspiration of gastric contents may be useful, including considering postpyloric feeding Premorbid health and course of the acute illness may differ between patients with similar diagnose; therefore an individual approach should always be applied Response rate was 100% in both Delphi rounds (all co-authors responded, methodologist did not participate). Agreement is calculated as percentage of "agree" answers from total Question 1A: Should we use EEN rather than early PN? Eight trials fulfilled the criteria and were included in meta-analyses (Supplement 5, . Results are presented in [fig_ref] Figure 1: Forest plots [/fig_ref].
For mortality, we included seven RCTs (2686 patients). EEN did not reduce mortality compared to early PN (RR 0.95; 95% CI 0.76-1.19; P = 0.64; I 2 = 9%). The certainty of evidence was moderate. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For infection, we included seven RCTs (2729 patients). EEN reduced the risk of infections compared to early PN (RR 0.55; 95% CI 0.35-0.86; P = 0.009; I 2 = 65%). The certainty of evidence was low. We rated down for risk of bias and inconsistency [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
Adding 11 additional studies identified during searches for questions in specified patient groups did not significantly change our results (included studies are presented in Supplement 5, ; evidence profiles in Supplement 6 and Forest plots in Supplement 7, . 1. Although the randomization method was inappropriate or unclear in four RCTs out of ϐive, we did not downgrade for risk of bias because the overall results did not change after excluding high risk of bias trials from the analysis, it is unlikely that risk of bias affected the mortality estimate. 2. We did not downgrade for inconsistency (I 2 = 9%) 3. We downgraded for imprecision by one level because the CI included signiϐicant beneϐit and harms (076, 1.19) 4. We downgraded for risk of bias by one level, most RCTs were non-blinded and had unclear or inappropriate methods of randomization 5. We downgraded for inconsistency by one level due to significant statistical heterogeneity (I 2 = 65%)
## Question 1b
Early EN vs delayed EN in unselected critically ill population (identiϐied during primary search using key words block on "critical illness") 1. We downgraded by one level for risk of bias, all RCTs had either inappropriate or unclear randomization methods 2. I 2 = 0% 3. We downgraded by one level for imprecision, the CI crosses the line of unity. 4. We did not downgrade for inconsistency, the I 2 = 25% 5. We downgraded the quality of evidence by one level for imprecision, the number of events was small, and the CI included small beneϐit Question 1B: Should we use EEN rather than delay nutritional intake? Fourteen studies fulfilled the criteria and were included in the meta-analysis (Supplement 5, . Results of the meta-analyses on EEN vs. delayed nutritional intake (including delayed EN, oral diet or PN) are presented in [fig_ref] Figure 2: Forest plots [/fig_ref].
For mortality, we included 12 RCTs (662 patients). EEN did not reduce mortality compared to delayed nutritional intake (RR 0.76; 95% CI 0.52-1.11; P = 0.149; I 2 = 0%).
For infection, we included 11 RCTs (597 patients). EEN reduced risk of infection compared to delayed EN (RR 0.64; 95% CI 0.46-0.90; P = 0.010; I 2 = 25%). We downgraded the quality of evidence by two levels for imprecision, the number of events is very low 2. We downgraded the quality of evidence for risk of bias by one level, studies were non-blinded 3. We downgraded the quality of evidence by two levels for imprecision, the CI is extremely wide contains signiϐicant substantial beneϐit and harm
The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
In one study it was not possible to determine whether early PN was also used in some patients in the EEN group [bib_ref] Early nutritional support in severe traumatic patients, Chuntrasakul [/bib_ref]. Adding eight additional studies identified via specific searches did not significantly change the results (included studies are presented in Supplement 5, ; evidence profiles in Supplement 6 and Forest plots in Supplement 7, .
## Recommendation 1. we suggest using een in critically ill adult patients rather than early pn (grade 2c) or delaying en (grade 2c).
## Question 2: should we delay en in patients with shock receiving vasopressors or inotropes?
No RCTs were retrieved. We identified and analysed four prospective cohort studies, four case series/retrospective cohort studies and two reviews (Supplement 5,. 1. We downgraded the quality of evidence by two levels for imprecision 2. We downgraded the quality of evidence for inconsistency by one level, the I2 = 76% 3. We downgraded the quality of evidence by one level for imprecision, the number of events was small and the CI includes small beneϐit 4. We downgraded the quality of evidence for risk of bias, trials were not blinded 5. We downgraded the quality of evidence for imprecision, the number of events is small 1. We downgraded by two levels for serious imprecision, the CI is very wide and includes substantial beneϐit and harm 2. All included trials were at high risk of bias 3. We downgraded by one level for imprecision, the number of events was low
There is concern that EN in shock further jeopardizes the already impaired splanchnic perfusion. Nonocclusive bowel necrosis or non-occlusive mesenteric ischaemia (NOMI) has been reported in fewer than 1% of patients [bib_ref] Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous..., Mancl [/bib_ref] [bib_ref] Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition..., Marvin [/bib_ref] , without evidence for causal relationship between shock, vasopressors, EN and NOMI [bib_ref] Tolerability and safety of enteral nutrition in critically ill patients receiving intravenous..., Mancl [/bib_ref] [bib_ref] Nonocclusive bowel necrosis occurring in critically ill trauma patients receiving enteral nutrition..., Marvin [/bib_ref] [bib_ref] Provision of enteral nutrition during vasopressor therapy for hemodynamic instability: an evidence-based..., Wells [/bib_ref] [bib_ref] Early enteral nutrition in patients with hemodynamic failure following cardiac surgery, Lasierra [/bib_ref]. In a large observational study, EEN (<48 h) in patients with 'stable' haemodynamics after fluid resuscitation, whilst receiving at least one vasopressor, was associated with reduced mortality compared to late EN (>48 h) [bib_ref] Early enteral nutrition and outcomes of critically ill patients treated with vasopressors..., Khalid [/bib_ref]. These results suggest that the use of concomitant vasopressors (especially with stable or decreasing doses) should not preclude a trial of EN, despite a high prevalence of feeding intolerance [bib_ref] Upper digestive intolerance during enteral nutrition in critically ill patients: frequency, risk..., Mentec [/bib_ref]. In very unstable patients, EN may not have priority and potential positive effects of EN are unlikely to help improve instability. Persisting lactic acidosis may help identify uncontrolled shock.
## Question 3: should we delay en in patients with:
A. Hypoxaemia; B. Hypercapnia; C. Acidosis?
We found no direct evidence on these subquestions in the literature, and RCTs in this population are unlikely to become available.
The rationale to withhold EN in patients with hypoxaemia, hypercapnia and acidosis is to limit oxygen consumption and CO 2 production. However, the process of starving mobilises endogenous stores and is energy-consuming [bib_ref] Adaptive alterations in metabolism: practical consequences on energy requirements in the severely..., Fontaine [/bib_ref]. Acidosis may represent persistent shock and possibly contribute to gut dysfunction. Identifying and treating the cause of shock has priority over the initiation of EN. Similarly, in uncontrolled life-threatening hypoxaemia and hypercapnia, EN should be delayed until the symptoms are resolving. EN enteral nutrition, PN parenteral nutrition, CI confidence interval, RR risk ratio, GI gastrointestinal
In patients with acute lung injury, an RCT comparing trophic to full EN for up to 6 days was associated with less gastrointestinal intolerance when compared to full EN, without affecting ventilator-free days, infectious complications, physical function, or survival [bib_ref] Permissive underfeeding or standard enteral feeding in critically ill adults, Arabi [/bib_ref] [bib_ref] One year outcomes in patients with acute lung injury randomised to initial..., Needham [/bib_ref]. There are no data suggesting EN in patients with chronic, subacute, compensated or permissive hypercapnia is unsafe or not feasible.
## Recommendation 3. we suggest delaying en in case of uncontrolled life-threatening hypoxaemia, hypercapnia or acidosis, but using een in patients with stable hypoxaemia, and compensated or permissive hypercapnia and acidosis (grade 2d).
## Question 4: should we delay en in patients receiving neuromuscular blocking agents?
One prospective study was identified (Supplement 5, , reporting similar gastric emptying as measured by gastric residual volume (GRV) in sedated patients with or without concomitant use of neuromuscular blocking agents [bib_ref] Gastric emptying in mechanically ventilated critically ill patients: effect of neuromuscular blocking..., Tamion [/bib_ref]. The critical condition necessitating the use of neuromuscular blocking agents always needs to be considered, but these agents per se should not preclude EN. Analgosedation is known to slow gastric emptying [bib_ref] The effects of sedation on gastric emptying and intra-gastric meal distribution in..., Nguyen [/bib_ref]. Increased rate of EN intolerance is expected in deeply sedated patients with/without concomitant use of neuromuscular blocking agents.
## Recommendation 4. we suggest that en should not be delayed solely because of the concomitant use of neuromuscular blocking agents (grade 2d).
## Question 5: should we delay en in patients receiving therapeutic hypothermia?
One case series study addressing EN during therapeutic hypothermia was identified [bib_ref] Is enteral feeding tolerated during therapeutic hypothermia?, Williams [/bib_ref] (Supplement 5, .
During therapeutic hypothermia, energy metabolism might be markedly reduced [bib_ref] Modification of the Harris-Benedict equation to predict the energy requirements of critically..., Saur [/bib_ref] [bib_ref] Fulfilling caloric demands according to indirect calorimetry may be beneficial for post..., Oshima [/bib_ref] when shivering is prevented. The rationale to withhold EN during therapeutic hypothermia is based on the presumed decrease in gut motility due to hypothermia [bib_ref] Experience with prolonged induced hypothermia in severe head injury, Bernard [/bib_ref] [bib_ref] Induced hypothermia in critical care medicine: a review, Bernard [/bib_ref] and required analgosedation [bib_ref] The effects of sedation on gastric emptying and intra-gastric meal distribution in..., Nguyen [/bib_ref]. It has been suggested that EN could be successfully administered to these patients [bib_ref] Is enteral feeding tolerated during therapeutic hypothermia?, Williams [/bib_ref]. Tolerance to enteral feeding was impaired during hypothermia, but improved during rewarming [bib_ref] Is enteral feeding tolerated during therapeutic hypothermia?, Williams [/bib_ref].
## Recommendation 5. we suggest starting low dose een in patients receiving therapeutic hypothermia and increase the dose after rewarming (grade 2d).
## Question 6: should we delay en in patients receiving extracorporeal membrane oxygenation (ecmo)?
No RCTs and no prospective cohort studies were identified. Four case series in adult patients with ECMO were assessed (Supplement 5, , suggesting that EN is feasible during ECMO.
## Recommendation 6. we suggest using een in patients receiving ecmo (grade 2d).
## Question 7: should we delay en during prone position?
One prospective cross-over, one cohort and three case series studies were identified (Supplement 5, .
Data on tolerance of EN in prone position are controversial. Observational studies found similar GRVs in prone and supine position [bib_ref] Enteral feeding in the critically ill: comparison between the supine and prone..., Van Der Voort [/bib_ref] , whereas poor feeding tolerance was improved with semi-recumbent position during supine periods and prokinetics [bib_ref] Early enteral nutrition in mechanically ventilated patients in the prone position, Reignier [/bib_ref] [bib_ref] Before-after study of a standardized ICU protocol for early enteral feeding in..., Reignier [/bib_ref]. Although no RCTs on EN tolerance during prone position are available, reported studies do not support withholding EN in
## Remark:
We suggest considering early use of prokinetics followed by post-pyloric feeding in case of persisting gastric retention.
## Question 8: should we delay en in patients with traumatic brain injury?
We identified a Cochrane review with two updates and one recent meta-analysis, comparing early vs. late feeding, independent on the route of nutrition (EN or PN) (Supplement 5, . We identified three RCTs comparing EEN vs. early PN, three RCTs comparing EEN vs. delayed EN (one with restricted randomisation), and one RCT comparing early PN vs. delayed EN (Supplement 5, .
## Question 8a: een vs. early pn
Three RCTs (116 patients) were included. EEN compared to early PN in patients with traumatic brain injury did not affect mortality (RR 1.91; 95% CI 0.59-6.18; P = 0.279; I 2 = 0%) or the risk of pneumonia (RR 1.23; 95% CI 0.79-1.90; P = 0.36; I 2 = 0%). The certainty of evidence for mortality outcome was low, for pneumonia it was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, .
## Question 8b: een vs. delayed en
For mortality, two RCTs (86 patients) were included. EEN did not affect mortality compared to delayed EN (RR 0.66; 95% CI 0.18-2.45; P = 0.53; I 2 = 0%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For pneumonia, three RCTs (118 patients) were included. EEN did not affect the risk of pneumonia compared to delayed EN (RR 0.86; 95% CI 0.55-1.35; P = 0.51; I 2 = 0%). The certainty of evidence was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, .
In addition to RCTs, five cohort studies addressing this question were identified (Supplement 5, .
Existing evidence did not allow determining or excluding any benefit or harm of EEN, therefore our recommendation is based on expert opinion.
## Recommendation 8. we suggest using een in patients with traumatic brain injury (grade 2d).
## Question 9: should we delay en in patients with stroke (haemorrhagic or ischaemic)?
We identified two RCTs in patients with ischaemic stroke and one retrospective study in patients with hypertensive intracerebral haemorrhage (Supplement 5, Tables 9A, B).
One small RCT compared early vs. delayed EN and reported amelioration of cell-mediated immunity [bib_ref] Impact of early versus late enteral nutrition on cell mediated immunity and..., Bakiner [/bib_ref] ; however, both groups received PN to meet caloric targets from day 1. A large RCT compared EEN ("as soon as possible") to no nutrition within 7 days and reported a trend towards reduction of long-term mortality (6 months) with EN, with an increased risk of poor neurologic outcome in survivors [bib_ref] Effect of timing and method of enteral tube feeding for dysphagic stroke..., Dennis [/bib_ref]. An observational study reported reduction in infectious complications with EEN vs. delayed EN [bib_ref] Impact of early enteral nutrition on in-hospital mortality in patients with hypertensive..., Lee [/bib_ref].
## Recommendation 9. we suggest using een in patients with stroke (ischaemic or haemorrhagic) (grade 2d).
## Question 10: should we delay en in patients with spinal cord injury?
One RCT addressed EEN (<72 h) vs. delayed EN in cervical spinal injury [bib_ref] Early vs late enteral feeding in patients with acute cervical spinal cord..., Dvorak [/bib_ref]. No differences in outcome variables were identified. One retrospective cohort study addressed safety of EN early after spinal cord injury and reported no major complications [bib_ref] Is early enteral feeding safe in patients who have suffered spinal cord..., Rowan [/bib_ref] (Supplement 5, Tables 10A, B).
## Recommendation 10. we suggest using een in patients with spinal cord injury (grade 2d).
## Question 11: should we delay en in patients with severe acute pancreatitis (sap)?
We identified five systematic reviews with meta-analyses comparing EN to PN while not considering timing (Supplement 5, . All meta-analyses concluded that EN was beneficial in reducing infections and three reported reduced mortality [bib_ref] Guidelines for the provision and assessment of nutrition support therapy in the..., Taylor [/bib_ref] [bib_ref] Enteral nutrition and the risk of mortality and infectious complications in patients..., Petrov [/bib_ref] [bib_ref] Meta-analysis of enteral nutrition versus total parenteral nutrition in patients with severe..., Cao [/bib_ref].
We identified five RCTs addressing EEN ("early" as defined by the authors) vs. early PN in SAP whereas only two studies defined "early" as <48 h. Three further RCTs addressed EEN vs. early PN and one RCT EEN vs. delayed EN in "predicted SAP". Two RCTs addressing acute pancreatitis independent of severity and one RCT studying mixed patients undergoing abdominal surgery were not included. Supplement 5, .
We performed three separate meta-analyses all comparing EEN vs. early PN: (A) SAP and "early" as defined by the authors of the original study; (B) predicted SAP and "early" as defined by the authors of the original study; (C) predicted SAP and early defined as <48 h.
## Question 11a: sap (as stated by the authors). early ("early" as defined by the authors) en vs. pn
For mortality we included five RCTs (283 patients). EEN did not reduce the risk of death compared to PN (RR 0.57; 95% CI 0.23-1.38; P = 0.21; I 2 = 35.1%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For any infections we included five RCTs (283 patients). EEN reduced the risk of infections compared to PN (RR 0.48; 95% CI 0.23-0.98; P = 0.045; I 2 = 76%). The certainty of evidence was low. We rated down for inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For pancreatic infections we included four RCTs (233 patients). EEN reduced the risk of pancreatic infections compared to PN (RR 0.33; 95% CI 0.21-0.52; P < 0.0001; I 2 = 0%) The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, .
## Question 11b: predicted sap. early ("early" as defined by the authors) en vs. pn
For mortality we included eight RCTs (417 patients). EEN did not reduce the risk of death compared to PN (RR 0.50; 95% CI 0.22-1.13; P = 0.09; I 2 = 38%). The certainty of evidence was low. We rated down for imprecision (Supplement 6).
For any infections we included eight RCTs (417 patients). EEN reduced the risk of infections compared to PN (RR 0.53; 95% CI 0.30-0.91; P = 0.023; I 2 = 63.5%). The certainty of evidence was low. We rated down for risk of bias and inconsistency (Supplement 6).
For pancreatic infections we included five RCTs (202 patients). The use of EEN reduced the risk of pancreatic infections compared to PN (RR 0.35; 95% CI 0.24-0.52; P < 0.0001; I 2 = 0%). The certainty of evidence was low. We rated down for risk of bias and imprecision (Supplement 6). Supplement 7, .
## Question 11c: predicted sap. early (<48 h) en vs. pn
For mortality we included five RCTs (232 patients). EEN (<48 h) did not reduce the risk of death compared to PN (RR 0.61; 95% CI 0.15-2.55; P = 0.50; I 2 = 41%). The certainty of evidence was low. We rated down for imprecision (Supplement 6).
For any infections we included five RCT (232 patients), EEN (<48 h) reduced the risk of infections compared to PN (RR 0.49; 95% CI 0.28-0.83; P = 0.008, I 2 = 9%). The certainty of evidence was low. We rated down for risk of bias, inconsistency and imprecision (Supplement 6).
For pancreatic infections we included three RCTs (167 patients). EEN (<48 h) reduced the risk of pancreatic infections compared to PN (RR 0.40; 95% CI 0.22-0.73; P = 0.003; I 2 = 0%). The certainty of evidence was low. We rated down for risk of bias and imprecision (Supplement 6). Supplement 7, .
Taken together, the studies in different subpopulations have demonstrated a reduction of infections but no convincing effect of EEN on mortality.
Recommendation 11. We suggest using EEN in patients with severe acute pancreatitis (Grade 2C).
## Question 12: should we delay en in patients after gi surgery?
Out of three published meta-analyses [bib_ref] Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a..., Osland [/bib_ref] [bib_ref] Early enteral nutrition within 24 h of intestinal surgery versus later commencement..., Lewis [/bib_ref] [bib_ref] Early enteral feeding versus "nil by mouth" after gastrointestinal surgery: systematic review..., Lewis [/bib_ref] addressing early postoperative feeding including early oral diet, the two more recent papers [bib_ref] Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a..., Osland [/bib_ref] [bib_ref] Early enteral nutrition within 24 h of intestinal surgery versus later commencement..., Lewis [/bib_ref] reached different conclusions: reduced mortality and length of stay (LOS) but increased risk of vomiting analysing 15 RCTs [bib_ref] Early enteral nutrition within 24 h of intestinal surgery versus later commencement..., Lewis [/bib_ref] vs. no difference in mortality and LOS, but reduced complications in early group from 13 RCTs [bib_ref] Early versus traditional postoperative feeding in patients undergoing resectional gastrointestinal surgery: a..., Osland [/bib_ref].
We identified three RCTs comparing early vs. delayed EN after emergency GI surgery and six RCTs in elective GI surgery. Two RCTs compared EEN vs. early PN in patients after elective GI surgery (Supplement 5,.
## Question 12a: emergency gi surgery. een vs delayed en
Three RCTs (343 patients) were included. EEN did not affect mortality compared to delayed EN (RR 0.80; 95% CI 0.46-1.40; P = 0.44; I 2 = 0%). EEN reduced the risk of infections compared to delayed EN (RR 0.61; 95% CI 0.40-0.93; P = 0.02; I 2 = 0%). The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].
## Question 12b: elective gi surgery. een vs. delayed en
For mortality three RCTs (346 patients) were included. EEN did not affect mortality compared to delayed EN in patients after elective GI surgery (RR 0.83; 95% CI 0.25-2.81; P = 0.77; I 2 = 17%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For any infections six RCTs (432 patients) were included. EEN reduced the risk of infections compared to delayed EN (RR 0.43; 95% CI 0.23-0.82; P = 0.01; I 2 = 46%). The certainty of evidence was low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
Five RCTs (404 patients) reported anastomotic leak. EEN reduced the risk of surgical leak compared to delayed EN (RR 0.43; 95% CI 0.20-0.93; P = 0.03; I 2 = 0%). The certainty of evidence was low. We rated down for imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].
## Question 12c: elective gi surgery. een vs early pn
Two RCTs (440 patients) were included. EEN did not reduce the risk of pneumonia compared to early PN (RR 0.59; 95% CI 0.31-1.14; P = 0.12, I 2 = 0%), but reduced the risk of anastomotic leak compared to early PN (RR 0.42; 95% CI 0.19-0.95; P = 0.04; I 2 = 63%). The certainty of evidence was low. We rated down for risk of bias, inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].
## Recommendation 12. we suggest using een in patients after gi surgery (grade 2c).
## Question 13: should we delay en in patients after abdominal aortic surgery?
No RCTs but two cohort studies were identified (Supplement 5, [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Cohort studies both in elective [bib_ref] A cohort study of nutrition practices in the intensive care unit following..., Ksienski [/bib_ref] and emergency repair [bib_ref] Nutrition therapy for the critically ill surgical patient with aortic aneurysmal rupture:..., Rahman [/bib_ref] did not compare EEN with any of our comparators, but showed that EEN was successful in a minority of patients. A multimodal approach has been proposed [bib_ref] Nutrition barriers in abdominal aortic surgery: a multimodal approach for gastrointestinal dysfunction, Van Zanten [/bib_ref] , including early removal of nasogastric tubes, immediate postoperative mobilisation early oral or enteral feeding, accepting GRV up to 500 ml and use of prokinetics. Although these patients are at risk of bowel ischaemia with prevalence reported between 7 and 17% [bib_ref] Circulating intestinal fatty acid-binding protein as an early marker of intestinal necrosis..., Vermeulen Windsant [/bib_ref] [bib_ref] Editor's choice-hybrid treatment of thoracic, thoracoabdominal, and abdominal aortic aneurysms: a multicenter..., Rosset [/bib_ref] , the risk itself should not lead to withholding EN, unless bowel ischaemia is suspected (see also .
## Recommendation 13. we suggest using een in patients after abdominal aortic surgery (grade 2d).
## Question 14: should we delay en in patients with abdominal trauma?
Ten RCTs and ten cohort studies addressing EEN in trauma patients (RCTs: within 6-48 h; cohort studies: within 12-96 h) were identified, but abdominal trauma specifically was addressed in six RCTs, four of them compared EEN to early PN and two EEN to delayed EN (Supplement 5, .
## Question 14a: een vs early pn
For mortality two RCTs (142 patients) were included. EEN did not affect mortality compared to early PN (RR 0.49; 95% CI 0.09-2.69; P = 0.41; I 2 = 0%). The certainty of evidence was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
For any infection four RCTs (219 patients) were included. EEN did not affect the risk of infections compared to early PN (RR 0.59; 95% CI 0.24-1.42; P = 0.24; I 2 = 59%). The certainty of evidence was very low. We rated down for risk of bias, inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].
## Question 14b: een vs delayed en
Two RCTs (101 patients) were included. EEN did not affect mortality compared to delayed EN (RR 0.74; 95% CI 0.18-3.11; P = 0.708). The certainty of evidence was very low. We rated down for risk of bias and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref].
EEN did not affect the risk of infections compared to delayed EN (RR 0.83; 95% CI 0.41-1.70; P = 0.837). The certainty of evidence was very low. We rated down for risk of bias, inconsistency and imprecision [fig_ref] Table 3: Evidence profiles for the questions where meta-analyses were performed [/fig_ref]. See Supplement 7, [fig_ref] Figure 1: Forest plots [/fig_ref].
Of note, earlier studies in this patient group almost exclusively used surgical jejunostomy for EN.
Existing evidence did not allow verifying or excluding any benefit or harm of EEN; therefore our recommendation is based on expert opinion. In addition to RCTs, nine observational studies were identified (Supplement 5, .
An earlier meta-analysis in adult trauma patients in ICU (not specifically abdominal trauma) showed survival benefit in EEN commenced within 24 h after trauma [bib_ref] Early enteral nutrition reduces mortality in trauma patients requiring intensive care: a..., Doig [/bib_ref].
## Recommendation 14. we suggest using een in patients with abdominal trauma when the continuity of the gi tract is confirmed/restored (grade 2d).
## Question 15: should we delay en in patients with bowel ischaemia?
We identified no clinical studies, but physiological knowledge and common sense support withholding EN in patients with overt bowel ischaemia. However, patients with endoscopic evidence of mild to moderate large bowel mucosal ischaemia, without signs of transmural ischaemia or bowel distension, might profit from low dose EN. In this case we support considering EN. In a recent retrospective study, survivors were more often fed enterally before the diagnosis of acute mesenteric ischaemia, but no independent association between EN and mortality was demonstrated [bib_ref] Outcome of acute mesenteric ischemia in the intensive care unit: a retrospective,..., Leone [/bib_ref].
## Recommendation 15. we suggest delaying en in patients with overt bowel ischaemia (grade 2d).
## Question 16: should we delay en in critically ill adult patients with intestinal fistula?
We identified one retrospective cohort study and two case series, all showing outcome benefit of "early" EN (Supplement 5, . However, "early" was defined as EN started within 7 days or 14 days of admission. Retrospective design further diminishes the importance of these studies.
Intolerance of EN or increasing fistula output causing skin breakdown or fluid/electrolyte imbalance are evident reasons to decrease or discontinue EN [bib_ref] Metabolic and nutritional support of the enterocutaneous fistula patient: a three-phase approach, Polk [/bib_ref].
## Recommendation 16. we suggest delaying en in patients with high-output intestinal fistula if reliable feeding access distal to the fistula is not achievable (grade 2d).
## Question 17: should we delay en in patients with an open abdomen?
Seven observational studies (one prospective cohort study, three retrospective cohort studies and four case series) were identified; two studies compared EEN (different definitions) vs delayed EN and reported higher rate of early abdominal closure, less fistula formation and lower incidence of ventilator-associated pneumonia in the "early" EN group (Supplement 5, . The largest study comparing EN to no EN in patients with open abdomen after abdominal trauma reported independent associations between EN and ultimate fascial closure and decreased mortality rate in patients without bowel injury, but no difference in a subgroup of patients with bowel injury [bib_ref] Who should we feed? Western Trauma Association multi-institutional study of enteral nutrition..., Burlew [/bib_ref].
## Recommendation 17. we suggest using een in patients with open abdomen (grade 2d).
## Question 18: should we delay en in patients with intra-abdominal hypertension?
Four observational studies were identified (Supplement 5, , only one addressed early vs. delayed EN [bib_ref] Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe..., Sun [/bib_ref]. All studies reported high incidence of feeding intolerance associated with intra-abdominal hypertension, but data are not conclusive regarding causality. A recently published study demonstrated that EEN did not increase intra-abdominal pressure, but values exceeding 15 mmHg were associated with higher rates of feeding intolerance in patients with severe acute pancreatitis [bib_ref] Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe..., Sun [/bib_ref].
No prospective study addressing EN in patients with abdominal compartment syndrome [bib_ref] Pediatric Guidelines Sub-Committee for the World Society of the Abdominal Compartment Syndrome..., Kirkpatrick [/bib_ref] was identified. As abdominal compartment syndrome is an immediately life-threatening condition with jeopardized splanchnic perfusion, we suggest to withhold or stop EN and try to lower intra-abdominal pressure.
Recommendation 18a. We suggest using EEN in patients with intra-abdominal hypertension without abdominal compartment syndrome, but consider temporary reduction or discontinuation of EN when intra-abdominal pressure values further increase under EN (Grade 2D).
Recommendation 18b. We suggest delaying EN in patients with abdominal compartment syndrome (Grade 2D).
## Question 19: should we delay en in patients with upper gi bleeding?
No studies addressing EEN were identified. One RCT in bleeding due to gastric or duodenal ulcer reported shorter hospital stay (4.2 ± 1.2 vs. 5.9 ± 1.4 days, P < 0.001) in the early oral feeding group [bib_ref] Effects of early oral feeding on relapse and symptoms of upper gastrointestinal..., Khoshbaten [/bib_ref].
EN as protection against stress ulceration and GI bleeding is suggested in one meta-analysis [bib_ref] Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis, Marik [/bib_ref] , one retrospective study in burns [bib_ref] The value of early enteral nutrition in the prophylaxis of stress ulceration..., Raff [/bib_ref] and several reviews [bib_ref] Stress prophylaxis in intensive care unit patients and the role of enteral..., Hurt [/bib_ref] [bib_ref] Use of enteral nutrition for stress ulcer prophylaxis, Maclaren [/bib_ref] [bib_ref] Prevention of gastrointestinal bleeding due to stress ulceration: a review of current..., Pilkington [/bib_ref]. An RCT comparing ranitidine and sucralfate reported EN as an independently protective factor against GI bleeding [bib_ref] Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical..., Cook [/bib_ref]. The main rationale to prohibit eating/EN is based on fear for disturbed visibility in a further endoscopy/intervention due to rebleeding. Therefore, delaying EN for 48-72 h in patients with a high risk of rebleeding has been suggested [bib_ref] Feeding the patients with upper gastrointestinal bleeding, Hébuterne [/bib_ref]. Considering the absence of evidence to support this time frame, we suggest starting EN during the first 24-48 h after bleeding has been stopped; prolonged postponement of EN is unnecessary or even harmful because of increased risk of stress ulceration. Importantly, there is no evidence that fine-bore nasogastric tubes cause variceal bleeding [bib_ref] Feeding the patients with upper gastrointestinal bleeding, Hébuterne [/bib_ref].
Recommendation 19. We suggest delaying EN in patients with active upper GI bleeding, and starting EN when the bleeding has stopped and no signs of rebleeding are observed (Grade 2D).
## Question 20: should we delay en in patients with acute liver failure?
We could not identify any study in acute or acute-onchronic liver failure patients. Some benefits of EN have been shown in patients with alcoholic hepatitis, malnourished patients with cirrhosis and patients with liver transplantation [bib_ref] Short and long term outcome of severe alcohol-induced hepatitis treated with steroids..., Cabré [/bib_ref] [bib_ref] Effect of total enteral nutrition on the short-term outcome of severely malnourished..., Cabré [/bib_ref] [bib_ref] Early enteral nutrition support in patients undergoing liver transplantation, Hasse [/bib_ref] , where glycogen stores may be depleted after an overnight fast and metabolic conditions resemble prolonged starvation in healthy individuals [bib_ref] Energy expenditure and substrate metabolism in patients with cirrhosis of the liver:..., Verboeket-Van De Venne [/bib_ref]. EN in fulminant acute liver failure has never been studied. These patients often present with hypoglycaemia, which should be corrected with intravenous glucose, sometimes together with insulin. Fulminant liver failure is associated with increased serum amino acid concentrations, especially glutamine [bib_ref] Plasma glutamine concentrations in liver failure, Helling [/bib_ref] [bib_ref] Aromatic amino acid metabolism during liver failure, Dejong [/bib_ref]. It seems likely that a failing liver is unable to provide effective metabolic support required for nutrition. The pathophysiological rationale to delay EN in fulminant hepatic failure would be to "spare" the severely injured liver from the duties of metabolising and storing nutrition during a period of stress and also to avoid additional increases in ammonia. Intravenous provision of nutrients except correction of hypoglycemia and appropriate provision of vitamins and trace elements may be futile or harmful early in the clinical course [bib_ref] Pathogenesis and treatment of parenteral nutritionassociated liver disease, Xu [/bib_ref].
Recommendation 20. We suggest starting low dose EN when acute, immediately life-threatening metabolic derangements are controlled with or without liver support strategies, independent on grade of encephalopathy (Grade 2D).
Remark: Arterial ammonia levels should be monitored.
## Question 21: should we delay en in patients with large gastric aspirate volumes (gav)?
We identified no study addressing this question. Based on existing evidence from two RCTs comparing the threshold volumes to stop already started EN [bib_ref] Gastric residual volume during enteral nutrition in ICU patients: the REGANE study, Montejo [/bib_ref] [bib_ref] Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia..., Reignier [/bib_ref] , a clear threshold volume (in ranges up to 500 ml) that increased the risk of ventilator-associated pneumonia was not identified. Measurements of GAV/GRV are not a gold standard and alternative methods (like ultrasound) can be applied to diagnose overfilling of the stomach. Gross distension of the stomach is likely to be undesirable and therefore we suggest that EN should be delayed when GAV/GRV is >500 ml/6 h [bib_ref] Gastric residual volume during enteral nutrition in ICU patients: the REGANE study, Montejo [/bib_ref] , either for a limited time period or until administration of prokinetics. For patients with persistently large GAV/GRVs the use of postpyloric feeding should be considered rather than withholding EN, unless bowel ischaemia or obstruction is suspected (see also .
## Recommendation 21.
We suggest delaying EN if gastric aspirate volume is above 500 ml/6 h (Grade 2D).
## Question 22: should we delay en in patients with absent bowel sounds?
One cohort study was identified [bib_ref] Early enteral feeding in intestinal anastomosis, Thapa [/bib_ref] (Supplement 5,. Bowel sounds are frequently absent in mechanically ventilated patients and this is associated with impaired outcome [bib_ref] Gastrointestinal symptoms in intensive care patients, Reintam [/bib_ref]. The concept that bowel sounds must be present before initiation of enteral feeding is not based on evidence and should be abandoned [bib_ref] Enteral nutrition in the critically ill patient: a prospective survey, Heyland [/bib_ref]. After laparotomy small intestinal motility is frequently preserved despite gastric and colonic paresis. The small intestine may contract silently (absence of gas), while feeding is well tolerated [bib_ref] Enteral nutrition in the critically ill patient: a prospective survey, Heyland [/bib_ref]. Gastric and colonic paresis may effectively be treated with prokinetics [bib_ref] Gastric emptying in the critically illthe way forward?, Frost [/bib_ref]. Initiation of EN in absence of bowel sounds might be associated with earlier return of bowel sounds, fewer episodes of vomiting, and shorter ICU and hospital stay [bib_ref] Early enteral feeding in intestinal anastomosis, Thapa [/bib_ref].
Recommendation 22. We suggest using EEN regardless of the presence of bowel sounds unless bowel ischaemia or obstruction is suspected (Grade 2D).
## Question 23: should we delay en in patients with diarrhoea?
There were no studies testing delay of EN in case of diarrhoea, but diarrhoea is often considered as a reason to delay EN [bib_ref] Enteral feeding in the critically ill: are nursing practices contributing to hypocaloric..., Marshall [/bib_ref]. Prevalence of diarrhoea in unselected ICU population is between 14 and 21% [bib_ref] Diarrhoea in the ICU: respective contribution of feeding and antibiotics, Thibault [/bib_ref] [bib_ref] Diarrhoea in the critically ill, Blaser [/bib_ref]. Causes include impaired digestion/absorption, bacterial overgrowth or infection such as Clostridium difficile. Observational studies [bib_ref] Managing diarrhoea in intensive care, Ferrie [/bib_ref] [bib_ref] Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The..., Montejo [/bib_ref] suggest that diarrhoea can be effectively managed with protocolised measures other than immediate cessation in EN. We recommend analysing the causes of diarrhoea and treat appropriately (e.g. C. difficile colitis). We also suggest considering treating bacterial overgrowth by selective decontamination, fibreenriched or semi-elementary diet or digestive enzymes to reduce diarrhoea.
## Recommendation 23. we suggest using een in patients with diarrhoea (grade 2d).
# Conclusions
We suggest using EEN, initiated at a low rate, in the majority of critically ill patients; however, the evidence is weak. Beneficial effects in terms of infection prevention have been demonstrated in unselected critically ill patients, as well as in patients with severe acute pancreatitis and after GI surgery. However, we suggest delaying EN in patients with uncontrolled shock (haemodynamic and tissue perfusion goals are not met despite of fluids and vasopressors), uncontrolled hypoxaemia and acidosis, uncontrolled GI bleeding, overt bowel ischaemia (occlusive or non-occlusive), bowel obstruction (mechanical ileus), abdominal compartment syndrome, gastric aspirate volume >500 ml/6 h or high-output fistula if reliable distal feeding access is not achievable.
[fig] Figure 1: Forest plots (a mortality; b infections) Question 1A: early EN (EEN) vs. early PN (EPN) in unselected critically ill patients [/fig]
[fig] Figure 2: Forest plots (a mortality; b infections) Question 1B: early EN (EEN) vs. delayed EN (DEN) in unselected critically ill patients prone position. Gastric emptying seems not to be significantly influenced by prone position and adverse events in most studies not increased. Recommendation 7. We suggest that EN should not be delayed solely because of prone positioning (Grade 2D). [/fig]
[table] Table 3: Evidence profiles for the questions where meta-analyses were performed [/table]
[table] Question 12: AEmergency GI surgery. Early EN vs delayed EN. [/table]
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Unusual cases of acute cholecystitis and cholangitis: Tokyo Guidelines
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Unusual cases of acute cholecystitis and cholangitis: Tokyo Guidelines
# Introduction
Unusual cases of acute cholecystitis and cholangitis include: (1) pediatric biliary tract infections, (2) geriatric biliary tract infections, (3) acalculous cholecystitis, cholangitis accompanying hepatolithiasis and intrahepatic cholangitis, (5) acute biliary tract infections accompanying malignant pancreatic biliary tumor, postoperative biliary tract infections, (7) acute biliary tract infections accompanying congenital biliary dilatation and pancreaticobiliary maljunction, and (8) primary sclerosing cholangitis.
This article discusses the characteristics, diagnostic criteria, treatment guidelines, and prognoses of these unusual types of biliary tract infection in a question and answer format.
## Pediatric biliary tract infections
## Q1. what are the causes of pediatric cholangitis and cholecystitis? abstract
Unusual cases of acute cholecystitis and cholangitis include (1) pediatric biliary tract infections, (2) geriatric biliary tract infections, (3) acalculous cholecystitis, (4) acute and intrahepatic cholangitis accompanying hepatolithiasis (5) acute biliary tract infection accompanying malignant pancreatic-biliary tumor, postoperative biliary tract infection, (7) acute biliary tract infection accompanying congenital biliary dilatation and pancreaticobiliary maljunction, and (8) primary sclerosing cholangitis. Pediatric biliary tract infection is characterized by great differences in causes from those of adult acute biliary tract infection, and severe cases should be immediately referred to a specialist pediatric surgical unit. Because biliary tract infection in elderly patients, who often have serious systemic conditions and complications, is likely to progress to a serious form, early surgery or biliary drainage is necessary. Acalculous cholangitis, which often occurs in patients with serious concomitant conditions, such as those in intensive care units (ICUs) and those with disturbed cardiac, pulmonary, and nephric function, has a high mortality and poor prognosis. Cholangitis accompanying hepatolithiasis includes recurrent pyogenic cholangitis, an epidemic disease in Southeast Asia. Biliary tract infections, which often occur after a biliary tract operation and treatment of the biliary tract, may have a fatal outcome, and should be carefully observed. The causes of acute cholangitis associated with pancreaticobiliary maljunction differ before and after operation. Direct cholangiography is most useful in the diagnosis of primary sclerosing cholangitis. If cholangiography visualizes a typical bile duct, differentiation from acute pyogenic cholangitis is easy. This article discusses the individual characteristics, diagnostic criteria, treatment guidelines, and prognosis of these unusual types of biliary tract infection.
## Offprint requests to: h. yasuda
Received: May 31, 2006 / Accepted: The causes of pediatric acute biliary tract infections are quite different from those of adult acute biliary tract infection.
Pediatric acute biliary tract infection is a rare disease, occurring most often in children (less than 15 years old) with specifi c diseases such as biliary atresia and pancre-aticobiliary maljunction, or after liver transplantation. Ascending cholangitis (hereinafter "cholangitis") occurs in as many as 50% of children after operation for biliary atresia, and these children should therefore be monitored carefully (level 4). The condition often occurs within a year after the operation.
Acute cholecystitis occurs very rarely (0.13%-0.22%) in children as compared with the incidence in adults. According to a review of 693 cases, conducted in 1989 by Friesen and Roberts, 1 the ages when pediatric cholecystitis occurs are distributed as follows: 9.8% (1 year old or younger), 4.5% (1-5 years old), .5% (6-10 years old), and 71.5% (age, 11-20 years) (level 3b-4). The causes of pediatric acute cholecystitis, including hemolytic hematopathy, congenital malformations, intravenous hyperalimentation, ileectomy, and shortbowel syndrome, are different from those of adult cholecystitis (level 3b-4). Pediatric acalculous cholecystitis has various causes, mainly serious burns and metabolic diseases, and it occurs after serious operations and bone marrow transplantation. Pediatric acalculous cholecystitis is very rare and accounts for only 2%-15% of all types of acute cholecystitis in children (level 4). 4
## Q2. what are the diagnostic criteria for pediatric acute biliary tract infection?
The majority of pediatric acute cholangitis occur in children who have undergone biliary operations for such diseases as biliary atresia and cholangiectasis, and those with liver transplantation. For children with abdominal pain and fever as the main complaints, it is essential to ask their past history of disease and surgery. If they have a history of the above diseases, the diagnosis should be performed with acute biliary tract infection in mind. The above diagnostic guidelines for pediatric cholangitis are not evidence-based, but are only draft guidelines.
Almost all patients with post-biliary atresia cholangitis have a fever of 38 °C or over. Reduced biliary excretion volume, leukocytosis, elevated levels of Creactive protein, bilirubin in plasma, and alkaline phosphatase may be observed in some patients (level 4). However, fever is the only fi nding observed in all patients, and even fever caused by a viral infection or cold-induced dyspepsia may often cause cholangitis with dehydration or reduced systemic immunity. In view of the fact that nearly half of those patients with fever and reduced biliary excretion (gray-white stool) later show an elevated plasma level of bilirubin, it is preferable to begin early treatment for those with fever as the only symptom, with the potential of cholangitis in mind. Therefore, patients with fever after operation for biliary atresia should be suspected of having acute cholangitis, and should receive treatment similar to that for acute cholangitis. Differentiation from other frequent diseases in children, such as acute pharyngitis and acute viral enteritis (rota-virus enteritis) is important. However, if these diseases are present after biliary atresia operation or liver transplantation in children, the diagnosis becomes more diffi cult.
Acute cholangitis in children without a history of surgery should be diagnosed comprehensively with ultrasonographic, blood biochemical, and pathological fi ndings, with the possibility of acute cholangitis always in mind.
The diagnosis of pediatric acute cholangitis should be done in accordance with the draft diagnostic, criteria shown below. Precautions should be taken, particularly for patients after operation for biliary atresia.
For the diagnosis of pediatric acute cholecystitis, the draft diagnostic criteria shown below should be referred to.
## Draft diagnostic criteria for pediatric acute cholecystitis
Patients with symptoms such as fever and abdominal pain and fi ndings of cholecystitis on abdominal ultrasonography are defi nitely diagnosed as having acute cholecystitis.
Fever, vomiting, right hypochondrial tenderness, abdominal pain (spontaneous pain), and jaundice are important fi ndings in the diagnosis of acute cholecystitis (level 4). Blood biochemical tests show elevated white blood cell counts, plasma bilirubin, alkaline phosphatase, asparatate aminotransferase, and alanine aminotransferase (level 4). Abdominal ultrasonography is
## Draft diagnostic criteria for pediatric acute cholangitis
Children after an operation for biliary atresia who have a fever of 38 °C or higher are diagnosed as having suspected acute biliary tract infection.
Children after a biliary atresia operation or after liver transplantation who have a fever of 38 °C or higher, and an increased white blood cell count or increased C-reactive protein, and/or increased transaminase level are defi nitely diagnosed having as acute cholangitis.
Those with sludge or gallstones in the bile duct observed by abdominal ultrasonography, a fever of 38 °C or higher, an increased white blood cell count or increased C-reactive protein, and/or increased transaminase level are defi nitely diagnosed as having acute cholangitis. useful for diagnosis in children, as well as for adults (level 3b-4). Q3. What are the appropriate criteria for primary care and patient transfer? and older)", "medium elderly (75 and older)", and "later elderly (85 years and older)". The ages at which biliary tract infections occur most frequently are the sixties and seventies, and many patients with biliary tract infection are categorized as "elderly". The defi nition of "elderly" employed in the references and reports on geriatric biliary tract infection is diverse, but it is useful to classify geriatric biliary tract infection at the higher age for understanding and identifying morbid conditions specifi c to geriatric patients. The Tokyo Guidelines defi ne biliary tract infections in those 75 years and over as "geriatric biliary tract infections".
## Q4. what treatment method is preferred for elderly patients?
Primary care for pediatric acute biliary tract infection consists of: (1) fasting, (2) adequate intravenous fl uid infusion, and (3) intravenous antimicrobial administration. Patients should be transferred, as required, to a specialist pediatric unit, according to the criteria below.
Primary care should be started and patients should be referred to a pediatric surgery unit if they have a history of biliary tract surgery or defi nitive cholangitis.
Primary care for pediatric acute biliary tract infection consists of: (1) fasting, (2) adequate intravenous fl uid infusion, and (3) intravenous antimicrobial administration, and the patients should be referred or transferred, as required, to a specialist unit where treatment by pediatricians is available, according to the above criteria.
As various causative bacteria for cholangitis occurring after a biliary atresia operation, broad spectrum antimicrobial drugs are effective as their bactericidal effect on enterobacteria, which are mainly gram-negative bacilli, is high (level 4). A third-generation cephem antimicrobial, or in some cases, an aminoglycoside antimicrobial as well, should therefore be administered, taking the production of drug-resistant bacteria into account (level 4-5). However, treatment of the cholangitis that may occur after an operation for biliary atresia is directly associated with the prognosis of the biliary atresia, and whether or not the cholangitis is successfully controlled is associated with an indication for liver transplantation; therefore, patients should undergo the treatment at a specialist unit after undergoing primary care.
The primary care of cholecystitis consists, in principle, of fasting (aspiration of stomach contents via a nasogastric tube as appropriate), adequate intravenous fl uid inffusion, and intravenous administration of appropriate antimicrobial drugs, and this should be accompanied by strict ultrasonographic follow-up (level 4). As cholecystitis in infants is likely to progress to a severe form, emergency treatment may be required in some cases.
## Geriatric biliary tract infections
There is no common defi nition of "elderly", and defi nitions differ by individuals, culture, and country. The World Health Organization defi nes the elderly as those aged 65 years and over. Geriatrically, the defi nition of "elderly" is subdivided into "early elderly (65 years old Biliary drainage is the treatment of choice for moderate or severe acute cholangitis in elderly patients (recommendation C).
Acute cholangitis in elderly patients often progresses to a serious form or to acute obstructive suppurative cholangitis, because of its anatomical characteristics. In patients 70 years and over with jaundice, this is likely to be accompanied by bactibilia and bacteremia, and they may require hospitalizion for a long period of time. Preferably, these patients should undergo early drainage. However, in view of the fact that elderly patients often have complications, there are many opinions that the fi rst treatment should be endoscopic biliary drainage rather than an invasive treatment. Endoscopic biliary drainage is applicable for elderly patients. Reports that the success rate of endoscopic lithotomy was 98% in 101 patients 75 years and over when endoscopic retrograde cholangiopancreatography (ERCP) was applied (level 4), and that ERCP was applied in 23 patients 90 years and over (level 4), 2 and that the success rate of endoscopic sphincterotomy (EST) was similar in patients 80 years and over (182 cases) and younger patients (level 3b), 3 encourage diagnosis and treatment with ERCP for elderly patients. One report recommends endoscopic nasobiliary drainage (ENBD) without sphincterotomy as the method of fi rst choice in the treatment of elderly patients 80 years and over (level 3b), while an other report suggests percutaneous transhepatic drainage (level 4). Because being elderly is one of the risk factors for progression to a severe form, as described in the severity classifi cation, even those with moderate and mild cases of acute cholangitis should be treated as a high-risk group.
## Q5. what are the morbid conditions in acute cholecystitis?
It is known that acute cholecystitis occurs frequently in elderly patients, who have age-related changes of the biliary tract structure and a frequent incidence of bacteria in bile. As acute cholecystitis in patients over 70 years old is often complicated by acalculous cholecystitis, choledocholithiasis, gallbladder necrosis, and cancer, and is likely to be associated with bacteremia, the importance of early treatment is indicated (level 3b). The complication of peritonitis increases in proportion to age, and the complication rate in patients in their eighties is signifi cantly higher than that at other ages. According to Andersson et al., biliary peritonitis was observed in 1.8% of patients with acute cholecystitis, two-thirds of whom showed clear gallbladder perforation. On the other hand, as the three-layer structure and the thickening of the gallbladder wall, which are frequently observed on abdominal ultrasonography in acute cholecystitis patients 75 years and over, are not observed in many "later" elderly patients, the diagnosis is diffi cult in many of these patients.
## Q6
. What is the optimal treatment of acute cholecystitis in elderly patients diagnosed as inoperable due to a high surgical risk?
years and over, in view of its favorable results (level 3b). Another study reports that, because, in the elderly aged 70 years and over, cholecystectomy as emergency surgery is likely to be complicated by sepsis, resulting in a mortality as high as 10% (level 4), the emergency surgery should be avoided. For acute cholecystitis in the elderly aged 70 years and over, primary care to improve the systemic condition with PTGBD prior to cholecystectomy reduces the postoperative mortality and morbidity rates (level 4), and delayed cholecystectomy is recommended only after the disappearance of infl ammation, by applying PTGBD to carefully examine and treat accompanying diseases, including choledocholithiasis (level 4). In a contrasting fi nding, a group of patients who underwent early surgery after PTGBD showed better results than those not undergoing PTG-BD or those undergoing delayed surgery after PTGBD: the higher the success rate of intraoperative cholangiography, the lower was the rate of conversion to open surgery and the shorter the time of operation (level 3b). No conclusion has been reached on the timing of surgery for acute cholecystitis in the elderly. In view of their worse systemic condition and more complications in general, including choledocholithiasis, as compared with younger patients, elderly patients should receive surgery only after careful and adequate examination of their systemic condition.
## Q8. what surgical method should be applied for acute cholecystitis in the elderly?
Percutaneous transhepatic gallbladder drainage is the treatment of choice for the elderly with acute cholecystitis who are diagnosed as inoperable due to a high surgical risk (recommendation C).
Some reports (case-series studies) have examined the effectiveness and safety of percutaneous transhepatic gallbladder drainage as the treatment of fi rst choice for acute cholecystitis in elderly patients, particularly in those with comorbid conditions, and they indicate its usefulness (level 4). The treatment of acalculous cholecystitis can be completed without cholecystectomy if the patiens' condition is successfully improved by percutaneous transhepatic gallbladder drainage (PTGBD) (level 4). For patients complicated by cholelith, on the other hand, cholecystectomy is recommended, ultimately, if patients are operable after the improvement of their systemic condition (level 4). 10 Q7. What is the optimal timing of surgical treatment for acute cholecystitis in elderly patients?
## Emergency surgery for acute cholecystitis in elderly patients (recommendation c).
According to randomized controlled trials (RCTs), early surgery is desirable for acute cholecystitis (7 days after the onset). Studies on the timing of surgery for acute cholecystitis in the elderly, most of which are retrospective, have recommended both early and delayed surgery. Edlund and Liungdahl 11 recommend early cholecystectomy for acute cholecystitis in the elderly 70
## Cholecystectomy for acute cholecystitis in the elderly (recommendation grade c). laparoscopic cholecystectomy is desirable in all eligible patients (recommendation c).
After the introduction and popularization of laparoscopic cholecystectomy, its superiority has been reported in an increasing number of studies. Laparoscopic cholecystectomy performed for acute cholecystitis in the elderly 75 years and over requires a shorter time of operation and a shorter length of hospitalization, and reduces the number of patients who need rehabilitation and the mortality rate, as compared with open cholecystectomy (level 3b). The mortality rate of laparoscopic cholecystectomy is the same as that of open cholecystectomy (level 4). The morbidity rate of open cholecystectomy is about seven times higher than that of laparoscopic cholecystectomy, and the elderly and highrisk patients in higher American Society of Anesthesiology (ASA) Physical Class System classes should undergo laparoscopic cholecystectomy (level 3b). Laparoscopic cholecystectomy performed in the elderly 75 years and over reduces the morbidity rate and shortens the duration of hospitalization, and thus reduces medical costs (level 3b). There is a report, in contrast, that laparoscopic cholecystectomy for elderly patients 75 years and over is not very benefi cial, because many of the elderly need to undergo open cholecystectomy later and to stay in hospital for the same length of time as those with open cholecystectomy (level 3b). There is an opinion that laparoscopic cholecystomy is preferable, similarly to delayed surgery, for patients without complications, whereas for patients 65 years and over with complications, early conversion to open cholecystectomy or the performance of open cholecystectomy is recommended (level 3b). 20
## Acalculous cholecystitis
## Q9. what are the points to be considered in the diagnosis of acalculous cholecystitis?
with acute acalculous cholecystitis, respectively, with a mortality of 41% (level 4). However, Ryu et al. reported that gangrenous changes and perforation were observed in 55% and 5.1% of patients with acute acalculous cholecystitis, respectively, while there were no fatal cases (level 4). A review of 33 case-series studies, including that by Kang and Williamson, 1 showed a total mortality of 15% (91 of 594 patients died) while the mortality of post-trauma patients was high, at 27% (level 4). [fig_ref] Table 1: Factors potentially associated with acute acalculous cholecystitis [/fig_ref] shows risk factors for acute acalculous cholecystitis. According to a survey by Ida et al.,
## Q11. what are the risk factors for acute acalculous cholecystitis?
Acute acalculous cholecystitis is likely to occur during the treatment of serious conditions such as trauma and burns, and in postoperative patients [fig_ref] Table 1: Factors potentially associated with acute acalculous cholecystitis [/fig_ref]. It is reported that the incidence of acute acalculous cholecystitis rises with the increasing number of patients with Factors associated with postoperative acute cholecystitis [fig_ref] Table 2: Incidence of postoperative acute cholecystitis [/fig_ref] shows the incidence of postoperative acute cholecystitis after various operations. After aortic aneurysm repair, particularly ruptured aneurysm, the incidence of acute cholecystitis is high. In aortic aneurysm patients, the incidence of acute cholecystitis after the repair of non-ruptured aneurysm is around 1%, 11-13 but the incidence after the repair of a ruptured aneurysm is as high as 13.6% (level 4). Although the incidence of acute cholecystitis after cardiac surgery is not very high (0.12%-0.94%), surgery combining valve replacement and coronary artery bypass is considered as a risk factor for postoperative acute cholecystitis. A comparison of 30 patients with post-cardiovascular operation acute cholecystitis and 11 300 who underwent the operation at the same time but showed no acute cholecystitis indicates that those subjected to surgery combining valve replacement and coronary artery bypass accounted for 23% (7/30) of patients with acute cholecystitis, but 11% (1299/11 300; P = 0.03) of those without appearance of the disease (level 3c). 14 After cardiac transplantation, postoperative cholecystitis appears at higher incidences (0.7%-5.7%). [bib_ref] Major abdominal complications following cardiac transplantation, Merrell [/bib_ref] [bib_ref] Gastrointestinal complications after pediatric cardiac transplantation, Rakhit [/bib_ref] Postoperative cholecystitis occurs at similar frequencies in both calculous and acalculous patients. The incidence of postoperative acute calculous cholecystitis is the same in male and female patients, whereas acalculous cholecystitis is more likely to occur in male patients. According to a review by
## Hepatic artery infusion
Hepatic artery infusion may be associated with drug toxicity and catheter complications. According to an examination by Barnett and Malafa 28 of complications in 3991 patients subjected to hepatic artery infusion, and the study of Lafon et al., [bib_ref] Acute cholecystitis associated with hepatic arterial infusion of fl oxuridine, Lafon [/bib_ref] the incidence of biliary complications, including acute cholecystitis, was 4% (level 4).
## Other factors
Other factors associated with the occurrence of biliary and other types of acute acalculous cholecystitis include abdominal vasculitis, [bib_ref] Vasculitis of the gallbladder in a 70-year-old man with giant cell (temporal)..., Papaioannou [/bib_ref] hemorrhagic shock, and cardiac arrest 31 (level 4 for all cases). With respect to a correlation between diabetes and acute cholecystitis, a report indicates that the incidence of infectious complications in acute cholecystitis is increased in diabetics (level 3b), [bib_ref] Acute cholecystitis in diabetic patients, Shpitz [/bib_ref] while on other report indicates that diabetes does not increase the risk of cholecystectomy in those with acute cholecystitis (level 2c). [bib_ref] The risk of cholecystectomy for acute cholecystitis in diabetic patients, Landau [/bib_ref] Acute acalculous cholecystitis has been observed in patients who have undergone interleukin-2 and lymphokine-activated killer cell therapy [bib_ref] Acalculous cholecystitis in patients undergoing bone marrow transplantation, Wiboltt [/bib_ref] and bone marrow transplantation. [bib_ref] Acalculous cholecystitis in patients undergoing bone marrow transplantation, Wiboltt [/bib_ref] Acute acalculous cholecystitis may occur as a secondary gallbladder infection following systemic candidiasis or leptospirosis, [bib_ref] Acalculous candida cholecystitis: a complication of critical surgical illness, Hiatt [/bib_ref] [bib_ref] Leptospirosis with acute acalculous cholecystitis and pancreatitis, Monno [/bib_ref] or it may occur with Salmonella typhi as causative bacteria [bib_ref] Acute acalculous cholecystitis caused by Salmonella typhi in a 6-year-old child, Yulevich [/bib_ref] [bib_ref] Acute acalculous cholecystitis caused by Salmonella typhi in an 11-year-old, Winkler [/bib_ref] (level 4 for references [bib_ref] Acalculous candida cholecystitis: a complication of critical surgical illness, Hiatt [/bib_ref] [bib_ref] Leptospirosis with acute acalculous cholecystitis and pancreatitis, Monno [/bib_ref] [bib_ref] Acute acalculous cholecystitis caused by Salmonella typhi in a 6-year-old child, Yulevich [/bib_ref] [bib_ref] Acute acalculous cholecystitis caused by Salmonella typhi in an 11-year-old, Winkler [/bib_ref].
An examination of acalculous cholecystitis in patients with cerebral vascular disorder in the acute stage showed an incidence of acalculous cholecystitis of 1%, which is almost equal to the post-trauma and postoperative incidence.
## Q12. what is the best method for the diagnosis of acute acalculous cholecystitis?
As many patients with acalculous cholecystitis are in ICUs (with extubation) due to complications, clinical signs highly specifi c for calculous acute cholecystitis, such as sonographic Murphy's sign, are often useless in these, acalculous, patients. Cholescintigraphy is very sensitive, but is less specifi c, with a high false-positive rate, in disease resulting from total parenteral nutrition, fasting, or liver failure. On abdominal ultrasonography and CT, (1) thickened gallbladder wall, (2) pericholecystic fl uid, and (3) subserous edema are useful signs for diagnosis. But their specifi city is lower than that in calculous cholecystitis. [bib_ref] Cholecystitis without gallstones, Kang [/bib_ref] [bib_ref] Acute acalculous cholecystitis, Babb [/bib_ref] Therefore, for infectious diseases which occur during the treatment of severe disease with an unknown cause, the possibility of acalculous cholecystitis should always be kept in mind. If the possibility of acalculous cholecystitis cannot be denied because of the absence of a focus of infection, percutaneous biliary drainage should be performed, for both microbial inspection and treatment. However, antimicrobial drugs have usually been administered to most of the patients, the positive rate of biliary culture is not high (33%)(level 4). [bib_ref] Acute acalculous cholecystitis, Babb [/bib_ref] [bib_ref] Surgical treatment of biliary tract infections, Lillemoe [/bib_ref] [fig_ref] Table 3: Diagnostic imaging accuracy for acalculous acute cholecystitis [/fig_ref] lists fi ndings for the accuracy of diagnostic imaging in acalenlous acute cholecystitis.
## Q13. can ultrasonography diagnose acalculous cholecystitis?
The diagnosis of acalculous cholecystitis is not easy, because it is diffi cult to collect information on abdominal pain and Murphy's sign in patients who have disease often associated with disturbance of consciousness that is or with treatment already received for other purposes. [bib_ref] Contribution of ultrasonography and cholescintigraphy to the diagnosis of acute acalculous cholecystitis..., Mariat [/bib_ref] Jeffrey and Sommer 51 examined 14 patients with clinically suspected acalculous cholecystitis, and reported that the possibility of acalculous cholecystitis was high if the thickness of the gallbladder wall at the fi rst examination was normal (3 mm or less) but had increased to 4 mm or more at the second examination within in 24 h (4 out of 4 cases). If the second inspection revealed that the thickness remained the same or had improved in patients with an abnormally thickened gallbladder wall at the fi rst inspection, the incidence of acalculous cholecystitis was low (1 of 6 cases)(level 4). Helbich et al., [bib_ref] Sonomorphology of the gallbladder in critically ill patients. Value of a scoring..., Helbich [/bib_ref] who performed ultrasonography in 21 ICU patients weekly, indicated that when 2 points were allotted to an enlarged gallbladder (long axis diameter, 8 cm or more; short axis diameter, 5 cm or more), thickened gallbladder wall (4 mm or more), and an image of debris, and 1 point to a striated intra-wall structure and fl uid collection localized to the pericholecystic area, the incidence of acalculous cholecystitis was zero in patients with 5 points or less but high in those with 6 points or more (level 4).
## Abdominal echo and computed tomography (ct) are useful in the diagnosis of acute acalculous cholecystitis, but care should be taken, as the diagnostic accuracy is lower than that in calculous cholecystitis.
Acute acalculous cholecystitis is likely to occur postoperatively and during the treatment of serious injuries and burns, and accounts for 2%-15% of all acute cholecystitis cases. The diagnosis is diffi cult, and, in Japan, the diagnostic accuracy of postoperative cholecystitis at onset is low, at only 63%. [bib_ref] Postoperative acute cholecystitis: a collective review of 494 cases in Japan, Inoue [/bib_ref] What is hepatolithiasis? Hepatolithiasis is a condition in which stones are present in the hepatic and/or intrahepatic bile duct. Seventy to eighty percent of cases of hepatolithiasis are of unknown cause. In countries in Asia, the incidence of hepatolithiasis differs depending on the country; thus, environmental factors are considered to be involved in the onset. Causes can be identifi ed for the hepatolithiasis that occurs secondary to surgery and is associated with biliary dysplasia. Specifi c disorders include Oriental cholangiohepatitis, known as recurrent pyogenic cholangitis, an epidemic disease in Southeast Asia.
## Epidemiology and etiology of hepatolithiasis
According to a study by Uchiyama and Tanimura, 2 acute cholangitis was observed in 8.5% of 1708 patients with hepatolithiasis. Cholelithiasis consists of bilirubincalcium stones in 74.8% of patients and cholesterol stones in 13.1%, but the etiology of this disease is unknown. However, in view of the fact that hepatolithiasis is not observed in western countries (although it has been reported that Escherichia coli is involved in choleithiasis), biliary tract infection is very unlikely to be a single cause of hepatolithiasis. There is a report suggesting the involvement of parasites and malnutrition. Clonorchiosis is asymptomatic when the count of Clonorchis sinensis remains low; however, when the count increases to 500-1000 pieces, disorders such as closure of the bile duct, suppurative cholangitis, and hepatolithiasis may occur. In the diagnosis of this disease, the presence of eggs in feces or bile, and eosinophilia on blood tests, are important fi ndings. A survey conducted by in 1998 in the Goto region, Nagasaki Prefecture, known as a region epidemic for hepatolithiasis in Japan, showed that HLA antigen positivity (A26, B44, BW54, CW7, DR6) was a parameter for a high risk of hepatolithiasis. It is also known that the formation of mucin protein on the bile duct epithelium plays an important role in the formation of stones. In view of these reports indicating diffi culty with the initial ultrasonographic diagnosis of acalculous cholecystitis, it is important to re-examine patients suspected of having acalculous cholecystitis.
## Q14. what is the treatment policy for acalculous cholecystitis?
## In principle, the treatment policy for acalculous cholecystitis is the same as that for calculous cholecystitis, but the treatment method is chosen by keeping the patients systemic condition in mind.
Basic primary care must be performed before the diagnosis is established. As acalculous cholecystitis is unlikely to respond to conservative treatment and is often complicated by gangrene (with or without perforation), early cholecystectomy seems to be desirable (level 4). [bib_ref] Acute acalculous cholecystitis in the critically ill, Shapiro [/bib_ref] [bib_ref] Acute acalculous cholecystitis, Barie [/bib_ref] [bib_ref] Acute acalculous cholecystitis, Frazee [/bib_ref] Recently, noninvasive PTGBD has been employed for acalculous cholecystitis, which is often observed in postoperative and post-trauma patients who are regarded as inoperable. There have been no RCTs which compared PTGBD and cholecystectomy, and the comparison in a retrospective study (level 5) [bib_ref] Acute acalculous cholecystitis, Frazee [/bib_ref] was unreliable because PTGBD was performed in patients who were inoperable. Some reports examining PTGBD performed for elderly patients or those in poor systemic condition indicate that PTGBD, which leads to a low incidence of recrudescence could replace surgery (recommendation grade B, level 4-5). [bib_ref] Acute acalculous cholecystitis, Babb [/bib_ref] [bib_ref] Surgical treatment of biliary tract infections, Lillemoe [/bib_ref] [bib_ref] Is percutaneous cholecystostomy the optimal treatment for acute cholecystitis in the very..., Sugiyama [/bib_ref] Acute and intrahepatic cholangitis associated with intrahepatic stones Diagnosis of hepatolithiasis Hepatolithiasis is diagnosed by the presence of stones in the intrahepatic bile duct, confi rmed by direct cholangiography. Charcot's triad (abdominal pain, fever, and jaundice) is observed in about 60% of the patients. In severe cases associated with shock and disturbed consciousness, patients may have a reduced platelet count and disseminated intravascular coagulation (DIC). Characteristic histological fi ndings in the liver include the growth of cholangioles and infl ammatory cellular infi ltration in the periportal area.
Blood tests. In general, an increased white blood cell count, a high level of hepatobiliary enzymes, and hyperbilirubinemia are observed, with hyperamylasemia in 20% of patients.
Microbial examination. The rate of detection of bacteria in bile is 85%, with gram-negatives such as E. coli, Klebsiella spp. and Enterobacter spp. as major causative bacteria. Enterococcus spp and Pseudomonas aeruginosa have been increasingly detected recently. 2
## Diagnostic imaging
Ultrasonographic diagnosis A marked dilated extrahepatic bile duct, the presence of stones, increased echogenicity in the regional intrahepatic portal area, and localized enlargement or stricture of intrahepatic segmental bile duct branches are observed. However, there is a pitfall with ultrasonography in that an enlarged bile duct may not be visualized if it is fi lled with high-luminance sludge (level 4). CT diagnosis CT diagnosis reveals an enlarged intrahepatic bile duct and zonal atrophy of the liver. Splenomegaly may be observed in patients with serious liver disorder. If the bile duct is fi lled with clay stones as a mold, cholelith may not be diagnosed. If there is pneumobilia due to previous treatment, CT is more useful than ultrasonography.
Cholangiography Enlargement of the bile duct and stones are observed, though enlargement of the intrahepatic bile duct is less than that of the extrahepatic bile duct. Cholangiography shows fi ndings such as straightening, rigidity, decreased arborization, increased branching angle, acute peripheral tapering, and multiple focal strictures of the bile duct (level 4). 13
## Acute biliary tract infection associated with malignant pancreatic-biliary tumor
## Acute cholangitis
## Q16. what is the principle of medical treatment for acute cholangitis associated with malignant biliary tumor?
Severity assessment should be performed upon the initiation of medical treatment. The examination should be done quickly to identify the feasibility of resection. Biliary drainage should be performed in a timely manner.
Malignant pancreatic-biliary tumor sometimes develops in patients with acute cholangitis, and emergency biliary drainage is then required. The acute cholangitis observed in these patients occurs in those patients in whom (1) endoscopic retrograde cholangiopancreatography (ERCP) has been performed only for diagnostic purposes, but not for biliary drainage, and (2) those in whom biliary drainage has been performed, but, due to troubles such as catheter obstruction, an undrained area still remains. No matter how severe the acute cholangitis is, either drainage or replacement of the catheter is required depending on the cause.
When malignant pancreatic-biliary tumor is associated with acute cholangitis, an appropriate drainage method should be selected according to the site of the causative stricture or obstruction (see Q17).
## Q17. which drainage method should be applied for acute cholangitis associated with pancreatic-biliary malignancies?
For patients in whom an occlusion in the hepatic hilus and bile duct extends upstream, percutaneous transhepatic drainage should be the method of fi rst choice, in principle, in view of the concern that endoscopic drainage may reduce the accuracy of diagnosis of upstream cancer metastases and induce cholangitis in the area of poor drainage. However, there are no RCTs comparing these two drainage methods, and the choice has been only empirical.
There are no reports that compare endoscopic nasobiliary drainage (ENBD, or biliary tube stent placement) and percutaneous transhepatic biliary drainage in patients with occlusion in the middle and lower bile duct. However, at the institutions where staff are skillful with endoscopic examinations the tendency is to use ENBD without EST as the method of fi rst choice, while at the institutions where staff cannot perform ENBD, percutaneous transhepatic biliary drainage is chosen. However, as it is often diffi cult to visualize the biliary tract clearly when endoscopic drainage is performed, percutaneous transhepatic biliary drainage is desirable.
It has been reported that the total morbidity and mortality rates after pancreaticoduodenectomy in patients who had occlusion in the middle and lower bile duct and received stenting (stent material not specifi ed), were not different from those without stenting, but there was a signifi cantly higher incidence of pancreatic fl uid leakage in those with stenting (level 4). Postoperative fi stula recurrence has been reported after percutaneous transhepatic biliary drainage employed for patients with biliary tract carcinoma (level 4). 2
## Acute cholecystitis
## Q18. what is the primary care policy for acute cholecystitis complicated by gallbladder cancer?
postoperatively with gallbladder cancer, two-stage radical surgery is indicated if the cancer is categorized as in the proper muscular layer or deeper. However, it is extremely diffi cult to choose the optimal surgical method, based on an assessment of the development of morbidity, in patients with cancer associated with extremely severe infl ammation. A diagnosis of gallbladder cancer after laparoscopic cholecystectomy is a risk factor for carcinomatous peritonitis and port-site recurrence. Therefore, for patients with acute cholecystitis associated with or suspected to be associated with gallbladder cancer, as soon as primary care is initiated, a preoperative examination should be conducted to enable a onestage radical operation whenever possible.
Biliary cytodiagnosis (rinsing cytodiagnosis and, aspiration cytodiagnosis) with PTGBD is useful for the diagnosis of gallbladder cancer. However, the drainage tubes used in PTGBD have interfered with diagnostic imaging or have induced recurrence of cancer at the drainage fi stula in some patients. Therefore, it must be noted that biliary drainage for acute cholecystitis in patients with or suspected of having gallbladder cancer entails a risk of cancer recurrence at the drainage fi stula, and a risk of carcinomatous peritonitis.
## Q19. what is the treatment policy when acute cholecystitis occurs during the surgical treatment of gallbladder cancer?
During the preoperative treatment of gallbladder cancer, the cystic duct may be obstructed due to the progress of cancer and/or bile duct stenting, and acute cholecystitis may occur. In such a case, PTGBD should be performed immediately. Severity assessment should be performed simultaneously with primary care. Preoperative examination should be done as early as possible so that a one-stage radical procedure can be performed whenever possible.
## Biliary tract infections in patients with
Postoperative biliary drainage, which has a risk of recurrence of drainage fi stula and carcinomatous peritonitis, should be avoided whenever possible.
The prognosis of gallbladder cancer complicated by acute cholecystitis depends on the degree of progress of the cancer itself, but most of these patients have a poor prognosis. Preoperative diagnosis is diffi cult when gallbladder cancer is complicated by acute cholecystitis, and a patient often has surgery after being diagnosed with acute cholecystitis, and gallbladder cancer is diagnosed intra-or postoperatively. In patients diagnosed
Patients who have undergone surgery of the biliary tract and the upper abdomen and liver and biliary tract treatment should be observed carefully, as cholecystitis and cholangitis may be hidden. Fever may occur postoperatively, resulting from various causes, but the potential association of the fever with cholangitis should be borne in mind.
## Cholangitis in patients with a history of biliary surgery
## Cholangitis in patients with a history of est and/or endoscopic papillary balloon dilatation (epbd)
As patients with calculous cholangitis often undergo cholecystectomy before or after cholelithotomy, there are not many reports of long-term observations of patients with gallstones after EPBD, without a surgical operation. According to an RCT comparing EST and EPBD, the incidence of cholecystitis post-EPBD was signifi cantly lower than that post-EST (9.9% and 1.3% after EST and EPBD, respectively) (level 4). This is because the function of Vater's papilla is kept intact by EPBD, whereas EST causes retroinfection. However, in light of the possibility gallstones remaining after EPBD and the incidence of conversion to EST in symptomatic cholelithiasis patients, more cases should be collected in order to identify whether or not cholecystectomy should be performed for post-EPBD cholecystolithiasis.
## Cholangitis in patients with a history of surgical sphincteroplasty
Sphincteroplasty is rarely performed currently because of the wide spread use of EST. The incidence of cholangitis in patients with sphincteroplasty is about 5.9% (level 4). 2
## Cholangitis in patients with a history of an end-to-side choledochojejunostomy
It is reported that postoperative cholangitis occurs in 9.2%-33% of patients who have had a pancreaticoduodenectomy, while 1.1% of patients who have biliary surgery need re-surgery. In general, cholangitis is caused by the disturbed and retrograde (ascending) fl ow of bile, due to stricture at the site of the choledochojejunostomy.
Stenosis at the site of a choledochojejunostomy. Stenosis at the site of a choledochojejunostomy was observed in 7%-23% of those who underwent cholangiojejunostomy (level 4), and it is a frequent cause of postoperative cholangitis. The incidence of stenos is higher if malignant tumor-induced stenosis is included.
## Retrograde cholangitis and other forms of cholangitis.
Patients with fever or abdominal pain and increased levels of biliary enzymes, such as aspartate aminotransferase and alanine aminotransferase, and an elevated infl ammatory reaction after treatment or surgery of the biliary tract, are often diagnosed as having retrograde cholangitis. Pneumobilia and a contrast effect of the bile duct wall on CT may be used as supplementary proof in the diagnosis, but there are neither specifi c signs nor specifi c examination fi ndings. Retrograde cholangitis occurs often after treatment or surgery, and is not diagnosed, or is missed, in many patients. The absence of clear diagnostic criteria for retrograde cholangitis complicates this issue.
## Side-to-side choledochojejunostomy
In addition to the problems described above, precautions should be takent to prevent cholangitis (sump syndrome) that may be caused by food and sludge collecting in the remaining lower bile duct when side-to-side choledochojejunostomy. 5
## End-to-side choledochoduodenostomy
According to an RCT, there is no signifi cant difference in perioperative mortality, the total incidence of morbidity, or the incidence of postoperative cholangitis between patients who have had a choledochoduodenostomy and those who have had a choledochojejunostomy (level 4). Side-to-side choledochoduodenostomy Precautions should be taken, because this method causes sump syndrome.
## Cholangitis and cholecystitis after operations other than those on the biliary tract
The incidence of postoperative cholecystitis after surgery other than that on the biliary tract ranges widely, from 0.1%-13%, depending on the primary disease and surgical method. Patients should be carefully observed in view of the high incidence of acalculous cholecystitis. It has been reported that transcatheter arterial embolization (TAE), radiofrequency ablation (RFA), and cryosurgery are followed by the occurrence of cholangitis or cholecystitis. It is diffi cult to identify whether these conditions are direct complications of these procedures. There is a report that intraperitoneal infectious diseases (hepatic abscess, intraperitoneal abscess, and infection from an inserted device) were observed in 12 of 158 patients who underwent cryosurgery, with 2 of the 12 patients having cholangitis (level 4). Post-gastrectomy acute cholecystitis, which is caused by intracystic cholestasis (under the infl uence of reduced gallbladder contraction caused by incision of the vagus nerve due to lymphadenectomy), disturbed blood fl ow in the gallbladder wall, and bacterial infection, occurred in 24 of 190 patients with gastric cancer (12.6%).
Primary sclerosing cholangitis (PSC) is a chronic infl ammatory disease with stricture of the bile duct caused by progressive and nonspecifi c infl ammation of the walls of the intra-and extrahepatic bile ducts. It is considered that autoimmunity is involved in the onset of PSC. The stricture and obstruction of the bile duct may cause obstructive jaundice, followed ultimately by secondary biliary cirrhosis of the liver and liver failure.
The etiology of PSC has not been identifi ed. A report indicates the involvement of HLA DR3 and DR2 in its onset, while there are other reports that bacterial and viral infections (associated with immunodefi ciency), occlusion of the hepatic artery, and disorders induced by chemotherapy are involved in the etiology.
Takikawa et al. reviewed 388 PSC patients in 2003 to examine the incidence and prognosis of the disease. According to their report, the age distribution of PSC patients in Japan has two peaks, one in the twenties and the other in the fi fties to sixties. Younger patients are often complicated by infl ammatory enteropathy, while the elderly patients are often complicated by autoimmune pancreatitis. It was also reported that the rates of complication with ulcerative colitis, autoimmune pancreatitis, cholelith, and biliary cancer were 37%, 7.2%, 16%, and 4.3%, respectively. The clinical symptoms of PSC include jaundice (44%), systemic itchiness (27%), abdominal pain (18%), fever (10%), and systemic weariness (4%). PSC may be complicated by retrograde bacterial cholangitis as a longterm outcome. There are no studies that have confi rmed bacterial cholangitis by examining for the presence of bacteria in bile while the patient has a fever, and it is not certain whether a fever directly represents the complication of bacterial cholangitis. If PSC presents with fever, however, the complication of bacterial cholangitis should be suspected. According to Olsson et al., fever was observed in 15% of PSC patients and in 50% of those whose bile duct lesion was limited to the intrahepatic bile duct.
In the diagnosis of PSC, the following diagnostic criteria, proposed by La Russo et al., are often used, except for cholelith, post-biliary operation cholangitis and secondary sclerosing cholangitis caused by biliary tract tumor.
(1) Increase in the serum alkaline phosphatase level of two times or more than the normal level (however, patients with an increase of less than two times normal account for 35% of PSC cases in Japan) (2) Diffuse stricture or bead-like change in the intraand extrahepatic bile ducts
The etiology of acute cholangitis associated with congenital biliary dilatation differs according to whether it occurs pre-or postoperatively (level 4).
Acute cholangitis associated with congenital biliary dilatation is roughly divided into two types: cholangitis as a primary symptom of congenital biliary dilatation and postoperative cholangitis. The incidence of acute cholangitis is 9.2%-23.4% in patients with congenital biliary dilatation without choledocholithiasis, with the complication of acute pancreatitis in many cases (level 4). 1,2 Mechanisms of the onset of cholangitis include the backfl ow of pancreatic fl uid into the bile duct and the incarceration of a gallstone protein plug in the papilla (level 4). Symptoms include abdominal pain, vomiting, jaundice, and fever. Abdominal pain is observed in over 80% of infant patients 1 year and older. In patients under 1 year old, who very rarely have abdominal pain as the main complaint, vomiting, fever, and jaundice are important proofs of the diagnosis (level 4). Postoperative acute cholangitis occurs in 8%-30% of patients who undergo an operation for congenital biliary dilatation. Postoperative cholangitis and hepatolithiasis are considered to be caused by stricture at the site of a choledochoenterostomy and congenital stricture of the intrahepatic bile duct (level 4). 5
Because of the high morbidity of postoperative cholangitis, various methods are used at the initial operation for congenital biliary dilatation (level 4).
To prevent postoperative cholangitis, the recommended methods are to cut and open the right and left hepatic ducts during surgery, to make a large anastomotic opening and to form a passage for the strictured intrahepatic bile duct. Particularly after Appleby surgery, the disease occurred frequently, in 10 of 37 patients. 9
Acute biliary tract infections associated with congenital biliary dilatation and pancreaticobiliary maljunction Q21. What is the characteristic etiology of acute cholangitis associated with congenital biliary dilatation?
(3) Histological fi ndings that include fi brosed bile duct, obstructive cholangitis, and disappearance of bile duct (4) No history of biliary tract operation other than cholecystectomy, and the absence of cholelith
The diagnostic criteria proposed by the Mayo Clinic group in 1994 5 attach the greatest importance to cholangiographic fi ndings, such as beaded appearance, band-like stricture, and diverticulum-like outpouching, and this group argues that the diagnosis of PSC only by liver biopsy is diffi cult. One of the important issues in the diagnosis of PSC is complication by and differentiation from bile duct cancer. As it has been reported that 7.1% (5/71) of the patients who died of PSC had bile duct cancer (cholangiocarcinoma), patients presenting with atypical stricture of the bile duct should undergo histopathological diagnosis with a biopsy, using percutaneous transhepatic cholangiography (PTCS).
## Q23. what is the optimal treatment method for localized psc
preparation of the Guidelines. This process was conducted as part of the Project on the Preparation and Diffusion of Guidelines for the Management of Acute Cholangitis (H-15-Medicine-30), with a research subsidy for fi scal 2003 and 2004 (Integrated Research Project for Assessing Medical Technology) sponsored by the Japanese Ministry of Health, Labour, and Welfare.
We also truly appreciate the panelists who cooperated with and contributed signifi cantly to the International Consensus Meeting, held on April 1 and 2, 2006.
## Surgical treatment is effective in some patients with localized psc (recommendation c). however, because the treatment has been done in few patients, the indication should be carefully chosen.
It is considered that the prognosis of PSC is poor, because it is associated with obstructive jaundice caused by the progressive sclerosing and stricture of the intraand extrahepatic bile ducts, and ultimately progresses to secondary biliary cirrhosis of the liver and liver failure. However, there are increasing numbers of reports of localized cases. According to a review of reports in Japan, the long-term prognosis of localized PSC is good, and 10 of 12 patients operated on were without recurrence, while all 4 patients not operated died of the disease. This result may indicate good prognosis for localized PSC, if the patients undergo excision of the lesion (level 4). 6
# Conclusion
The characteristics, diagnostic criteria, treatment guidelines for, and prognoses of specifi c biliary tract infections have been discussed, and it is hoped that the Guidelines will be useful.
[table] Table 1: Factors potentially associated with acute acalculous cholecystitis (Review ofBarie and Fischer 19 ) Acalculous cholecystitis occurs often in patients with severe acute cholecystitis.• The prognosis of acalculous cholecystitis is worse than that of ordinary acute cholecystitis. • Acalculous cholecystitis may be relieved by biliary drainage alone in some cases.Acalculous cholecystitis often occurs in patients in the intensive care unit (ICU) and in those with cardiopulmonary-nephrotic dysfunction. The total mortality is 15%, with the post-trauma mortality as high as 27% (level 4). 1Q10. What are the incidence and prognosis of acute acalculous cholecystitis?• Acute acalculous cholecystitis accounts for 2%-15% of acute cholecystitis. Common risk factors of acalculous cholecystitis are operation, serious trauma, burns, and parenteral nutrition. It is also reported that the spread of malignant tumor to the hilus of the liver, hepatic arterial infusion, diabetes, specifi c drugs and specifi c infections are associated with acalculous cholecystitis. According to reports of Japanese patients, acute acalculous cholecystitis occurs often after an abdominal operation.Acute acalculous cholecystitis accounts for 2%-15% of all types of acute cholecystitis (level 4).[2][3][4][5] Acalculous cholecystitis is likely to occur in patients with serious disease, and has a poor prognosis in general, due to the high incidence of morbidity, such as gangrenous cholecystitis and gallbladder perforation. According to Kalliafas et al.,6 gangrenous changes, perforation, and abscess are observed in 63%, 15%, and 4% of patients [/table]
[table] Table 2: Incidence of postoperative acute cholecystitis [/table]
[table] Table 3: Diagnostic imaging accuracy for acalculous acute cholecystitis [/table]
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ACC Health Policy Statement on Cardiovascular Disease Considerations for COVID-19 Vaccine Prioritization
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ACC Health Policy Statement on Cardiovascular Disease Considerations for COVID-19 Vaccine Prioritization
PREFACEThe American College of Cardiology (ACC) has a long history of developing documents (e.g., decision pathways, health policy statements [HPS], appropriate use criteria) to provide members with guidance on both clinical and nonclinical topics relevant to cardiovascular care. In most circumstances, these documents have been created to complement clinical practice guidelines and to inform clinicians about areas where evidence may be new and evolving or where sufficient data may be more limited. Despite this, numerous care gaps continue to exist, highlighting the need for more streamlined and efficient processes to implement best practices in service to improved patient care.Central to the ACC's strategic plan is the generation of "actionable knowledge"-a concept that places emphasis on making clinical information easier to consume, share, integrate, and update. To this end, the ACC has evolved from developing isolated documents to developing integrated "solution sets." Solution sets are groups of closely related activities, policy, mobile applications, decision support, and other tools necessary to transform care and/or improve heart health.Solution sets address key questions facing care teams and attempt to provide practical guidance to be applied at the point of care. They use both established and emerging methods to disseminate information for cardiovascular conditions and their related management. The success of the solution sets rests firmly on their ability to have a measurable impact on the delivery of care. Because solution sets reflect current evidence and ongoing gaps in care, the associated tools will be refined over time to best match changing evidence and member needs.HPS represent a key component of solution sets. The methodology for HPS is grounded in assembling a group of experts to develop content that addresses key policy issues facing our members. Topics selected for HPS vary widely, but connect to scientific, quality, and/or advocacy efforts within the ACC. HPS are not written to provide clinical guidance; rather, they are intended to advocate a position, be informational in nature, and apprise stakeholders of the ACC's stance on healthcare policies and programs.
# Methodology
To provide this policy document, the American College of Cardiology convened a writing group with expertise in CVD, epidemiology, and risk assessment. We conducted a literature review of published reports relating to CVD and COVID-19. Where the literature was absent, we achieved consensus among the writing group. However, in some cases, there was insufficient evidence and/or experience to present an informed opinion, which needs to be considered in the interpretation of this document.
We attempted to include data from geographically diverse areas, when available, recognizing that variability in COVID-19 testing, treatment strategies, and the prevalence of CV conditions can affect estimates of prevalence.
It is also noteworthy that most published data have been retrospective in nature and have been conducted at various timepoints during the pandemic. As such, we attempted to emphasize data from larger meta-analyses, when available. It should be noted that our recommendations are based on limited data collected since the pandemic onset. Future recommendations may change over time with higher-quality data.
## Overall considerations for vaccine allocation decisions
Although the focus of this document is the specific clinical risk associated with CV risk factors and disease in COVID- [bib_ref] Potential effects of coronaviruses on the cardiovascular system: a review, Madjid [/bib_ref] vulnerable, but not frail; 5 to 6 ¼ initial signs of frailty but with some degree of independence; and 7 to 9 ¼ severe or very severe frailty) found that higher levels of frailty were associated with worse adjusted 7-day mortality,
## Central illustration considerations for prioritization of covid-19 vaccination allocation
Poorly controlled hypertension is defined as >140/90 mm Hg. Poorly controlled diabetes is defined using A 1c >10%. Overweight is defined as BMI 25-29 kg/m 2 ; obese as BMI 30-40 kg/m 2 , and morbidly obese as BMI >40 kg/m 2 . Obstructive CAD is defined using $70% obstruction in major epicardial arteries, $50% in left main coronary artery. High-grade PAD is defined using ABI $0.5. Malignant tachyarrhythmia includes atrial fibrillation with poor rate control and/or VT with prior ICD therapy or antiarrhythmic medication. ACHD ¼ adult congenital heart disease; ABI ¼ ankle brachial index; BMI ¼ body mass index; CAD ¼ coronary artery disease; CVD ¼ cardiovascular disease; NYHA ¼ New York Heart Association; PAD ¼ peripheral arterial disease; VT ¼ ventricular tachycardia.
Driggin et al.
## Cvd and covid-19 vaccination
A P R I L 2 0 , 2 0 2 1 : 1 9 3 8 -4 8 independent of age and comorbidity [bib_ref] The effect of frailty on survival in patients with COVID-19 (COPE): a..., Hewitt [/bib_ref]. Given this collective evidence, older patients with multiple comorbidities, including CV conditions, and/or frailty should be considered at high risk and thus prioritized for COVID-19
vaccination.
Finally, it is imperative to recognize the racial, ethnic, and socioeconomic disparities that may influence the risk for adverse outcomes, including mortality, in COVID-19 [bib_ref] Racial disparities in COVID-19 mortality are driven by unequal infection risks, Zelner [/bib_ref] [bib_ref] Disparities in the population at risk of severe illness from COVID-19 by..., Raifman [/bib_ref]. Reports from the CDC show that compared with age-adjusted standardized mortality rates, the risk of death from COVID-19 increased by nearly 3-fold in Blacks, non-Black Hispanics/Latinos, and American Indians/ Alaskan Natives (12). The reasons behind these disparities are multifactorial. First, the exposure risk among these populations tends to be higher, given the higher prevalence of multigenerational households and "essential" jobs necessitating more frequent contact with the public.
Second, patients in racial and ethnic minority populations have a higher prevalence of CV risk factors and disease and therefore are at higher clinical risk compared with those without comorbidity [bib_ref] Association of race and ethnicity with comorbidities and survival among patients with..., Kabarriti [/bib_ref] [bib_ref] Hospitalization and mortality among black patients and white patients with Covid-19, Price-Haywood [/bib_ref]. Higher transmission rates are also observed among those who experience social inequalities [bib_ref] COVID-19 and the impact of social determinants of health, Abrams [/bib_ref]. Third, healthcare accessibility is another important driver of these disparities. 1.1 to 2.7) (28). Additionally, the presence of CVD is a key risk factor for the CV complications of COVID-19, which are also associated with increased morality (29,30).
Below, we review the available data regarding the prevalence and association of specific CV conditions and risk factors with outcomes in patients with COVID-19.
## Hypertension
Since the earliest cohort studies from China, hypertension has been consistently reported as a common CV comorbidity in patients with COVID-19 (31-34). In a large U.S. cohort study using hospital claims data for 11,721 patients across 38 states, pre-existing hypertension was noted in 46.7% of COVID-positive patients [bib_ref] Patient characteristics and outcomes of 11,721 patients with COVID19 hospitalized across the..., Fried [/bib_ref]. In a critically ill cohort of 257 patients from New York City, the prevalence of pre-existing hypertension among patients in the ICU was even higher, at 63.0% (35).
Although the baseline prevalence of hypertension varies significantly by geographic region, multinational data have consistently demonstrated worse outcomes associated with COVID-19 in patients with pre-existing hypertension (23,33). In a large meta-analysis from Driggin et al.
A P R I L 2 0 , 2 0 2 1 : 1 9 3 8 -4 8 especially those with poorly controlled disease with older age and additional comorbidities, should be considered to have elevated risk of adverse outcomes associated with COVID-19.
## Diabetes
Diabetes mellitus is a highly prevalent CV risk factor among patients with COVID-19. In a large cohort study using medical record data including 31,461 patients from 24 U.S. healthcare systems, diabetes was present in 15% of patients with COVID-19. In this analysis, diabetes was the second most common medical comorbidity overall, aside from pre-existing pulmonary disease, which was prevalent in 17.5% of patientsAccordingly, we recognize obesity as an important CV risk factor and postulate the risk of obesity to be incremental, such that patients with morbid obesity are at the highest risk for poor outcomes associated with COVID-19.
Furthermore, it is important to recognize that obesity contributes to other risks such as hypertension, diabetes, sleep apnea, and secondary pulmonary hypertension.
## Atherosclerotic cardiovascular disease
Although the data from China demonstrated pre-existing atherosclerotic cardiovascular disease (ASCVD) in only a small minority of patients with COVID-19, studies from the United States demonstrate ASCVD to be a more common CV comorbidity, likely due to higher baseline prevalence (40). Data from inpatients and outpatients with COVID-19 in a large New York City health system reported an 8.6% prevalence of pre-existing coronary artery Nonetheless, the presence of ASCVD appears to be a clear risk factor for poor outcomes in COVID-19. Furthermore, we believe that patients with extensive, high-risk ASCVD are the most susceptible to adverse outcomes.
## Cardiac dysrhythmia
The risk of COVID-19 infection to patients with preexisting cardiac dysrhythmias has not been well defined.
However, patients with marginally controlled heart rhythm disorders may be at increased risk for exacerbations of their underlying conditions if infected with COVID-19. Interestingly, an association between atrial fibrillation (AF) and elevated angiotensin-converting enzyme 2 (ACE2) levels has led to speculation that patients with known AF may have a higher risk for morbidity and mortality associated with COVID-19 (51-53). Certain populations with AF have a higher risk for morbidity and mortality from arrhythmia recurrence, which COVID-19 seems to provoke (54,55).
## Heart failure
In distinction to many other CVDs, there is robust evidence for poor outcomes in COVID-19 in the presence of pre-existing heart failure. Among a cohort of 31,461 patients with COVID-19 across the United States, 7.3% had a history of heart failure (9). Compared with those who survived, those who died had a significantly higher proportion of pre-existing heart failure (30.8% vs. 6.3%). In a multivariable model controlling for relevant demographic and CV risk factors, pre-existing heart failure was independently associated with death in this cohort (OR: 1.42; 95% CI: 1.21 to 1.67). These findings have been replicated in 2 large New York City cohorts as well (49,59). In an analysis of 1,212,153 patients with heart failure who were included in the Premier health care database, patients with heart failure who were hospitalized for COVID-19 had markedly greater risk for in-hospital mortality in multivariable analysis (OR: 14.48; 95% CI: 12.23 to 17.12) [bib_ref] Clinical outcomes in patients with heart failure hospitalized with COVID-19, Bhatt [/bib_ref]. In multivariable models for the outcomes of death or mechanical ventilation, pre-existing heart failure was also a significant independent risk factor (OR: 8.04; 95% CI: 7.10 to 9.12). Notably, these associations were persistent over 2 distinct time periods in the pandemic, although overall mortality was lower later in the pandemic. Therefore, heart failure is a clear, established risk factor for poor outcomes, and patients who are decompensated and/or those with poor functional status should be considered at the highest risk.
## Prior heart transplant
Patients who have undergone heart transplantation are at Pregnant women with CVD should also be considered high risk, given the potential for pregnancy to decompensate certain CVDs, such as heart failure, that may be exacerbated in the setting of COVID-19 infection. In addition to other non-CV comorbidities, other behaviors may amplify CV risk, such as smoking, medical noncompliance, and alcohol or substance abuse. Although these interactions are all important to consider, more data are needed to make recommendations for these specific populations.
[fig] INTRODUCTION: The coronavirus disease 2019 (COVID-19) has had a devastating impact on healthcare systems around the world, with nearly 99 million cases and 2.1 million associated deaths as of January 2021 (1). As such, the rapid development and availability of multiple vaccines are welcome in the long and arduous fight against COVID-19. A coherent vaccine allocation policy promoting the greatest benefit for the greatest number would prioritize individuals with the highest risk for adverse outcomes of COVID-19 ahead of lower-risk populations. There are numerous factors that influence the risk for adverse outcomes in COVID-19, including the exposure risk for contracting COVID-19 and the clinical risk for adverse health outcomes with infection. The phased rollout of the vaccines by the Centers for Disease Control and Prevention (CDC) mirrors this framework by prioritizing older age groups and patients with significant medical comorbidities (2). The guidance specifies that during the Phase 1c allocation, all patients from 16 to 64 years of age with medical conditions that increase the risk for severe COVID-19 infection should receive the vaccine. Although the guidance specifies that heart conditions, hypertension, diabetes, obesity, and smoking are examples of such high-risk medical conditions, further delineation of varying levels of risk among patients with cardiovascular disease (CVD) is absent. As the largest professional society of cardiovascular (CV) professionals in the United States, the ACC aims to offer specific guidance about how CV conditions contribute to the risk for adverse outcomes with COVID-19 infection to inform its membership and the patients they serve. In this policy document, we: 1) outline the overall considerations of both exposure and clinical risk needed for vaccine allocation efforts; 2) present the specific evidence and risk considerations related to CVD and COVID-19; and 3) propose a schema of CV risk to incorporate into vaccine allocation decisions. [/fig]
[fig] 47: Tartof SY, Qian L, Hong V, et al. Obesity and mortality among patients diagnosed with COVID-19: results from an integrated health care organization. Ann Intern Med. 2020;173:773-81. 48. Hamer M, Gale CR, Kivimaki M, Batty GD. Overweight, obesity, and risk of hospitalization for COVID-19: A community-based cohort study of adults in the United Kingdom. Proc Natl Acad Sci U S A. 2020;117: 21011-3. 49. Kuno T, Takahashi M, Obata R, Maeda T. Cardiovascular comorbidities, cardiac injury, and prognosis of COVID-19 in New York City. Am Heart J. 2020;226:24-5. 50. Chen R, Liang W, Jiang M, et al. Risk factors of fatal outcome in hospitalized subjects with Coronavirus Disease 2019 from a nationwide Analysis in China. Chest. 2020;158:97-105. 51. Walters TE, Kalman JM, Patel SK, Mearns M, Velkoska E, Burrell LM. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017;19: 1280-7. [/fig]
[fig] 52: Wallentin L, Lindback J, Eriksson N, et al. Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation. Eur Heart J. 2020;41: 4037-46. 53. Sanchis-Gomar F, Perez-Quilis C, Lavie CJ. Should atrial fibrillation be considered a cardiovascular risk factor for a worse prognosis in COVID-19 patients? Eur Heart J. 2020;41:3092-3. 54. Lakkireddy DR, Chung MK, Gopinathannair R, et al. [/fig]
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Diagnosis and Management of Adenocarcinoma in Situ
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Diagnosis and Management of Adenocarcinoma in Situ
This publication represents an extensive literature review with the goal of providing guidelines for the evaluation and management of cervical adenocarcinoma in situ (AIS). The authors drafted the guidelines on behalf of the Society of Gynecologic Oncology, and the guidelines have been reviewed and endorsed by the ASCCP. These guidelines harmonize with the ASCCP Risk-Based Management Consensus Guidelines and provide more specific guidance beyond that provided by the ASCCP guidelines. Examples of updates include recommendations to optimize the diagnostic excisional specimen, AIS management in the setting of positive compared with negative margins on the excisional specimen, surveillance and definitive management after fertility-sparing treatment, and management of AIS in pregnancy. The increasing incidence of AIS, its association with human papillomavirus-18 infection, challenges in diagnosis owing to frequent origin within the endocervical canal, and the possibility of skip lesions all make AIS a unique diagnosis whose management needs to be differentiated from the management of the more prevalent squamous cell dysplasia.T he incidence of cervical adenocarcinoma in situ (AIS) is rising, and though an increase in the number of diagnoses of in situ squamous cell carcinoma has been associated with a concomitant decrease in the incidence of invasive squamous cell carcinoma owing to earlier diagnosis and treatment, a similar decrease in subsequent invasive adenocarcinoma has not occurred. 1 This suggests delayed diagnosis of AIS, a shorter interval of disease progression from clinically evident AIS to invasive adenocarcinoma, or both. Although other cervical cancer screening management guidelines provide specific algorithms for initial screening and management, 2-5 they do not provide detailed recommendations for management and surveillance of AIS, especially when conservative management is desired. The purpose of these guidelines is to provide clinicians with information and recommendations for diagnosis and management of cervical AIS.BACKGROUND EpidemiologyThe incidence of cervical AIS has increased over the past few decades, especially among individuals aged 30-40 years. 1,6 The mean age at diagnosis is 35-37 years, 6,7
and the current incidence rate is approximately 6.6 per 100,000 persons, increasing to 11.2 per 100,000 persons at the peak age of 30-39 years. [bib_ref] Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients..., Salani [/bib_ref] The average interval between a diagnosis of clinically detectable AIS and early invasive cancer is at least 5 years. [bib_ref] Prevalence of high-risk human papilloma virus genotypes and associated risk of cervical..., Monsonego [/bib_ref] Additionally, approximately 55% of patients with AIS have a coexisting squamous lesion.
## Etiology and risk factors
Human papillomavirus (HPV) infection, particularly infection with HPV-16, -18, or both, is the primary risk factor for AIS and associated cervical cancer. Although HPV-18 is associated with only 8% of all high-grade dysplasia (cervical intraepithelial neoplasia [CIN] 2 or worse and AIS) diagnoses (compared with 46-58% for HPV- [bib_ref] User perception of endocervical sampling: a randomized comparison of endocervical evaluation with..., Undurraga [/bib_ref] , it is associated with 38-50% of AIS diagnoses and 50% of all invasive cancer diagnoses (squamous cell carcinoma plus adenocarcinoma). [bib_ref] Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients..., Salani [/bib_ref] [bib_ref] Human papillomavirus genotypes in high-grade cervical lesions in the United States, Hariri [/bib_ref] [bib_ref] Human papillomavirus genotype-specific prevalence across the continuum of cervical neoplasia and cancer, Joste [/bib_ref] [bib_ref] Human papillomavirus and long-term oral contraceptive use increase the risk of adenocarcinoma..., Madeleine [/bib_ref] Therefore, factors that inhibit suppression of HPV are additional risk factors for AIS, such as immunosuppression (eg, rheumatologic disease on two or more immunosuppressants, human immunodeficiency virus , solid organ transplant) and smoking. Some studies also suggest oral contraceptive pill use as a risk factor for AIS. [bib_ref] ASCCP colposcopy standards: risk-based colposcopy practice, Wentzensen [/bib_ref] Conversely, vaccination against HPV is anticipated to be protective, with early evidence of this demonstrated by a decrease in incidence rate of AIS in the first 8 years of the HPV Vaccine Impact Monitoring Project among women aged 21-24 years, despite stable incidence rates in women aged 25-29 years and increases in women aged 30-39 years. [bib_ref] Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients..., Salani [/bib_ref]
## Guideline questions
This clinical practice guideline addresses the following clinical questions: 1) What clinical evaluation and diagnostic tests should be performed for individuals with suspected cervical AIS? 2) How should diagnostic or therapeutic excisional procedures be performed? 3) What are the recommendations for patients undergoing definitive surgical management with positive compared with negative excisional biopsy margins? 4) Which patient and disease criteria should be used to identify individuals who are eligible for fertility-sparing therapy? 5) What is the recommended surveillance after treatment of AIS? 6) How should AIS be managed during pregnancy? .
# Methods
## Guideline development process
The authors reviewed the available evidence, contributed to the development of the guidelines, provided critical review of the guidelines, and finalized the guideline recommendations. The guidelines were also reviewed and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Education Committee, SGO Publications Committee, and the SGO board members before submission for publication.
The recommendations were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current cervical cancer screening and dysplasia management guidelines, observational studies, and metaanalyses; phase III randomized clinical trials for management of AIS do not currently exist. A list of the MeSH terms searched are included in Appendix 1, available online at http://links.lww.com/AOG/B790. . Summary of adenocarcinoma in situ management recommendations. *Cold knife conization or loop electrosurgical excision procedure acceptable provided an adequate specimen can be obtained: 1) intact, nonfragmented (top-hat serial endocervical excisions unacceptable); 2) length of specimen must be at least 10 mm. HPV, human papillomavirus.
The terminology used in these guidelines was adopted from the American Society for Colposcopy and Cervical Pathology (ASCCP) management guidelines 3 using a two-part rating system to grade the strength of recommendation and quality of evidence [fig_ref] Table 1: Rating the Recommendations Modified with permission from [/fig_ref]. The rating for each recommendation is given in parentheses. Similar to the ASCCP guidelines, the terms "recommended," "preferred," "acceptable," "unacceptable," and "not recommended" are used to describe interventions.
## Clinical considerations and recommendations
## Clinical question 1
What clinical evaluation and diagnostic tests should be performed for patients with suspected cervical AIS? Recommendation 1.1 Evaluation of abnormal cytology or a positive HPV test result or both is recommended per the ASCCP Risk-Based Management Consensus Guidelines (BII), and colposcopic examination should be performed using the ASCCP colposcopy standards [fig_ref] Table 2: ASCCP Risk-Based Colposcopy Standards and Atypical Glandular Cells Evaluation HSIL, high-grade squamous... [/fig_ref]. [bib_ref] Clinical significance of atypical glandular cells on cervical cytology, Schnatz [/bib_ref] Atypical glandular cells (AGC) and HPV-16 and -18 are associated with AIS and should be evaluated with colposcopy, endocervical sampling, and endometrial biopsy, as recommended by the ASCCP Risk-Based Management Consensus Guidelines (http://www. asccp.org/consensus-guidelines). Given the association of HPV-18 with AIS, endocervical sampling in the setting of a positive HPV-18 test result regardless of colposcopy findings is acceptable (CIII).
## Recommendation 1.2
A diagnostic excisional procedure is recommended for all patients with AIS diagnosed on cervical biopsy, as well as all patients whose cervical biopsy and endocervical curettage results are negative in the setting of cytology results showing AIS or AGCfavor neoplasia. For persistent AGC-not otherwise specified, refer to ASCCP Risk-Based Management Consensus Guidelines. A diagnostic excisional procedure is recommended to rule-out an invasive adenocarcinoma, even when definitive hysterectomy is planned (AII).
## Literature review
Nearly all AIS lesions are asymptomatic and thus are diagnosed during cervical cancer screening examina-tions. A cytologic diagnosis of AGC results in a diagnosis of AIS in 3-4% of cases and invasive cervical adenocarcinoma in 2%. 14 However, any degree of cytologic atypia can be indicative of AIS, and one study showed AIS diagnosis is most often preceded by a low-grade cytologic abnormality (atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion). [bib_ref] Adenocarcinoma in situ of the uterine cervix: a metaanalysis of 1278 patients..., Salani [/bib_ref] Moreover, because these lesions originate from inside the endocervix, the abnormal cells are often missed on cytology. [bib_ref] Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement, Moyer [/bib_ref] The ASCCP Risk-Based Management Consensus Guidelines provide individualized recommendations for evaluation of abnormal cytologic or positive HPV test results or both (http://www.asccp.org/consensusguidelines). Although not specified by the ASCCP management guidelines, given the high rate of HPV-18-positive AIS, endocervical sampling for any patient who tests positive for HPV-18 is acceptable. An endocervical sample can be obtained using an endocervical curette, which may provide cervical stroma to aid in grading of dysplasia, or an endocervical brush, which is less prone to insufficient sampling and may have higher sensitivity. [bib_ref] Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement, Moyer [/bib_ref] [bib_ref] Cytobrush and endocervical curettage in the diagnosis of dysplasia and malignancy of..., Mogensen [/bib_ref] [bib_ref] User perception of endocervical sampling: a randomized comparison of endocervical evaluation with..., Undurraga [/bib_ref] Adenocarcinoma in situ frequently coexists with squamous dysplasia. When concomitant AIS and CIN are diagnosed, management should proceed per the recommendations for AIS. When AIS is diagnosed on cervical biopsy, approximately 15% will be associated with an invasive adenocarcinoma. [bib_ref] Adenocarcinoma in situ of the cervix: significance of cone biopsy margins, Wolf [/bib_ref] Therefore, the next step in evaluation is a diagnostic excisional procedure to confirm the diagnosis, assess the extent of disease, evaluate for coexisting squamous lesions, and exclude invasive adenocarcinoma before definitive management. A diagnostic excisional procedure is also recommended when cervical biopsies and endocervical curettage are negative in the setting of cytology results of AIS, AGC-favor neoplasia, or persistent AGC-not otherwise specified. A diagnostic excisional procedure before definitive management with hysterectomy is recommended to evaluate for invasive adenocarcinoma, which may require radical hysterectomy; if negative margins are not achieved on the first excision specimen, a second excisional procedure is recommended before hysterectomy to exclude an invasive cancer unless this cannot be performed safely.
## Clinical question 2
How should diagnostic or therapeutic excisional procedures be performed?
## Recommendation 2.1
Excisional procedures optimally result in removal of an intact specimen to facilitate accurate interpretation of margin status. Thus, excision by cold knife conization is preferred unless the surgeon is able to consistently remove an intact ("top hat" endocervical excision is unacceptable) specimen of adequate length and width (AII).
## Recommendation 2.2
Length of the excisional specimen of at least 10 mm is preferred and can be increased to 18-20 mm in patients who have completed childbearing (BII). Endocervical sampling above the excisional bed to evaluate for residual disease is preferred (CIII).
## Literature review
Traditionally, cold knife conization has been recommended over loop electrosurgical excision procedures (LEEP) owing to concern that cautery artifact could obscure the diagnosis. However, a meta-analysis of retrospective studies showed no difference in residual disease (LEEP 9.1% vs cold knife conization 11%) or recurrence risk (LEEP 7.0% vs cold knife conization 5.6%) by excisional method despite a higher risk of positive margins with LEEP (44%) compared with cold knife conization (29%; relative risk 1.55, 95% CI 1.34-1.80). [bib_ref] Comparison of cold-knife conization versus loop electrosurgical excision for cervical adenocarcinoma in..., Jiang [/bib_ref] Thus, the ASCCP management guidelines allow diagnostic excision using any modality, but it is imperative that, "care must be taken to keep the specimen intact and margins interpretable, avoiding fragmentation of the specimen, including 'top-hat' serial endocervical excisions." 3 Therefore, except in the hands of a highly skilled LEEP surgeon who is able to obtain an adequate specimen without fragmentation (ie, one intact specimen removed with one pass of the loop; "top hat" excision is unacceptable), excision by cold knife conization is preferred because there is a higher likelihood of the specimen being removed in one piece with adequate depth and width.
Length of the conization specimen should be at least 10 mm and can increase to 18-20 mm for patients who have completed childbearing. [bib_ref] Optimal cone size to predict positive surgical margins after cold knife conization..., Oz [/bib_ref] [bib_ref] The anatomic distribution of cervical adenocarcinoma in situ: implications for treatment, Bertrand [/bib_ref] For surgeons who are not able to consistently obtain intact excisional specimens with adequate length, referral for the initial excisional procedure to a gynecologic oncologist or other surgeon who specializes in the management of cervical dysplasia is preferred. Data on utility of sampling above the excisional bed are conflicting, but endocervical sampling with endocervical curettage or endocervical brushing above the excisional bed to evaluate for residual disease is preferred owing to the frequent location of AIS within the endocervical canal, which makes determining the extent of the lesion more difficult, and the potential for multifocal disease. [bib_ref] Endocervical curettage at conization to predict residual cervical adenocarcinoma in situ, Lea [/bib_ref] [bib_ref] Endocervical curettage, cone margins, and residual adenocarcinoma in situ of the cervix, Denehy [/bib_ref] Clinical Question 3
What are the recommendations for patients undergoing definitive surgical management with positive compared with negative excisional biopsy margins? Recommendation 3.1 Simple hysterectomy is preferred for patients with confirmed diagnosis of AIS with negative margins on the conization specimen (BIII).
## Recommendation 3.2
Either modified radical hysterectomy or simple hysterectomy is acceptable for patients with confirmed diagnosis of AIS with positive margins on the conization specimen (CIII).
## Recommendation 3.3
Surgical assessment of lymph nodes is acceptable at the time of hysterectomy (CIII).
## Literature review
Margin status is a predictor for residual and recurrent disease and progression; thus, it is essential that the margin status can be assessed and that margins are negative. Recurrence risk of AIS is only 2.6% with negative margins but increases to 19% when margins are positive.Adenocarcinoma in situ is also associated with "skip lesions"-foci of adenocarcinoma cells that are not contiguous. Therefore, even with negative margins, the risk of residual AIS on a second excisional specimen is 20% (compared with 53% if margins are positive), and 2% of patients will be diagnosed with an invasive cancer (compared with 6% if margins are positive). Therefore, simple hysterectomy is recommended for all patients with a confirmed diagnosis of AIS with negative margins on conization. For patients with a persistent positive margin despite repeat excisional procedures, a modified radical hysterectomy or radical trachelectomy for those who desire future pregnancy is acceptable owing to an increased risk of diagnosing an occult invasive carcinoma. [bib_ref] Laparoscopic modified radical hysterectomy: a strategy for a clinical dilemma, Eisenkop [/bib_ref] [bib_ref] Risk of residual disease and invasive carcinoma in women treated for adenocarcinoma..., Costales [/bib_ref] Although, historically, radical hysterectomy has been the treatment of choice for microinvasive adenocarcinoma of the cervix owing to concerns about skip lesions and difficulty determining depth of invasion, retrospective observational studies have not shown that radical surgery for microinvasive adenocarcinoma is associated with a survival benefit compared with simple hysterectomy [bib_ref] Conservative therapy in microinvasive adenocarcinoma of the uterine cervix is justified: an..., Baalbergen [/bib_ref] [bib_ref] Analysis of outcomes of microinvasive adenocarcinoma of the uterine cervix by treatment..., Reynolds [/bib_ref] [bib_ref] Is there a difference in survival for IA1 and IA2 adenocarcinoma of..., Smith [/bib_ref] [bib_ref] Survival of women with microinvasive adenocarcinoma of the cervix is not improved..., Bean [/bib_ref] ; therefore, simple hysterectomy even for patients in whom a negative margin cannot be achieved with excisional procedures is acceptable. The ongoing prospective Gynecologic Oncology Group protocol 278 (NCT01649089), in which patients with stage IA1-IB1 cervical carcinomas, including adenocarcinomas, will be surgically treated with simple hysterectomy and pelvic lymphadenectomy, may help clarify whether simple hysterectomy is sufficient for all microinvasive cervical cancers.
For patients who are ultimately diagnosed with microinvasive adenocarcinoma after hysterectomy, the risk of lymph node metastases ranges from less than 1% to 3%, with observational study data limited by the fact that lymphadenectomy was not performed in all patients. [bib_ref] Is there a difference in survival for IA1 and IA2 adenocarcinoma of..., Smith [/bib_ref] [bib_ref] Survival of women with microinvasive adenocarcinoma of the cervix is not improved..., Bean [/bib_ref] Therefore, lymph node assessment at the time of surgery for AIS is acceptable but not required and should be guided by the surgeon's risk assessment, which may include factors such as margin status of the preceding excisional specimen or postexcisional endocervical sampling results, pathologist concern for malignancy, HPV results (HPV-16-or -18-positive vs other high-risk HPV type), and patient risk factors (eg, immunosuppression).
The risk of ovarian metastases in patients with invasive adenocarcinoma is 2-5% 29-34 (compared with a less than 1% risk in the setting of squamous cell carcinoma). Risk of ovarian metastases increases with increasing clinical stage of disease and deeper stromal invasion and thus is rare in the setting of microinvasive disease. [bib_ref] Should ovaries be removed or not in early-stage cervical adenocarcinoma: a multicenter..., Hu [/bib_ref] [bib_ref] Is ovarian preservation feasible in early-stage adenocarcinoma of the cervix?, Lu [/bib_ref] [bib_ref] Ovarian metastasis in stage IB and II cervical adenocarcinoma, Natsume [/bib_ref] [bib_ref] Safety of ovarian preservation in women with stage I and II cervical..., Chen [/bib_ref] Furthermore, retrospective observational studies have not shown a difference in recurrence rates or survival when ovaries are left in situ. Therefore, decisions regarding ovarian management at the time of hysterectomy should be individualized based on patient age, hormonal status, and other risk factors. Opportunistic salpingectomy at the time of hysterectomy should be discussed with patients for potential ovarian or fallopian tube cancer risk reduction per the American College of Obstetricians and Gynecologists' Committee Opinion 35 but is not required for management of AIS or adenocarcinoma of the cervix.
## Clinical question 4
Which patient and disease criteria should be used to identify patients who are eligible for fertility-sparing surgery?
## Recommendation 4.1
For patients of reproductive age who desire future pregnancy, for whom negative margin status on conization has been achieved, and who are willing and able to adhere to surveillance recommendations, fertility-sparing management with a conization procedure is acceptable (AII).
## Recommendation 4.2
For patients in whom negative margins cannot be achieved after multiple excisional procedures, fertility-sparing management is not recommended (DIII).
## Recommendation 4.3
For patients who initially underwent fertility-sparing management of AIS and have subsequently completed childbearing, either hysterectomy or continued surveillance is acceptable for those who have had consistently negative HPV test results during surveillance (CIII). For patients who have had positive HPV test results during surveillance, hysterectomy after completion of childbearing is preferred (CIII).
## Literature review
Unfortunately, AIS is often diagnosed in patients of reproductive age who desire future pregnancy. For these individuals, conservative management with an excisional procedure achieving negative margins is acceptable. Data on long-term outcomes after conservative management of AIS are limited, with small study populations ranging from 28 to 136 patients and average follow-up period of 3-5 years. The recurrence risk for AIS among patients undergoing an excisional procedure is approximately 3% 36-41 but has been reported to be as high as 12%. [bib_ref] Factors predicting the outcome of conservatively treated adenocarcinoma in situ of the..., Costa [/bib_ref] One study showed positive HPV test results during surveillance to be the only significant predictor for recurrence (odds ratio [OR] 2.72, 95% CI 1.08-6.87) and positive HPV test results (OR 3.74, 95% CI 1.85-7.62) and positive margins (OR 5.0, 95% CI 1.09-20.0) to be the only predictors for progressive disease. [bib_ref] Factors predicting the outcome of conservatively treated adenocarcinoma in situ of the..., Costa [/bib_ref] Therefore, for patients with consistently negative HPV test results during surveillance, either hysterectomy or continued observation without hysterectomy after completion of childbearing is acceptable. However, for patients who have positive HPV test results during surveillance, hysterectomy after completion of childbearing is preferred.
For patients in whom negative margins cannot be achieved after multiple excisional procedures, hysterectomy is recommended, and fertility-sparing management should be pursued only in select cases and after a frank discussion about the significantly increased risk of persistent or recurrent AIS and cancer. Data are lacking on outcomes after radical trachelectomy for treatment of persistent AIS, but it could be considered as an alternative for patients who strongly desire future fertility.
## Clinical question 5
What is the recommended surveillance after treatment of AIS?
## Recommendation 5.1
For patients who undergo definitive management with hysterectomy, surveillance per the ASCCP Risk-Based Management Consensus guidelines (http://www.asccp. org/consensus-guidelines) is recommended for at least 25 years after diagnosis, even if that extends the testing period beyond the age of 65 years (CIII).
## Recommendation 5.2
i) For patients who undergo fertility-sparing management, surveillance with Pap plus HPV co-testing and endocervical sampling is recommended every 6 months for the first 3 years, then annually for at least 2 years or until hysterectomy is performed (BII). ii) For patients who have consistently negative cotesting results in the first 5 years of surveillance, extending surveillance to every 3 years indefinitely is acceptable (CIII).
## Literature review
Owing to an increased risk of developing vaginal dysplasia after a history of cervical dysplasia, it is recommended that definitive surgical management should be followed by at least 25 years of surveillance per the ASCCP Risk-Based Management Consensus Guidelines, with vaginal colposcopy performed to evaluate high-grade cytology results, persistent lowgrade cytology results, or persistent positive HPV test results (two or more); although the HPV test is not currently U.S. Food and Drug Administrationapproved for vaginal screening or surveillance, the high negative predictive value of the test can identify those individuals who are at low risk for developing vaginal cancer. [bib_ref] A common clinical dilemma: management of abnormal vaginal cytology and human papillomavirus..., Khan [/bib_ref] Management of abnormal vaginal cytology and positive HPV test results in this setting is beyond the scope of these management guidelines and is well-defined in the review article by Khan et al. [bib_ref] A common clinical dilemma: management of abnormal vaginal cytology and human papillomavirus..., Khan [/bib_ref] After fertility-sparing management, "long-term follow-up with a combination of co-testing and colposcopy with endocervical sampling" is recommended per the ASCCP guidelines. [bib_ref] Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement, Moyer [/bib_ref] However, the ASCCP guidelines do not specify the frequency of follow-up. A prospective study of 119 conservatively treated patients with AIS showed a persistent, recurrent, or progressive disease rate of 13%, with 4% of recurrences occurring as late as 3 years after the initial excisional procedure. [bib_ref] Factors predicting the outcome of conservatively treated adenocarcinoma in situ of the..., Costa [/bib_ref] Notably, there were no recurrences among patients whose posttreatment surveillance HPV test results were negative, and multivariate analysis showed that HPV status was the strongest predictor for recurrent disease. Sensitivity of HPV testing for persistent, recurrent, or progressive disease is 90%, compared with 60% for cytology. [bib_ref] Performance of HPV DNA testing in the follow-up after treatment of high-grade..., Costa [/bib_ref] Preliminary data suggest the median time to HPV clearance is longer for patients with AIS compared with those with CIN, and thus prolonged surveillance is recommended. [bib_ref] Performance of HPV DNA testing in the follow-up after treatment of high-grade..., Costa [/bib_ref] Given the increased risk of recurrent or progressive disease in the first 36 months after excisional procedure, we recommend co-testing (Pap plus HPV tests) with endocervical sampling (endocervical curettage or endocervical brushing) every 6 months for 3 years, then annual co-testing with or without endocervical sampling for at least 2 years or until hysterectomy at the completion of childbearing. [bib_ref] Five-year risk of recurrence after treatment of CIN 2, CIN 3, or..., Katki [/bib_ref] For patients with a history of AIS who have at least two consecutive negative co-test results after treatment, the 5-year risk of CIN 2 or worse is 1.5%. [bib_ref] Five-year risk of recurrence after treatment of CIN 2, CIN 3, or..., Katki [/bib_ref] Although this risk is still substantial compared with the 5-year risk of CIN 2 or worse after negative screening test results without a history of high-grade dysplasia, lengthening the surveillance interval to every 3 years is acceptable for individuals who have consistently negative co-testing results in the first 5 years of surveillance.
## Clinical question 6
How should AIS be managed during pregnancy?
[formula] Recommendation 6.1 [/formula]
In the absence of a clinical or histologic suspicion of invasive cancer, excisional procedures are not recommended during pregnancy. Colposcopy omitting endocervical sampling is recommended each trimester, with an excisional procedure performed postpartum. Delaying excision to approximately 6-8 weeks postpartum is preferred, but an excisional procedure as early as 4 weeks postpartum is acceptable (BII).
## Recommendation 6.2
If an excisional procedure is performed during pregnancy owing to suspicion for an invasive cancer, placement of a prophylactic cerclage is acceptable (CIII).
## Literature review
Excisional procedures during pregnancy are associated with an increased risk of hemorrhage, spontaneous abortion, and preterm delivery. Additionally, there is a higher rate of residual disease after excisional procedures performed during pregnancy compared with those performed in a nongravid state.Therefore, although conization is generally recommended for evaluation of AIS diagnosed on biopsy, it is not recommended during pregnancy unless there is suspicion for an invasive cancer, which would affect the timing of delivery, owing to risk of hemorrhage, infection, premature rupture of membranes, and preterm delivery. If conization is necessary during pregnancy, ideal timing of the procedure is during the second trimester. Excisional procedures should not be performed within 4 weeks of expected delivery owing to increased risk of hemorrhage or extension of the wound. If an excisional procedure is performed during pregnancy, immediate postprocedure placement of a prophylactic cerclage should be considered to decrease risk of hemorrhage and preterm delivery. [bib_ref] Cone cerclage in pregnancy, Goldberg [/bib_ref] [bib_ref] Haemostasis after coldknife conisation: a randomised prospective trial comparing cerclage suture versus..., Dane [/bib_ref] If conization is delayed until after delivery, colposcopy each trimester with conization after delivery is recommended owing to a high rate of persistent high-grade dysplasia. [bib_ref] Prognosis and recurrence risk for patients with cervical squamous intraepithelial lesions diagnosed..., Kaplan [/bib_ref] [bib_ref] Cervical dysplasia in pregnancy: a multiinstitutional evaluation, Fader [/bib_ref] Delaying an excisional procedure until 6-8 weeks postpartum is preferred, but, owing to concern for loss to follow-up resulting from expiration of health insurance postpartum or other factors, performing an excisional procedure as early as 4 weeks postpartum is acceptable.
## Summary of recommendations
- Incorporating age-appropriate HPV testing into cervical cancer screening is recommended, because HPV testing increases the sensitivity of screening for adenocarcinoma lesions, which often originate inside the endocervical canal and may not be detected on cytology. - An excisional procedure to rule out an invasive adenocarcinoma before definitive surgical therapy with hysterectomy is recommended. Obtaining an intact specimen ("top hat" excision is unacceptable) with a length of at least 10 mm is preferred, with a goal of achieving negative margins. For surgeons who are unable to consistently obtain intact excisional specimens with adequate length, referral to a gynecologic oncologist or other cervical dysplasia specialist for excisional biopsy is preferred. Endocervical sampling above the excisional site is preferred to evaluate for residual disease. - Hysterectomy is preferred for all patients who have completed childbearing. If negative margins on the excisional specimen(s) cannot be achieved, either a modified radical hysterectomy or simple hysterectomy is acceptable, recognizing the increased (6%) risk of an occult invasive adenocarcinoma. Surgical assessment of lymph nodes is acceptable at the time of hysterectomy. - For patients who desire future pregnancy, conservative management with close follow-up provided negative margins can be achieved is acceptable. Cotesting with endocervical sampling every 6 months for 3 years followed by annual co-testing with or without endocervical sampling for at least 2 years or until hysterectomy at the completion of childbearing is recommended. Lengthening the surveillance interval to every 3 years is acceptable for patients who have consistently negative co-testing results in the first 5 years of surveillance.
[fig] Figure: 1. Summary of adenocarcinoma in situ management recommendations. *Cold knife conization or loop electrosurgical excision procedure acceptable provided an adequate specimen can be obtained: 1) intact, nonfragmented (top-hat serial endocervical excisions unacceptable); 2) length of specimen must be at least 10 mm. HPV, human papillomavirus. [/fig]
[table] Table 1: Rating the Recommendations Modified with permission from: Gross PA, Barrett TL, Dellinger EP, et al. Purpose of quality standards for infectious diseases. Infectious These tables are available in free-to-view only with the permission of Oxford University Press on behalf of the Infectious Diseases Society of America. Ó The Author(s). All rights reserved. For permissions, please email: journals.permission-s@oup.com. This table is not included under the Creative Commons license of this publication. † The assignment of these terms represents an opinion ratified by vote during the 2012 consensus conference. [/table]
[table] Table 2: ASCCP Risk-Based Colposcopy Standards and Atypical Glandular Cells Evaluation HSIL, high-grade squamous intraepithelial lesions; HPV, human papillomavirus; ASC-H, atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions; SGO, Society of Gynecologic Oncology; AGC, atypical glandular cells; AIS, adenocarcinoma in situ. Data from Wentzensen N, Schiffman M, Silver MI, Khan MJ, Perkins RB, Smith KM, et al. ASCCP colposcopy standards: risk-based colposcopy practice. J Low Genit Tract Dis 2017;21:230-4. * ASCCP minimal colposcopic reporting standards: squamocolumnar junction visibility (fully visualized or not fully visualized); acetowhitening(yes or no); lesion(s) present (yes or no; acetowhite or other); colposcopic impression (normal or benign; low-grade; high-grade; cancer). † Insufficient evidence for or against nontarget biopsies in this population. ‡ Endocervical sampling can be done with a curette or a brush. § ASCCP Risk-Based Management Guidelines: http://www.asccp.org/consensus-guidelines. [/table]
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Cervical adenocarcinoma in situ is a unique diagnosis whose management needs to be differentiated from the management of the more prevalent squamous cell dysplasia.
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Diabetes Management in Correctional Institutions
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Diabetes Management in Correctional Institutions
[bib_ref] Challenges of improving quality in the correctional setting, Puisis [/bib_ref]
## Intake medical assessment
## Reception screening
Reception screening should emphasize patient safety. In particular, rapid identification of all insulin-treated persons with diabetes is essential in order to identify those at highest risk for hypo-and hyperglycemia and diabetic ketoacidosis (DKA). All insulin-treated patients should have a capillary blood glucose (CBG) determination within 1-2 h of arrival. Signs and symptoms of hypo-or hyperglycemia can often be confused with intoxication or withdrawal from drugs or alcohol. Individuals with diabetes exhibiting signs and symptoms consistent with hypoglycemia, particularly altered mental status, agitation, combativeness, and diaphoresis, should have finger-stick blood glucose levels measured immediately.
## Intake screening
Patients with a diagnosis of diabetes should have a complete medical history and physical examination by a licensed health care provider with prescriptive authority in a timely manner. If one is not available on site, one should be consulted by those performing reception screening. The purposes of this history and physical examination are to determine the type of diabetes, current therapy, alcohol use, and behavioral health issues, as well as to screen for the presence of diabetes-related complications. The evaluation should review the previous treatment and the past history of both glycemic control and diabetes complications. It is essential that medication and medical nutrition therapy (MNT) be continued without interruption upon entry into the correctional system, as a hiatus in either medication or appropriate nutrition may lead to either severe hypo-or hyperglycemia that can rapidly progress to irreversible complications, even death.
## Intake physical examination and laboratory
All potential elements of the initial medical evaluation are included in of the ADA's "Standards of Medical Care in Diabetes," referred to hereafter as the "Standards of Care" (4). The essential components of the initial history and physical examination are detailed in People with diabetes should ideally receive medical care from a physiciancoordinated team. Such teams include, but are not limited to, physicians, nurses, dietitians, and mental health professionals with expertise and a special interest in diabetes. It is essential in this collaborative and integrated team approach that individuals with diabetes assume as active a role in their care as possible. Diabetes selfmanagement education is an integral component of care. Patient selfmanagement should be emphasized, and the plan should encourage the involvement of the patient in problem solving as much as possible.
It is helpful to house insulin-treated patients in a common unit, if this is possible, safe, and consistent with providing access to other programs at the correc-tional institution. Common housing not only can facilitate mealtimes and medication administration, but also potentially provides an opportunity for diabetes selfmanagement education to be reinforced by fellow patients.
## Nutrition and food
SERVICES -Nutrition counseling and menu planning are an integral part of the multidisciplinary approach to diabetes management in correctional facilities. A combination of education, interdisciplinary communication, and monitoring food intake aids patients in understanding their medical nutritional needs and can facilitate diabetes control during and after incarceration.
Nutrition counseling for patients with diabetes is considered an essential component of diabetes self-management. People with diabetes should receive individualized MNT as needed to achieve treatment goals, preferably provided by a registered dietitian familiar with the components of MNT for persons with diabetes.
Educating the patient, individually or in a group setting, about how carbohydrates and food choices directly affect di- abetes control is the first step in facilitating self-management. This education enables the patient to identify better food selections from those available in the dining hall and commissary. Such an approach is more realistic in a facility where the patient has the opportunity to make food choices.
The easiest and most cost-effective means to facilitate good outcomes in patients with diabetes is instituting a hearthealthy diet as the master menu. There should be consistent carbohydrate content at each meal, as well as a means to identify the carbohydrate content of each food selection. Providing carbohydrate content of food selections and/or providing education in assessing carbohydrate content enables patients to meet the requirements of their individual MNT goals. Commissaries should also help in dietary management by offering healthy choices and listing the carbohydrate content of foods.
The use of insulin or oral medications may necessitate snacks in order to avoid hypoglycemia. These snacks are a part of such patients' medical treatment plans and should be prescribed by medical staff.
Timing of meals and snacks must be coordinated with medication administration as needed to minimize the risk of hypoglycemia, as discussed more fully in the MEDICATION section of this document. For further information, see the ADA Position Statement "Nutrition Principles and Recommendations in Diabetes".
URGENT AND EMERGENCY ISSUES -All patients must have access to prompt treatment of hypo-and hyperglycemia. Correctional staff should be trained in the recognition and treatment of hypoand hyperglycemia, and appropriate staff should be trained to administer glucagon. After such emergency care, patients should be referred for appropriate medical care to minimize risk of future decompensation.
Institutions should implement a policy requiring staff to notify a physician of all CBG results outside of a specified range, as determined by the treating physician (e.g., Ͻ50 or Ͼ350 mg/dl).
## Hyperglycemia
Severe hyperglycemia in a person with diabetes may be the result of intercurrent illness, missed or inadequate medication, or corticosteroid therapy. Correctional institutions should have systems in place to identify and refer to medical staff all patients with consistently elevated blood glucose as well as intercurrent illness.
The stress of illness in those with type 1 diabetes frequently aggravates glycemic control and necessitates more frequent monitoring of blood glucose (e.g., every 4 -6 h). Marked hyperglycemia requires temporary adjustment of the treatment program and, if accompanied by ketosis, interaction with the diabetes care team. Adequate fluid and caloric intake must be ensured. Nausea or vomiting accompanied with hyperglycemia may indicate DKA, a life-threatening condition that requires immediate medical care to prevent complications and death. Correctional institutions should identify patients with type 1 diabetes who are at risk for DKA, particularly those with a prior history of frequent episodes of DKA. For further information see "Hyperglycemic Crisis in Diabetes".
## Hypoglycemia
Hypoglycemia is defined as a blood glucose level Ͻ70 mg/dl. Severe hypoglycemia is a medical emergency defined as hypoglycemia requiring assistance of a third party and is often associated with mental status changes that may include confusion, incoherence, combativeness, somnolence, lethargy, seizures, or coma. Signs and symptoms of severe hypoglycemia can be confused with intoxication or withdrawal. Individuals with diabetes exhibiting signs and symptoms consistent with hypoglycemia, particularly altered mental status, agitation, and diaphoresis, should have their CBG levels checked immediately.
Security staff who supervise patients at risk for hypoglycemia (i.e., those on insulin or oral hypoglycemic agents) should be educated in the emergency response protocol for recognition and treatment of hypoglycemia. Every attempt should be made to document CBG before treatment. Patients must have immediate access to glucose tablets or other glucose-containing foods. Hypoglycemia can generally be treated by the patient with oral carbohydrates. If the patient cannot be relied on to keep hypoglycemia treatment on his/her person, staff members should have ready access to glucose tablets or equivalent. In general, 15-20 g oral glucose will be adequate to treat hypoglycemic events. CBG and treatment should be repeated at 15-min intervals until blood glucose levels return to normal (Ͼ70 mg/dl). Staff should have glucagon for intramuscular injection or glucose for intravenous infusion available to treat severe hypoglycemia without requiring transport of the hypoglycemic patient to an outside facility. Any episode of severe hypoglycemia or recurrent episodes of mild to moderate hypoglycemia require reevaluation of the diabetes management plan by the medical staff. In certain cases of unexplained or recurrent severe hypoglycemia, it may be appropriate to admit the patient to the medical unit for observation and stabilization of diabetes management.
Correctional institutions should have systems in place to identify the patients at greater risk for hypoglycemia (i.e., those on insulin or sulfonylurea therapy) and to ensure the early detection and treatment of hypoglycemia. If possible, patients at greater risk of severe hypoglycemia (e.g., those with a prior episode of severe hypoglycemia) may be housed in units closer to the medical unit in order to minimize delay in treatment. MEDICATION -Formularies should provide access to usual and customary oral medications and insulins necessary to treat diabetes and related conditions. While not every brand name of insulin and oral medication needs to be available, individual patient care requires access to short-, medium-, and long-acting insulins and the various classes of oral medications (e.g., insulin secretagogues, biguanides, ␣-glucosidase inhibitors, and thiazolidinediones) necessary for current diabetes management. Patients at all levels of custody should have access to medication at dosing frequencies that are consistent with their treatment plan and medical direction. If feasible and consistent with security concerns, patients on multiple doses of shortacting oral medications should be placed in a "keep on person" program. In other situations, patients should be permitted to self-inject insulin when consistent with security needs. Medical department nurses should determine whether patients have the necessary skill and responsible behavior to be allowed selfadministration and the degree of supervision necessary. When needed, this skill should be a part of patient education. Reasonable syringe control systems should be established.
## Recommendations
In the past, the recommendation that regular insulin be injected 30 -45 min before meals presented a significant problem when "lock downs" or other disruptions to the normal schedule of meals and medications occurred. The use of multiple-dose insulin regimens using rapid-acting analogs can decrease the disruption caused by such changes in schedule. Correctional institutions should have systems in place to ensure that rapidacting insulin analogs and oral agents are given immediately before meals if this is part of the patient's medical plan. It should be noted however that even modest delays in meal consumption with these agents can be associated with hypoglycemia. If consistent access to food within 10 min cannot be ensured, rapid-acting insulin analogs and oral agents are approved for administration during or immediately after meals. Should circumstances arise that delay patient access to regular meals following medication administration, policies and procedures must be implemented to ensure the patient receives appropriate nutrition to prevent hypoglycemia.
Both continuous subcutaneous insulin infusion and multiple daily insulin injection therapy (consisting of three or more injections a day) can be effective means of implementing intensive diabetes management with the goal of achieving near-normal levels of blood glucose. While the use of these modalities may be difficult in correctional institutions, every effort should be made to continue multiple daily insulin injection or continuous subcutaneous insulin infusion in people who were using this therapy before incarceration or to institute these therapies as indicated in order to achieve blood glucose targets.
It is essential that transport of patients from jails or prisons to off-site appointments, such as medical visits or court appearances, does not cause significant disruption in medication or meal timing. Correctional institutions and police lockups should implement policies and procedures to diminish the risk of hypo-and hyperglycemia by, for example, providing carry-along meals and medication for patients traveling to off-site appointments or changing the insulin regimen for that day. The availability of prefilled insulin "pens" provides an alternative for off-site insulin delivery.
## Recommendations
- Formularies should provide access to usual and customary oral medications and insulins to treat diabetes and related conditions. (E) - Patients should have access to medication at dosing frequencies that are consistent with their treatment plan and medical direction. (E) - Correctional institutions and police lock-ups should implement policies and procedures to diminish the risk of hypo-and hyperglycemia during offsite travel (e.g., court appearances). (E) ple with diabetes to evaluate diabetes management regimens. The frequency of monitoring will vary by patients' glycemic control and diabetes regimens. Patients with type 1 diabetes are at risk for hypoglycemia and should have their CBG monitored three or more times daily. Patients with type 2 diabetes on insulin need to monitor at least once daily and more frequently based on their medical plan.
## Routine screening for and management of diabetes complications
Patients treated with oral agents should have CBG monitored with sufficient frequency to facilitate the goals of glycemic control, assuming that there is a program for medical review of these data on an ongoing basis to drive changes in medications. Patients whose diabetes is poorly controlled or whose therapy is changing should have more frequent monitoring. Unexplained hyperglycemia in a patient with type 1 diabetes may suggest impending DKA, and monitoring of ketones should therefore be performed. Glycated hemoglobin (A1C) is a measure of long-term (2-to 3-month) glycemic control. Perform the A1C test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control) and quarterly in patients whose therapy has changed or who are not meeting glycemic goals.
Discrepancies between CBG monitoring results and A1C may indicate a hemoglobinopathy, hemolysis, or need for evaluation of CBG monitoring technique and equipment or initiation of more frequent CBG monitoring to identify when glycemic excursions are occurring and which facet of the diabetes regimen is changing.
In the correctional setting, policies and procedures need to be developed and implemented regarding CBG monitoring that address the following. SELF-MANAGEMENT EDUCATION -Self-management education is the cornerstone of treatment for all people with diabetes. The health staff must advocate for patients to participate in self-management as much as possible. Individuals with diabetes who learn self-management skills and make lifestyle changes can more effectively manage their diabetes and avoid or delay complications associated with diabetes. In the d e v e l o p m e n t o f a d i a b e t e s s e l fmanagement education program in the correctional environment, the unique circumstances of the patient should be considered while still providing, to the greatest extent possible, the elements of the "National Standards for Diabetes Self-Management Education". A staged approach may be used depending on the needs assessment and the length of incarceration. [fig_ref] Table 2 -: Major components of diabetes self-management education [/fig_ref] sets out the major components of diabetes self-management education. Survival skills should be addressed as soon as possible; other aspects of education may be provided as part of an ongoing education program. Ideally, self-management education is coordinated by a certified diabetes educator who works with the facility to develop polices, procedures, and protocols to ensure that nationally recognized education guidelines are implemented. The educator is also able to identify patients who need diabetes self-management education, including an assessment of the patients' medical, social, and diabetes histories; diabetes knowledge, skills, and behaviors; and readiness to change.
STAFF EDUCATION -Policies and procedures should be implemented to ensure that the health care staff has adequate knowledge and skills to direct the management and education of persons with diabetes. The health care staff needs to be involved in the development of the correctional officers' training program. The staff education program should be at a lay level. Training should be offered at least biannually, and the curriculum should cover the following.
- what diabetes is - signs and symptoms of diabetes - risk factors - signs and symptoms of, and emergency response to, hypo-and hyperglycemia - glucose monitoring - medications - exercise - nutrition issues including timing of meals and access to snacks
[formula] Recommendations - Include diabetes in correctional staff education programs. (E) [/formula]
ALCOHOL AND DRUGS -Patients with diabetes who are withdrawing from drugs and alcohol need special consideration. This issue particularly affects initial police custody and jails. At an intake facility, proper initial identification and assessment of these patients are critical. The presence of diabetes may complicate detoxification. Patients in need of complicated detoxification should be referred to a facility equipped to deal with high-risk detoxification. Patients with diabetes should be educated in the risks involved with smoking. All inmates should be advised not to smoke. Assistance in smoking cessation should be provided as practical.
TRANSFER AND DISCHARGE -Patients in jails may be housed for a short period of time before being transferred or released, and it is not unusual for patients in prison to be transferred within the system several times during their incarceration. One of the many challenges that health care providers face working in the correctional system is how to best collect and communicate important health care information in a timely manner when a patient is in initial police custody, is jailed short term, or is transferred from facility to facility. The importance of this communication becomes critical when the patient has a chronic illness such as diabetes. Transferring a patient with diabetes from one correctional facility to another requires a coordinated effort. To facilitate a thorough review of medical information and completion of a transfer summary, it is critical for custody personnel to provide medical staff with sufficient notice before movement of the patient.
Before the transfer, the health care staff should review the patient's medical record and complete a medical transfer summary that includes the patient's current health care issues. At a minimum, the summary should include the following.
- the patient's current medication schedule and dosages - the date and time of the last medication administration - any recent monitoring results (e.g., CBG and A1C) - other factors that indicate a need for immediate treatment or management at the receiving facility (e.g., recent episodes of hypoglycemia, history of severe hypoglycemia or frequent DKA, concurrent illnesses, presence of diabetes complications) - information on scheduled treatment/ appointments if the receiving facility is responsible for transporting the patient to that appointment - name and telephone/fax number of a contact person at the transferring facility who can provide additional information, if needed
The medical transfer summary, which acts as a quick medical reference for the receiving facility, should be transferred along with the patient. To supplement the flow of information and to increase the probability that medications are correctly identified at the receiving institution, sending institutions are encouraged to provide each patient with a medication card to be carried by the patient that contains information concerning diagnoses, medication names, dosages, and frequency. Diabetes supplies, including diabetes medication, should accompany the patient.
The sending facility must be mindful of the transfer time in order to provide the patient with medication and food if needed. The transfer summary or medical record should be reviewed by a health care provider upon arrival at the receiving institution.
Planning for patients' discharge from prisons should include instruction in the long-term complications of diabetes, the necessary lifestyle changes and examinations required to prevent these complications, and, if possible, where patients may obtain regular follow-up medical care. A quarterly meeting to educate patients with upcoming discharges about community resources can be valuable. Inviting community agencies to speak at these meetings and/or provide written materials can help strengthen the community link for patients discharging from correctional facilities.
Discharge planning for the patients with diabetes should begin 1 month before discharge. During this time, application for appropriate entitlements should be initiated. Any gaps in the patient's knowledge of diabetes care need to be identified and addressed. It is helpful if the patient is given a directory or list of community resources and if an appointment for follow-up care with a community provider is made. A supply of medication adequate to last until the first postrelease medical appointment should be provided to the patient upon release. The patient should be provided with a written summary of his/her current heath care issues, including medications and doses, recent A1C values, etc.
## Recommendations
## Sharing of medical information and
RECORDS -Practical considerations may prohibit obtaining medical records from providers who treated the patient before arrest. Intake facilities should implement policies that 1) define the circumstances under which prior medical records are obtained (e.g., for patients who have an extensive history of treatment for complications); 2) identify person(s) responsible for contacting the prior provider; and 3) establish procedures for tracking requests. Facilities that use outside medical providers should implement policies and procedures for ensuring that key information (e.g., test results, diagnoses, physicians' orders, appointment dates) is received from the provider and incorporated into the patient's medical chart after each outside appointment. The procedure should include, at a minimum, a means to highlight when key information has not been received and designation of a person responsible for contacting the outside provider for this information.
All medical charts should contain CBG test results in a specified, readily accessible section and should be reviewed on a regular basis.
## Children and adolescents with
DIABETES -Children and adolescents with diabetes present special problems in disease management, even outside the setting of a correctional institution. Children and adolescents with diabetes should have initial and follow-up care with physicians who are experienced in their care. Confinement increases the difficulty in managing diabetes in children and adolescents, as it does in adults with diabetes. Correctional authorities also have different legal obligations for children and adolescents.
## Nutrition and activity
Growing children and adolescents have greater caloric/nutritional needs than adults. The provision of an adequate amount of calories and nutrients for adolescents is critical to maintaining good nutritional status. Physical activity should be provided at the same time each day. If increased physical activity occurs, addi- Medical management and follow-up Children and adolescents who are incarcerated for extended periods should have follow-up visits at least every 3 months with individuals who are experienced in the care of children and adolescents with diabetes. Thyroid function tests and fasting lipid and microalbumin measurements should be performed according to recognized standards for children and adolescents [bib_ref] Consensus Guidelines 2000: ISPAD Consensus Guidelines for the Management of Type 1..., Pediatric [/bib_ref] in order to monitor for autoimmune thyroid disease and complications and comorbidities of diabetes. Children and adolescents with diabetes exhibiting unusual behavior should have their CBG checked at that time. Because children and adolescents are reported to have higher rates of nocturnal hypoglycemia [bib_ref] Nocturnal hypoglycemia detected with the continuous glucose monitoring system in pediatric patients..., Kaufman [/bib_ref] , consideration should be given regarding the use of episodic overnight blood glucose monitoring in these patients. In particular, this should be considered in children and adolescents who have recently had their overnight insulin dose changed.
PREGNANCY -Pregnancy in a woman with diabetes is by definition a high-risk pregnancy. Every effort should be made to ensure that treatment of the pregnant woman with diabetes meets accepted standards. It should be noted that glycemic standards are more stringent, the details of dietary management are more complex and exacting, insulin is the only antidiabetic agent approved for use in pregnancy, and a number of medications used in the management of diabetic comorbidities are known to be teratogenic and must be discontinued in the setting of pregnancy.
## Summary and key
POINTS -People with diabetes should receive care that meets national standards. Being incarcerated does not change these standards. Patients must have access to medication and nutrition needed to manage their disease. In patients who do not meet treatment targets, medical and behavioral plans should be adjusted by health care professionals in collaboration with the prison staff. It is critical for correctional institutions to identify particularly high-risk patients in need of more intensive evaluation and therapy, including pregnant women, patients with advanced complications, a history of repeated severe hypoglycemia, or recurrent DKA.
A comprehensive, multidisciplinary approach to the care of people with diabetes can be an effective mechanism to improve overall health and delay or prevent the acute and chronic complications of this disease.
[fig] Figure 1 -: Essential components of the initial history and physical examination. Alb/Cr ratio, albumin-to-creatinine ratio; ALT, alanine aminotransferase; AST, aspartate aminotransferase. [/fig]
[table] Table 2 -: Major components of diabetes self-management education [/table]
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A t any given time, over 2 million people are incarcerated in prisons and jails in the U.S (1). It is estimated that nearly 80,000 of these inmates have diabetes, a prevalence of 4.8% (2). In addition, many more people pass through the corrections system in a given year. In 1998 alone, over 11 million people were released from prison to the community (1). The current estimated prevalence of diabetes in correctional institutions is somewhat lower than the overall U.S. prevalence of diabetes, perhaps because the incarcerated population is younger than the general population. The prevalence of diabetes and its related comorbidities and complications, however, will continue to increase in the prison population as current sentencing guidelines continue to increase the number of aging prisoners and the incidence of diabetes in young people continues to increase. People with diabetes in correctional facilities should receive care that meets national standards. Correctional institutions have unique circumstances that need to be considered so that all standards of care may be achieved (3). Correctional institutions should have written policies and procedures for the management of diabetes and for training of medical and correctional staff in diabetes care practices. These policies must take into consideration issues such as security needs, transfer from one facility to another, and access to medical personnel and equipment, so that all appropriate levels of care are provided. Ideally, these policies should encourage or at least allow patients to self-manage their diabetes. Ultimate ly , d iabetes management i s dependent upon having access to needed medical personnel and equipment. Ongoing diabetes therapy is important in order to reduce the risk of later complications, including cardiovascular events, visual loss, renal failure, and amputation. Early identification and intervention for people with diabetes is also likely to reduce short-term risks for acute complications requiring transfer out of the facility, thus improving security. This document provides a general set of guidelines for diabetes care in correctional institutions. It is not designed to be a diabetes management manual. More detailed information on the management of diabetes and related disorders can be found in the American Diabetes Association (ADA) Clinical Practice Recommendations, published each year in January as the first supplement to Diabetes Care, as well as the “Standards of Medical Care in Diabetes” (4) contained therein. This discussion will focus on those areas where the care of people with diabetes in correctional facilities may differ, and specific recommendations are made at the end of each section.
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Epithelial tumours of the thymus
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Epithelial tumours of the thymus
Epithelial tumours of the thymus, including thymomas and thymic carcinomas are rare tumours (250 new cases a year). Because of its anatomic situation and rarity, this cancer poses special problems in both diagnosis and treatment. Clinical management requires the input of a multidisciplinary team. These guidelines were validated in February 2000 and an update is planned for 2001. A new classification system for thymic tumours was published in 1999. Its place will be considered in the next update.
## Terminology
There is no standard terminology, but it is recommended that the particular characteristics of these tumours are taken into consideration: the term 'encapsulated' (65% of cases) or 'invasive' (35% of cases) should be used in preference to benign or malignant thymoma; the term 'epithelial tumour of the thymus' includes the thymomas and the thymic carcinomas in the same group and excludes benign epithelial cysts, germ cell epithelial tumours (such as teratomas or embryonal carcinomas) and intrathymic parathyroid tumours; the term 'epithelial tumour of the thymus' should be used in preference to 'thymoma'.
## Classification
There is no standard histological classification. Central review of the histological slides by a panel of experienced pathologists is recommended, as well as the routine documentation of any cellular atypia. The classification of Marino and Muller-Hermelink in a simplified form (cortical, medullary and mixed) is the most widely used internationally. It is recommended that this classification is used in conjunction with the more established classifications such as those of Verley or Rosai and Levine.
## Staging
The staging system of Masaoka should be used (standard). The system of the Thymic Tumour Study Group or that of Regnard can also be used (option) as they may be better adapted to treatment strategies. However, these need to be validated against the reference classification of Masaoka, which should therefore still be used outside a trial context.
## Diagnosis
The diagnosis of an epithelial tumour of the thymus is made by the histological examination of a biopsy obtained by anterior mediastinotomy (except in the case of an encapsulated tumour which is usually resectable 'en mass' (standard)). In the case of undifferentiated or lymphocyte-predominant forms, the differential diagnosis must include Hodgkins lymphoma, non-Hodgkins lymphoma or a germ cell tumour (standard). For carcinomas of the thymus, a metastasis from a non-small cell carcinoma must be excluded. A transparietal needle biopsy is an alternative to anterior mediastinotomy (option). A mediastinoscopy is not recommended as it does not provide adequate access to the anterior mediastinal space.
## Pretherapeutic assessment
The standard pretherapeutic investigations are: imaging (chest X-ray (AP and lateral), thoracic CT scan with high abdominal cuts), respiratory function tests full blood count and immunoelectrophoresis of paraproteins to exclude an autoimmune syndrome.
Optional investigations include: thoracic MRI (instead of CT scanning) or a venocavogram if infiltration or compression of vasculature by tumour is suspected; fibreoptic bronchoscopy in cases of suspicion of compression or invasion of the trachea or bronchus; electromyography and auto-antibody screen (for acetylcholine, antithymus, antistriated muscle) if myasthenia gravis is suspected.
## Prognostic factors
The extent of resection and the stage of the disease are the only factors to have unequivocal prognostic value on multivariate analysis (standard).
## Treatment modalities
## Surgery
The object is to achieve complete excision of tumour with the thymus and perithymic fat (standard). Sternotomy is the principle route of approach (standard). Videothoracoscopy is at present contraindicated. In advanced stages, the surgery must in all cases preserve the integrity of at least the phrenic nerve (standard).
For very large thymic tumours and/or those extending to the pleura and/or where a pulmonary resection is likely to be necessary, a bilateral anterior thoracotomy with transverse sternotomy can be considered (option). For small-volume thymic tumours in myasthenic patients, a cervicomanubrial approach can be used (option). In the case of ectopic thymomas a posterolateral thoracotomy can be undertaken (option).
## Radiotherapy
There is no standard approach. The recommendations for target volume and dose are as follows.
## Treatment field
The entire thymic region should be treated including sites of spread (pericardium, large vessels, pleura, lung parenchyma). The fields are defined with the help of pre-and postoperative imaging and also by the operative description and the positioning of radio-opaque clips/markers.
The upper border should be positioned at the level of the cervicothoracic junction. The lower limit should be the mid mediastinum, except in the case of ectopic forms. Irradiation of the supra-clavicular spaces is not recommended as it has not been shown to be useful (level of evidence C).
## Dose
Following complete resection, a dose of 50-55 Gy, depending on the size of the original tumour, the mediastinal structures involved and the dose that will be delivered to normal tissue. Following incomplete resection treatment should be according to conformational techniques, after consideration of dose-volume histograms both for planning target volume and for critical organs, in particular the lung parenchyma and the spinal cord.
In the absence of neoadjuvant treatment, 50-55 Gy to the target volume with a boost to 60-65 Gy at the level of any residual tumour as identified from the operative report and markers left at the time of operation, should be applied. In the case of a simple biopsy, a dose of 65 Gy is recommended for the entire target volume.
## Scheduling
Nine to 10 Gy weekly in five sessions. It is recommended that patients be included in therapeutic trials.
## Chemotherapy
Chemotherapy is indicated for those patients presenting with metastatic disease (10%), and for patients with local recurrence or metastases who have already been treated with radiotherapy (standard). Polychemotherapy appears superior to monotherapy (level of evidence C).
The reference combination is the CAP protocol (cyclophosphamide/doxorubicin/cisplatin). In stages IIIA and IIIB, the value of chemotherapy in addition to surgery and radiotherapy has not been proven. The inclusion of patients in prospective studies is recommended in order to demonstrate the efficacy of these combinations, particularly in the neoadjuvant setting.
## Therapeutic strategy
The objective is to achieve complete excision of the tumour with all the thymus and the perithymic fat. It must be carried out by a surgeon who is familiar with the diagnostic and therapeutic constraints of the procedure (standard). Treatment depends on the stage of the disease and the completeness of resection. It can be planned around the three existing classifications. Stage IV disease (mixed population) Pleural invasion, completely resected (stage IVA): postoperative radiotherapy to mediastinum and pleura to a dose of 55 Gy according to perioperative markers. Pleural invasion not amenable to surgical excision (Masaoka and GETT stage IVA): neoadjuvant chemotherapy followed by surgery and radiotherapy. Pleural invasion with incomplete surgical excision (Masaoka and GETT stage IVA, Regnard stage IVB) or distant metastases: chemotherapy then surgical re-evaluation and/or subsequent radiotherapy .
## Follow-up
In the absence of objective data, the frequency of surveillance has not been clearly defined, but it must be continued for at least 15 years in view of the possibility of very late relapses. The appearance of signs and symptoms of an autoimmune syndrome, particularly myasthenia gravis, should result in an early search for recurrence.
## Macroscopic disease stages ii−iii
Complete tumour resection possible?
Complete resection ?
Biopsy, marginal resection Standard surgery
[fig] Figure 1: Stage IA (encapsulated tumour, without invasion of the capsule) Complete resection, no additional treatment ().Stage IB (encapsulated tumour but with adhesion and/or suspicion of macroscopic invasion of the capsule) Complete resection, postoperative radiotherapy at a dose in the order of 50 Gy ().Stage II (tumour with microscopic invasion into capsule, mediastinal pleura or sub-pleural fat) Complete resection, postoperative radiotherapy at a dose in the order of 50-55 Gy(Figure 2).Stage III (tumour with macroscopic invasion to lung, superior vena cava, pericardium) Complete resection (Regnard stage IIIA disease): postoperative radiotherapy at a dose of at least 55 Gy. Incomplete resection (GETT stage IIIA, Regnard stage IIIB): postoperative radiotherapy at 55-60 Gy with a boost to residual tumour as marked by operative clips. Resection initially impossible (biopsy alone, Treatment of stage I carcinoma of the thymus GETT and Regnard stage IIIB disease): neoadjuvant chemotherapy followed by resection or radiotherapy. These patients should be included in therapeutic trials (Figure 2). [/fig]
[fig] Figure 2: Treatment of stage II and III disease [/fig]
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https://europepmc.org/articles/pmc2408832?pdf=render
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Epithelial tumours of the thymus, including thymomas and thym carcinomas are rare tumours (250 new cases a year). Because anatomic situation and rarity, this cancer poses special problem both diagnosis and treatment. Clinical management requires input of a multidisciplinary team. These guidelines were valida in February 2000 and an update is planned for 2001. A new cl fication system for thymic tumours was published in 1999. place will be considered in the next update.
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86612f73b077cf9275cf51a107bb3e9b65011b03
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pubmed
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Society of behavioral medicine statement on COVID-19 and rural health
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Society of behavioral medicine statement on COVID-19 and rural health
# Introduction
According to the United States (U.S.) Census Bureau(2017), approximately one in five Americans live in rural areas. While the operational definition of "rural" may vary by federal, state, and local agencies, rurality is multidimensional, is typically defined based on geographic and/or population density criteria, and is characterized by small population size, low population density, and/or remoteness. Rural areas are comprised predominantly of non-Hispanic white residents [80%], though many rural areas are becoming more diverse (e.g., Latinx [9%], African Americans [8%], Native American [2%], and Asian and Pacific Islanders [1% and 0.1%]) [bib_ref] Racial/ethnic health disparities among rural adults-United States, James [/bib_ref]. Poverty rates are higher among rural (16.1%) versus urban residents (12.6%), with rural Black Americans and Native Americans/Alaska Natives having the highest poverty rates.
As of July 30, 2020, rural areas reported increased prevalence rates of COVID-19 in the U.S., with the Southeast (12.7%) and South Central U.S. incurring some of the highest per capita positive test rates in the U.S.. The Great Lakes, Midwest, Southeast Coast, and the West also report elevated rates of COVID-19 prevalence. Furthermore, as of October 14, 2020, high U.S. per capita rates of COVID-19 were found in North and South Dakota, Montana, Utah, Nebraska, Iowa, Idaho, Wyoming, Montana, Arkansas, and Oklahoma-all states with swaths of remote rural areas.
While urban areas report more total COVID-19 cases, proportionally the incidence rate is higher in rural regions of the U.S.. Because of the high rates of risk factors for severe COVID-19 illness in rural populations, specifically older age (60 and older), and younger adults with heart disease, cancer, chronic obstructive pulmonary disease (COPD), or diabetes, it is projected that 50% of noninstitutionalized rural adults are at high risk for hospitalization and serious illness if they are infected with COVID-19, compared to 46.9% and 40% of micropolitan and metropolitan adults, respectively [bib_ref] Brief report: half of rural residents at high risk of serious illness..., Kaufman [/bib_ref]. While similar rates of asthma have been found in rural versus urban areas (e.g., Ownby et al. [bib_ref] Comparison of asthma prevalence among African American teenage youth attending public high..., Ownby [/bib_ref] , hypertension [bib_ref] Prevalence of self-reported hypertensive and antihypertensive medication use by county and urban-rural..., Samanic [/bib_ref] , and obesity and overweightare found to be more common in rural than urban areas. The Centers for Disease Control (CDC) also recently added asthma, hypertension, and obesity and overweight to risk factors for severe COVID-19 illness .
Rural populations are uniquely at risk for COVID-19-related inequities for a variety of reasons. First, rural populations are on average, older, poorer, and have higher age-adjusted rates of underlying chronic conditions (e.g., obesity, diabetes, cancer, and respiratory illnesses) and disabilities than non-rural populations in the U.S. [bib_ref] Potentially excess deaths from the five leading causes of death in metropolitan..., Garcia [/bib_ref] [bib_ref] Quality of life in rural and urban adults 65 years and older:..., Baernholdt [/bib_ref] [bib_ref] Rural health disparities, population health, and rural culture, Hartley [/bib_ref].
Second, occupation is a major social determinant of respiratory illness in rural residents. This risk factor is particularly true for jobs in rural industries such as coal mining, farming, and food processing. Approximately 3.6% of rural Americans [25]-51,000 mostly male residentsfrom central Appalachia (e.g., Kentucky, Virginia, and West Virginia) [bib_ref] Continued increase in prevalence of coal workers' pneumoconiosis in the United States, Blackley [/bib_ref] -work in the coal mining industry. Due to coal dust inhalation, miners disproportionally suffer from lung diseases, notably coal workers pneumoconiosis (CWP), commonly known as "black lung disease" or simply, "black lung" [bib_ref] Continued increase in prevalence of coal workers' pneumoconiosis in the United States, Blackley [/bib_ref]. While there is insufficient tracking of COVID-19 related morbidity and mortality in coal miners, these lung diseases are risk factors for COVID-19 diagnoses and complications. The seriousness of COVID-19 and its threats to health prompted the United Mine Workers of America International Union to sue the Mine Safety and Health Administration, U.S. Department of Labor to adopt legally enforceable rules and procedures (e.g., adequate PPE and social distancing) to protect miners from COVID-19 transmission. Exposures to pesticides and fungicides, commonly used in the farming industry, are also associated with compromised lung functioning [bib_ref] Occupational pesticide exposures and respiratory health, Ye [/bib_ref]. The respiratory conditions resulting from prolonged occupational exposure to toxins place many rural residents (primarily males) at higher risk for COVID-19 complications, if infected.
Rural areas also house many agricultural and foodprocessing industries in the U.S. Working in these industries poses further risk of COVID-19 infection due to close physical proximity in working conditions and the nature of this work, which rules out remote work options for most employees. Major COVID-19 outbreaks have been reported in multiple ruralbased food industries, such as meat packing plants. Hence, in areas where these rural industries exist, there is the risk of accelerated and rapid community spread of the coronavirus [bib_ref] COVID-19 among workers in meat and poultry processing facilities-19 states, Dyal [/bib_ref].
Third, the healthcare infrastructure of rural communities is often limited. Many rural hospitals are less equipped and less accessible than their nonrural counterparts [bib_ref] Disparities in access to trauma care in the United States: a population-based..., Carr [/bib_ref]. Many rural communities are characterized as "hospital deserts" (located 30-50 miles away from the nearest hospital center), impacting an estimated 16% of the population [bib_ref] Disparities in access to trauma care in the United States: a population-based..., Carr [/bib_ref]. Lack of healthcare access ultimately limits access to care for rural populations, making delayed or foregoing of care a concern. With respect to COVID-19, many rural counties in the U.S. lack intensive care unit (ICU) beds [bib_ref] Rural America's hospitals are not prepared to protect older adults from a..., Davoodi [/bib_ref]. Rural hospitals also often lack adequate personal protection equipment (PPE) and COVID-19 test kits to meet demands. Insufficient testing for COVID-19 in rural areas subsequently leads to underreporting of disease prevalence, which can inadvertently promote the relaxation of COVID-19 virus prevention, testing, and mitigation efforts [bib_ref] A commentary on rural-urban disparities in Covid-19 testing rates per 100,000 and..., Souch [/bib_ref].
Fourth, rural hospitals have been closing at alarming rates (172 closures since 2005, with another 700 hospitals currently at risk for closing) due to systemic and ongoing factors. Factors for rural hospital closures include rising costs, revenue pressures, and the complications involved in caring for an older, sicker patients who require enhanced health and social services. Moreover, challenges in hiring and retaining providers in remote areas [bib_ref] 172 rural hospital closures, Cecil [/bib_ref] are an ongoing concern. Also contributing to rising costs are state variations in Medicaid expansion. For example, states that did not participate in Medicaid expansion programs increased rural hospitals' burden of caring for uninsured populations compared to states that expanded coverage. Finally, most rural hospitals have limited value-based or qualitybased reimbursement mechanisms in place, which poses a barrier to implement social, behavioral, or population health initiatives that are critical during COVID-19.
Limitations on elective surgeries, physical therapy, and lab tests may further threaten the financial solvency of some rural area hospitals and clinics [bib_ref] National Rural Health Association. Urgent Federal action needed for rural health workers..., Weber [/bib_ref] and their ability to respond to crises, such as the ongoing COVID-19 pandemic. According to the National Rural Health Association [44], cashflow, inadequate supplies and tests, staff (especially Emergency Medical Services [EMS] shortages), workforce shortages, telehealth waivers, critical access hospital waivers, and needs for loan forbearance emerge as "grave" concerns facing rural healthcare systems. Combined with limited numbers of hospital and ICU beds and ventilators, limited access to tertiary support, and the limited number of physicians qualified to manage ICU patients, rural hospitals and clinics are severely restricted in their ability to treat COVID-19 patients. Altogether, rural populations are particularly vulnerable to COVID-19 infection, morbidity, and mortality and in need of strategic interventions to mitigate rural-based inequities that are emerging during this pandemic.
## Addressing rural health inequities in covid-19: research, policy, and practice implications
## Research
Social and behavioral science plays a central role in monitoring as well as mitigating health inequities, including those related to COVID-19. Unfortunately, sparsely populated small towns and remote areas of the U.S. are sometimes not well suited to traditional research models. Logistical barriers in communication and time required to travel long distancespose major measurement challenges that lead to a lack of high-quality research on health outcomes among rural populations. The usefulness of existing models for evaluating rural healthcare outcomes is currently under debate. Synthesizing health outcome measures across rural healthcare systems has also proved difficult due to low patient volumeand subsequently inadequate power to produce statistically significant results.
## Recommendations for health services research
Tracking relevant quality measures across hospitals and healthcare systems could improve quality of rural healthcare and reimbursement for rural providers. There is tremendous value in investing in online and mobile-based research to expand data monitoring and intervention delivery to rural populations and the infrastructure to support such studies (e.g., expansion of internet coverage). Efforts that harness existing technology and networks can facilitate COVID and non-COVID-related research in rural areas. The evaluation of these expanded intervention delivery methods by health services researchers will be critical for assessing the accessibility and effectiveness of these platforms for rural populations.
## Policy and practice
From implementing social distancing and quarantine requirements to travel restrictions and business and school closings, public health policy dominates the management of this pandemic. However, public policies can reflect and even exacerbate social inequities. The policy recommendations below identify strategies to facilitate healthcare delivery to rural patients during the COVID-19 pandemic, as well as address long-term healthcare needs of rural populations.
## Short-term recommendations
- Increase OSHA inspections for rural industry COVID mitigation policies and practices. To better protect the health of essential "front line" employees, especially those working in rural health industries such as coal miningand food processing, OSHA should conduct inspections to ensure that employers implement COVID-19-related safety policies and practices, such as regular testing, enforced social distancing, and the provision of effective PPE for all front line employees. - Fund, develop, and implement systematic widespread rural COVID-related outreach, testing, and treatment. Congress should prioritize the funding, development, and implementation of widespread affordable, accessible, culturally appropriate and systematic health-related outreach [bib_ref] Awareness, attitudes, and actions related to COVID-19 among adults with chronic conditions..., Wolf [/bib_ref] , including ramping up rural healthcare systems' capacity for COVID-19 testing and treatment, specifically targeting underrepresented and marginalized rural areas. Additionally, COVID-19 outreach and education should directly address misinformation and misperceptions regarding COVID-19 (e.g., the validity and risk of the virus, prevention through health behaviors such as handwashing, social distancing, and wearing masks). Restoration in funding and/or the equivalent of expected patient reimbursements to smaller, community-centric health delivery systems such as Community Based Health Clinics, family practices, and School-Based Health Centerscan facilitate their reopening and operations as safely as possible.
## Long-term recommendations
- Bridge broadband gaps in Internet coverage. Lack of broadband and Internet connectivity is an ongoing and serious problem in rural communities. Expansion of these services can increase opportunities for occupational telecommuting and telecommunicationand promote access to medical telehealthand online educationat primary, secondary, and postsecondary levels [bib_ref] Expanding broadband access for all learners, Deye [/bib_ref]. To address pre-existing gaps in Internet broadband availabilityand restrictions in Internet access due to COVID-19 related closures of businesses, schools, and libraries, local, state, and federal governments should provide more affordable and accessible internet access. should be prioritized, particularly for rural communities lacking healthcare providers or clinics and for rural hospitals already stretched thin with administrative burdens. The development of flexible and affordable healthcare delivery options that are adaptive to the current circumstances and that harness existing technology (e.g., mobile clinics) can bridge health disparities experienced by "hospital deserts" [bib_ref] It's all about trust and respect: cultural competence and cultural humility in..., De Peralta [/bib_ref] [bib_ref] How can we save black and brown lives during a pandemic? Data..., Gibbons [/bib_ref]. Recent examples from rural practices spanning the U.S. include creating and expanding telehealth services to settings that do not have health clinics, expansion of drive-through testing, offering curbside lab services and health care, and provision of behavioral online support groups. Finally and critically, allowing rural (and all) healthcare systems to bill for telehealth services in the short-and long-term expands the capacity of such systems to deliver care and reach additional, harder-to-reach segments of the population.
# Conclusions
Targeting COVID-19 inequities experienced by rural populations in the U.S. requires an understanding of the unique factors that shape rural health and rural healthcare systems' capacity to manage a pandemic. Increasing funding for rural healthcare facilities, staffing, and capacity for COVID-19 testing and enhancing broadband Internet infrastructure are vital to mitigate the impact of COVID-19 in rural areas. Implementing consistent OSHA inspections and enforcing COVID-19 mitigation procedures, such as provision of effective PPE and enactment of standardized testing and social distancing measures, is paramount to protect the health of the rural workforce in higher risk industries (e.g., food processing). Finally, incentivizing rural healthcare systems to deliver value-based care will increase the capacity of such systems to prioritize and implement population health strategies. Altogether, these recommendations are critical for the successful implementation and evaluation of policy and behavioral interventions that are central to protecting the well-being of rural residents during and following a pandemic.
## Compliance with ethical standards
Conflicts of Interest Pamela Behrman, Marian Fitzgibbon, Akilah Dulin, Monica Wang, and Monica Baskin declare they have no conflicts of interest.
Ethical Standards This manuscript is not being simultaneously submitted elsewhere. All procedures were conducted in accordance with ethical standards.
Human Rights This article does not contain studies with human participants. This article does not involve human participants and informed consent was therefore not required.
Welfare of Animals This article does not contain studies with animals. In June 2020, a shorter version of this manuscript was posted, in policy brief format, on the Society of Behavioral Medicine website and on Society of Behavioral Medicine's Twitter and Facebook pages. The authors have full control of the entire content of this manuscript and allow the journal to review the information and sources.
Acknowledgements: We thank John Bustle, MD, MHCM for his expert input. We also deeply thank our colleagues on the Health Policy Council (HPC) and the Civic Public Engagement Committee (CPEC) for their support and feedback.This project was not funded.
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https://academic.oup.com/tbm/article-pdf/11/2/625/36678599/ibaa114.pdf
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Abstract This position statement provides researchers, practitioners, and policymakers an overview of pre-existing and COVID-related rural health inequities in the United States (U.S.) and how they have been exacerbated by the COVID-19 pandemic. “Health deserts,” defined as “large areas with inadequate or nonexistent medical and trauma facilities,” are common in rural regions of the U.S. While telehealth could address some of these health-related inequities, significant gaps in broadband Internet availability are also common in these more remote areas. The Society of Behavioral Medicine urges Congress to authorize increased funding to rural healthcare facilities and staffing, along with the development of enhanced broadband Internet infrastructure. In addition, incentivizing rural healthcare systems to deliver value-based care could enhance their capacity to implement population health and behavioral health strategies. To stem the spread of COVID-19 in higher-risk rural-based industries (e.g., food processing plants), SBM urges Congress to require the Occupational Safety and Health Administration (OSHA) to routinely inspect for and enforce COVID-19 mitigation procedures, such as provision of effective Personal Protective Equipment (PPE) to all front-line workers and consistent implementation of standardized testing and social distancing advisories. The context of rural communities underscores the importance of tailored approaches to mitigate rural health inequities and promote the well-being of rural residents.
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87c052ff98ca14accd3a92a99905739855ef29f0
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Best Practice Guidance for Adult Infusion Centres during the COVID-19 Pandemic: Report from the COVID-19 International Organization for the Study of IBD [IOIBD] Task Force
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Best Practice Guidance for Adult Infusion Centres during the COVID-19 Pandemic: Report from the COVID-19 International Organization for the Study of IBD [IOIBD] Task Force
Infusion centres are a central part in the management of patients with inflammatory bowel disease [IBD] and could be a source of transmission of SARS-COV-2. Here we aimed to develop global guidance for best practices of infusion centres for IBD patients and to determine the impact of the COVID-19 pandemic on these centres. Under the auspices of the International Organization for the Study of Inflammatory Bowel Disease [IOIBD], a task force [TF] was formed, an online survey was developed to query infusion centre protocols during COVID-19, and recommendations were made, based on TF experience and opinion. Recommendations focus mainly on patients screening, infusion centres re-organization, personnel protection, and protocol modifications such as shortening infusion duration or replacing it with subcutaneous alternatives. Implementing these recommendations will hopefully reduce exposure of both IBD patients and care givers to SARS-COV-2 and improve the function and safety of infusion centres during the COVID-19 pandemic as well as potential future threats.
# Introduction
The global emergence of SARS-COV-2 virus and the COVID-19 pandemic has led to rethinking how we deliver medical service. This has affected many patient populations including those with inflammatory bowel diseases . [bib_ref] Implications of COVID-19 for patients with pre-existing digestive diseases, Mao [/bib_ref] [bib_ref] Management of IBD during the COVID-19 outbreak: resetting clinical priorities, Danese [/bib_ref] Early in the pandemic there were concerns regarding how vulnerable IBD patients may have been given their disease state and the medications they are exposed to. Over time, there has been a greater understanding of conditions that promoted the spread of the virus and concurrently measures that could decrease transmission and protect both patients and healthcare providers .
Infusion centres have become central to the way care is delivered to patients with IBD. Globally, these centres may be part of hospitals, private offices or free standing. The global standards and operating practices may vary. However, it was quickly identified that these centres could be a source of transmission of SARS-COV-2 and that guidance to decrease the risk to patients and HCPs was paramount. Therefore, under the auspices of the International Organization for the Study of Inflammatory Bowel Disease [IOIBD] a task force was formed to develop global guidance for best practices of infusion centres caring for IBD patients and to determine the impact of the COVID-19 pandemic on these centres. copies] 5. Provide access to guidance/help/support lines 6. Extend operating hours to accommodate infusions 7. Home infusions are discouraged due to safety issues, medical and logistic efficiency https://www.ioibd.org/ioibd-update-on-covid19-forpatients-with-crohns-disease-and-ulcerative-colitis/ The specific assignments were to point out the challenges and suggest how they may be addressed, to study the actions taken in various areas in the world and various health systems, and to follow up the effects of modified infusion centre protocols, if modifications took place. Beyond relevance to the COVID-19 pandemic and expected future waves until a vaccine is found, the insights and recommendations may be relevant to future pandemics. This is specifically meaningful as widespread infectious diseases may be one of the 21st century's global challenges.
# Methods
Six TF members were appointed [I.D., J.O.L., C.O., G.K., M.T.A., R.P.], representing Europe, North America and Israel. A survey was developed to query infusion centre protocols during COVID-19. A total of 36 IOIBD members replied. The data are presented graphically.
After identifying the key challenges, recommendations for infusion centre operation were made, based on TF experience and opinion. These were discussed in two calls with IOIBD membership [n = 89], as well as additional IBD experts. Recommendations were then modified according to comments made, and uploaded to the IOIBD site in order to provide immediate, practical, comprehensive recommendations, until evidence-based ones can be generated [ centres, all from the USA, more than 10% of infusions were home infusions. In the vast majority of centres, evaluation of clinical disease activity, laboratory tests and therapeutic drug monitoring were performed routinely. In 23/36 [64%], the duration of infliximab infusion was shortened to 60 minutes or less, and in 15/36 [41/7%] centres, those patients would be discharged immediately after infusion, without further monitoring in patients who are clinically stable.
During the COVID19 pandemic, 5/36 centres had to change location to a site remote from the acute care facility; this did not require a change in staffing. However, in 12/36 [33.3%] the capacity of the centre was reduced, without significant change of the case mix. Interestingly, while all centres screened patients on site for signs/symptoms of SARS-COV-2 infection and for a history of exposure, previsit screening calls were performed in 70%. Multiple modifications have taken place during the COVID-19 pandemic. Those changes related to several aspects of infusion centre operations, logistics and protocols. Specifically, 29/36 [80.6%] increased spacing between patients and increased cleaning between infusions.
In 24/36 [66.7%] there was reduced number of patients in the centre to allow for social distancing, and for this reason 10/36 [27.8%] increased the hours of operation [ [fig_ref] Figure 1: Changes in infusion centre dynamics since the start of the COVID-19 pandemic [/fig_ref] ].
Importantly, treatment protocol modifications with potential clinical implications were made. Those included changing intravenous to subcutaneous preparations where applicable [i.e. subcutaneous infliximab instead of intravenous] in 6/36 [16.7%] of centres, and increasing intervals between a patient's infusions in 5/36 [14%]. Changes were also made to infusion protocols; in 5/33 [15.2%] centres, stable patients had shorter infusion durations, post-infusion monitoring was reduced, and premedication was switched to the oral route, where applicable. In almost all centres there has always been a telephone help line and email address for patients. About half the infusion centres produced patient information sheets in response to the COVID-19 pandemic. The estimated cancellation of infusions was less than 10% in the majority of centres [26/36, 72%], but at the time the survey was sent, no report of disease exacerbation due to these changes was noted.
## Guidance for patients attending infusion centers for the management of their ibd
Based on the survey results and our TF deliberations we have generated guidance for infusions of IBD-related medications. The guidelines are based on survey results and expert opinion. We have intentionally made these broad to encompass differences in practice settings internationally.
## Infusion centre operations
Infusion centres and their administration may be different across jurisdictions. They may be hospital-based, community-based or in private practice. Often, the services offered may be shared across multiple disciplines.
1. To ease and simplify operations, a central schedule and pooling of resources [including staff] should be considered. This should include cross-specialty training of infusion nurses so that they are comfortable with different protocols [where possible protocols for each drug should be reviewed so that they are the same across specialities]. 2. If the infusion centre is within/next to a medical admission department or active gastrointestinal department, an alternative location should be sought, where possible, to enable minimal exposure for IBD patients visiting the infusion centre to patients potentially infected with SARS-COV-2. 3. Patients attending the centre should be re-screened for symptoms and have a temperature check before entering the centre. Patients exhibiting symptoms and/or fever should be isolated away from the main infusion area, wear a surgical mask, and recommended to self-isolate and referred for SARS-COV-2 testing if available. The infusion should be rescheduled consistent with recommendations above. 4. Infusion centres should re-organize their layout to comply with recommendations of personal hygiene and social distancing. This includes the following:
a. a minimum of 2 m distance during check-in or check-out b. a minimum of 2 m distance between infusion chairs or beds c. a minimum of 2 m distance between chairs/stations for laboratory draws d. chairs should be cleaned between patients, and/or disposable covers used.
## Personnel should use surgical masks and gloves for protection.
Where applicable, full personal protective equipment should be readily available [including gloves, gowns, ±eye protection and surgical mask]. 6. Personnel should be appropriately trained with the donning and doffing procedures of PPE. 7. Personnel are required to adhere to proper hand hygiene before and between any patient contact. This includes the removal of gloves/gowns and handwashing between patient encounters. 8. When possible, patients receiving infliximab infusions should be transitioned to a shorter rapid [30-60 min] infusion protocol to limit time within the clinic and increase clinic capacity. 9. Any pre-medication that is necessary should be converted to oral administration or subcutaneous medication once again to limit time in the clinic. 10. Consider changing infusion into subcutaneous injections of the same drug, where applicable [e.g. subcutaneous infliximab, subcutaneous vedolizumab]. 11. In patients with adequate drug levels, consider increasing intervals between infusions, where applicable. 12. A mechanism should exist for reporting and allowing for contact tracing of any patient or personnel who test positive for COVID-19. Any contacts should be isolated for a period of 10-14 days according to regional guidelines. a. inability to properly screen personnel and patients b. the increased possibility of spreading infection to patients and their households c. the difficulty with tracing and tracking d. difficulty to ensure personnel training e. inefficient use of personnel in times of extreme shortage. This provides guidance for what is thought to be the best practices during the COVID-19 pandemic. The TF recognizes that local, regional, and national differences and disparities exist. Therefore, this guidance should be integrated with local, regional and national guidelines.
## Personnel in infusion centres
# Discussion
During this COVID-19 pandemic, HCP and health systems have had to address unprecedented challenges. In IBD, the operation of infusion centres required specific attention due to several distinct features. First, the rapid spread of the SARS-COV-2 pandemic across the world and within specific countries has not left time for systematic evidence-based changes to established protocols and recommendations. Patients with IBD receiving intravenous biologics are dependent on timely scheduled infusions, as a delay of even a few days may affect treatment efficacy and immunogenicity. [bib_ref] Adalimumab induces deep remission in patients with Crohn's disease, Colombel [/bib_ref] [bib_ref] Randomised clinical trial: deep remission in biologic and immunomodulator naïve patients with..., Colombel [/bib_ref] [bib_ref] Response to biologic therapy in Crohn's disease is improved with early treatment:..., Rubin [/bib_ref] In addition, patients on immune-modifying medication including biological therapy are more susceptible to infection. The safety profile of specific biologics is relevant because vedolizumab 6 / ustekinumab 7 may be safer than infliximab. However, during the initial stages of the COVID-19 pandemic there was no information regarding viral spread; thus all biologics might have been considered risk factors for susceptibility to infection and/or worse COVID-19 outcomes. Preliminary outcomes from the SECURE-IBD registry suggest that tumour necrosis factor antagonists do not appear to be associated with severe COVID-19. [bib_ref] but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients..., Brenner [/bib_ref] Other issues that made the development of infusion centre guidance critical is that medical teams are considered a population at risk for infection with SARS-COV-2. [bib_ref] Protecting healthcare workers from subclinical coronavirus infection, Chang [/bib_ref] Thus, the teams operating an infusion centre are also at risk. Therefore, there is concern that staff will serve as conveyors of infection to their susceptible patients, or vice versa, that patients will 'import' infection from their environment to the infusion centre. In some overloaded health systems, staff members were often diverted to emergency care facilities, thus decreasing resources in infusion centres.
The IOIBD is composed of experts from around the globe who treat patients with IBD. Importantly, the centres represented in the survey are all tertiary academic referal centres, infusing thousands of patients per week combined. A rapid response to the challenges related to COVID-19 was deemed to be of the highest importance by the organization in order to ensure patient and HCP safety. In a series of meetings and surveys conducted between March 20 and April 25, 2020, practical guidelines were drafted and made available at the IOIBD.org website. Those related to infusion centre operations are presented here [ [fig_ref] Table 1: Main recommendations for infusion center guidance regarding COVID-19 and IBD Update contact... [/fig_ref] ]. It was soon recognized that the COVID-19 pandemic may have a vast effect not only on current operations but on future patient care and clinical outcomes. Thus, in addition to providing practical guidelines, a survey to assess the immediate impact of the pandemic was conducted. One immediate surprise was that only 70% of centres performed previsit screening, highlighting the importance of practical guidelines.
A third of the centres saw a reduction in capacity despite no significant changes in the case mix. This may have been due to several reasons. Most notably, the majority of the infusion centres [80.6%] increased spacing between patients and implemented more stringent cleaning protocols between infusions. In addition, 14% reported increasing the time between infusions. This necessitated a reduction in patient volume and an increase in operation hours to allow physical distancing. Operationally, this may lead to specific allocation of resources such as ensuring staff availability after hours, payment of over-time and re-scheduling efforts.
In an effort to limit patient attendance at infusion centres, several changes were implemented, specifically, a change of intravenous drugs to subcutaneous ones where applicable. Such modification was seen in 16.7% of centres. Although IBD clinicians supported the concept of using subcutaneous versions of intravenous biologics [i.e. infliximab and vedolizumab subcutaneously], these are not available in all countries. To this end the IOIBD appealed to drug approval agencies around the world, requesting expedited review of subcutaneous substitution of intravenous drugs.
The IOIBD will follow up with further surveys to assess the consequences that result from changes in infusion centre protocols. Such implications were indeed noticed. Addressing patient anxiety is of utmost importance in times of uncertainty. The use of telephone helplines, web-based fora and non-printed information is advisable, and was performed by most centres. Whether post-traumatic effects will also affect IBD patients' health remains to be determined in further studies.
At the time of writing, COVID-19 seems to be contained in most areas of the world. At this point, it is important to assess specific outcomes in patients with IBD treated with biologics, and to note which infusion centre modifications had a negative or positive consequence. An example may be the use of home infusions which were implemented in several American centres [10%], but not utilized in other countries. The general recommendation of the IOIBD was to refrain from diverting patients to receive home infusions. This was mainly due to safety concerns for patients and HCPs, as well as the need to avoid sending trained staff to patients' homes [or worsehaving untrained staff perform infusions of biologics]. Follow up of clinical implications is one of the important research gaps for future studies.
There are several areas to consider for future pandemics, including development of subcutaneous substitutes for existing intravenous drugs; providing operation standards for infusion centres, including size, staffing positions, equipment and sanitation requirements; redefining treatment protocols and follow up; and addressing patient and staff psycosocial sequaelae.
In summary, widespread infections may be one of the risks of the 21st century. While the challenges of the COVID-19 pandemic have been unprecedented, a second wave is expected by many experts before a vaccine is found. Furthermore, other similar challenges may unfortunately occur in the future. Thus, being more prepared, and evaluating outcomes of the current event, may be of particular importance. The current paper represents one attempt at outlining a universal protocol.
[fig] Figure 1: Changes in infusion centre dynamics since the start of the COVID-19 pandemic. [/fig]
[table] Table 1: Main recommendations for infusion center guidance regarding COVID-19 and IBD Update contact details at each visit to facilitate contact tracing in event a patient is/becomes SARS-COV2positive Personnel 1. Daily personal symptom assessment, health statement and temperature check 2. Glove removal and hand washing between patient encounters 3. Log off where personnel is working/has worked if in-Provide COVID-IBD-related information [no hard [/table]
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https://academic.oup.com/ecco-jcc/article-pdf/14/Supplement_3/S785/33977536/jjaa147.pdf
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Abstract Infusion centres are a central part in the management of patients with inflammatory bowel disease [IBD] and could be a source of transmission of SARS-COV-2. Here we aimed to develop global guidance for best practices of infusion centres for IBD patients and to determine the impact of the COVID-19 pandemic on these centres. Under the auspices of the International Organization for the Study of Inflammatory Bowel Disease [IOIBD], a task force [TF] was formed, an online survey was developed to query infusion centre protocols during COVID-19, and recommendations were made, based on TF experience and opinion. Recommendations focus mainly on patients screening, infusion centres re-organization, personnel protection, and protocol modifications such as shortening infusion duration or replacing it with subcutaneous alternatives. Implementing these recommendations will hopefully reduce exposure of both IBD patients and care givers to SARS-COV-2 and improve the function and safety of infusion centres during the COVID-19 pandemic as well as potential future threats.
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0353e8f21e929aa1c9056cc16a1a5083a2226b99
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pubmed
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Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians
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Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians
Insomnia is a prevalent disorder with deleterious effects such as decreased quality of life, and a predisposition to a number of psychiatric disorders. Fortunately, numerous approved hypnotic treatments are available. This report reviews the state of the art of pharmacotherapy with a reference to cognitive behavioral therapy for insomnia (CBT-I) as well. It provides the clinician with a guide to all the Food and Drug Administration (FDA) approved hypnotics (benzodiazepines, nonbenzodiazepines, ramelteon, low dose sinequan, and suvorexant) including potential side effects. Frequently, chronic insomnia lasts longer than 2 years. Cognizant of this and as a result of longer-term studies, the FDA has approved all hypnotics since 2005 without restricting the duration of use. Our manuscript also reviews off-label hypnotics (sedating antidepressants, atypical antipsychotics, anticonvulsants and antihistamines) which in reality, are more often prescribed than approved hypnotics. The choice of which hypnotic to choose is discussed partially being based on which segment of sleep is disturbed and whether co-morbid illnesses exist. Lastly, we discuss recent label changes required by the FDA inserting a warning about "sleep-related complex behaviors", e.g., sleep-driving for all hypnotics. In addition, we discuss FDA mandated dose reductions for most zolpidem preparations in women due to high zolpidem levels in the morning hours potentially causing daytime carry-over effects.
## Treatment options for insomnia: a primer for clinicians
Chronic insomnia is a prevalent (10%) medical disorder defined by difficulty falling or staying asleep or non-restorative sleep combined with impaired daytime functioning. It is associated with increased motor vehicle accidents, and falls [bib_ref] Consequences of insomnia and its therapies, Benca [/bib_ref] , increased healthcare utilization [bib_ref] Chronic insomnia and health care utilization in young adults, Bramoweth [/bib_ref] , and decreased survival rates [bib_ref] Heritability and mortality risk of insomnia-related symptoms: A genetic epidemiologic study in..., Hublin [/bib_ref]. Insomnia predisposes to the development of a number of psychiatric disorders, particularly depressive and anxiety disorders [bib_ref] Place of chronic insomnia in the course of depressive and anxiety disorders, Ohayon [/bib_ref] [bib_ref] Sleep disturbances and psychiatric disorders: A longitudinal epidemiological study of young adults, Breslau [/bib_ref]. When psychiatric disorders are present, insomnia is associated with greater severity of illness including suicidal behavior [bib_ref] Sleep disturbances and suicidal behavior in patients with major depression, Agargün [/bib_ref] [bib_ref] Insomnia severity is an indicator of suicidal ideation during a depression clinical..., Mccall [/bib_ref] [bib_ref] Sleep disturbances and suicidality: A common association to look for in clinical..., Nora [/bib_ref]. Successful treatment of insomnia frequently leads to an earlier antidepressant and anxiolytic response [bib_ref] Zolpidem extended-release improves sleep and next-day symptoms in comorbid insomnia and generalized..., Fava [/bib_ref] [bib_ref] Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety..., Pollack [/bib_ref]. Insomnia also interacts with various medical conditions; it can predispose to the development of type 2 diabetes, metabolic syndrome, and obesity [bib_ref] Effects of poor and short sleep on glucose metabolism and obesity risk, Spiegel [/bib_ref]. In addition, treatment of insomnia co-morbid with a medical illness may lead to improvement of both conditions [bib_ref] The effect of eszopiclone in patients with insomnia and coexisting rheumatoid arthritis:..., Roth [/bib_ref]. Thus, there is a clear need to treat insomnia.
This paper explores what alternatives (and their side effects) clinicians have available to treat insomnia, focusing predominantly on pharmacotherapy, and what situations warrant one treatment over another.
The two most widely accepted treatments for insomnia are hypnotic medications and cognitive behavioral therapy for insomnia (CBT-I). The latter is a structured treatment utilizing behavioral strategies including relaxation techniques, sleep hygiene, stimulus control, sleep restriction and cognitive techniques. These methods spotlight negative and distorted cognitions and behaviors associated with insomnia. CBT-I is administered over a 5 h period (4 to 6 weeks) and can be administered monthly (maintenance treatment) [bib_ref] Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: A..., Morin [/bib_ref].
Hypnotic medications act quickly, usually after the first dose in contrast to CBT-I which takes weeks. Thus, many prefer medication. Few studies have compared hypnotic medications directly to CBT-I; short-term outcomes were similar. After discontinuing treatments, CBT patients did better than the medication group for periods assessed up to 1 year [bib_ref] Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: A..., Morin [/bib_ref] ; thus, there seems to be a learned carry-over effect for CBT-I.
CBT-I has many advantages for they avoid side effects of hypnotics. In addition, CBT use during pregnancy and breast feeding avoids the exposure of a fetus/newborn to medication. Also, many patients prefer CBT-I, avoiding difficulties in swallowing pills, and avoiding the concept of using a pharmacological approach. Unfortunately, CBT services are extremely limited (particularly amongst general practicioners) and costly. Efforts to increase delivery of CBT have been promising via self-help groups, computer and internet programs.
Thus, pharmacotherapy is the primary treatment for insomniawith CBT being used in approximately 1% of chronic insomniacs [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref]. Combining both treatments offers no major advantage acutely and only minimal advantage long-term [bib_ref] Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: A..., Morin [/bib_ref].
In the 1970s, benzodiazepines came to the forefront in treating insomnia and are still widely prescribed. They provided a welcomed increase in safety profile over barbiturates (e.g., secobarbital and butalbital) and other barbiturate-like substances (e.g., ethchlorvynol and chloral hydrate). In particular, it was difficult to successfully overdose on them unless combined with other CNS suppressants such as alcohol [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref]. Since many with insomnia have co-morbid psychiatric disorders, particularly depressive and anxiety disorders with suicidal behavior [bib_ref] Place of chronic insomnia in the course of depressive and anxiety disorders, Ohayon [/bib_ref] [bib_ref] Sleep disturbances and psychiatric disorders: A longitudinal epidemiological study of young adults, Breslau [/bib_ref] , suicide attempts with hypnotics frequently occur in this population. The dangers inherent with barbituates and barbiturate-like agents cannot be overemphasized. For example, chloral hydrate is a toxic dose at about five times the therapeutic dose and tolerance can develop after only days. This is one of the main reasons why the usage of these drugs has been discouraged by sleep experts; clearly, benzodiazepines are safer hypnotics. Although benzodiazepines have many positive safety features, they too have a number of undesirable effects. Most notably, benzodiazepines can induce dependence with subsequent withdrawal and rebound symptoms if they are suddenly discontinued. Furthermore, these drugs are subject to abuse, particularly in patients with a history of alcohol and drug abuse [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref]. Since most of the approved benzodiazepines for insomnia have half-lives of over 8 hours (except for triazolam), it is not surprising that next-day (residual) fatigue, psychomotor and neuropsychological dysfunction are potential side effects; the longer the half-life of the drug, the more likely the occurrence of residual adverse events. There are five FDA approved benzodiazepines for insomnia (estazolam, flurazepam, quazepam, temazepam and triazolam) [bib_ref] Hypnotic medications: Mechanisms of action and pharmacological effects, Mendelson [/bib_ref].
Triazolam, flurazepam, quazepam and estazolam are effective in sleep onset and sleep maintenance problems whereas temazepam is effective in only sleep-onset problems in adults, 18-65 years old; in adults 65 years and older, triazolam and flurazepam are helpful for sleep onset and maintenance problems, whereas temazepam has been shown to be helpful for only sleep maintenance problems [bib_ref] A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for..., Krystal [/bib_ref].
In an attempt to improve the safety profile of benzodiazepines, the non-benzodiazepines (but also benzodiazepine receptor agonists) were developed in 1989 and FDA approved in 1993 [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref] [bib_ref] Hypnotic medications: Mechanisms of action and pharmacological effects, Mendelson [/bib_ref] [bib_ref] Zolpidem for insomnia, Greenblatt [/bib_ref]. Zolpidem was the first of these drugs developed; zolpidem as well as another nonbenzodiazepine, zaleplon, selectively attaches to the benzodiazepine recognition site on the GABA-A receptor at the level of the α-1 subunit while eszopiclone, also a non-benzodiazepine, is predominantly selective for the α-2 and α-3 subtypes with lesser sensitivity for α-1 subtype. In contrast, bezodiazepines have a more diffuse (non-selective) effect at the α subunit (α-1, α-2, α-3 and α-5 subtypes) [bib_ref] Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABA(A)..., Sanna [/bib_ref] [bib_ref] The modulation of synaptic GABA A receptors in the thalamus by eszopiclone..., Jia [/bib_ref]. This preferential selectivity by non-benzdiazepines and their short half-lives (8 h or less) are probably responsible for the suggested (but still debated) finding of a reduction in next-day fatigue as well as less psychomotor and neuropsychological dysfunction in comparison to benzodiazepines. Like benzodiazepines, these drugs are safe regarding overdoses. In contrast, dependence and withdrawal symptoms rarely develop with some believing that this is related to its specificity at the GABA-A receptor described above [bib_ref] GABA A receptor subtypes: Dissecting their pharmacological functions, Rudolph [/bib_ref]. In addition, non-benzodiazepines tend not to be abused nor sought out by drug abusing populations in comparison to benzodiazepines. Thus, non-benzodiazepines are effective in insomnia and may offer a better safety profile over benzodiazepines. Nonetheless, they still share similar potential adverse events-sedation, anterograde amnesia, complex sleep-related behaviors, and impaired balance with subsequent falls. As suggested above, the superiority of non-benzodiazepines over benzodiazepines have recently been questioned. Although the 2005 NIH consensus conferenceand a recent meta-analysis [bib_ref] The efficacy and safety of drug treatments for chronic insomnia in adults:..., Buscemi [/bib_ref] supported a superiority of nonbenzodiazepines over benzodiazepines, the reality is that there have been a minimal number of head to head studies. Recent reports suggest that that benzodiazepines and non-benzodiazepines have equivalent efficacy and side effect profiles leading NICE (The National Institute of Clinical Excellence) and other regulatory groups to support using benzodiazepines over non-benzodiazepines due to lower prices. Currently there are seven FDA approved nonbenzodiazepines for insomnia which consist of zaleplon, eszopiclone, zolpidem and four derivative zolpidem preparations including zolpidem-extended release, zolpidem sublingual high dose (Edluar), zolpidem sublingual low dose (Intermezzo), and zolpidem oral spray (Zolpimist) (see [fig_ref] Table 1: The Food and Drug Administration [/fig_ref].
As referred to above, various zolpidem modifications recently have provided alternative delivery systems in order to increase the drug's efficacy and target specific sleep disturbances (see [fig_ref] Table 2: Zolpidem and its derivatives [/fig_ref]. Zolpidem CR (6.25 and 12.5 mg dose) is a composite preparation which has a component that releases immediately and a component that is slowly released, supposedly allowing higher blood levels later in the sleep cycle (greater than for zolpidem IR) effecting sleep onset and sleep maintenance disturbances. This drug dissolves over an extended time with an increased half-life. Unfortunately, there have been no head to head studies comparing zolpidem CR to zolpidem IR. Therefore, the superiority of the zolpidem CR preparation for sleep maintenance problems has not been definitively proven. In addition, two sublingual oral tablets (not to be swallowed) were developed-zolpidem SL (sublingual) (Edluar and Intermezzo) which dissolve in the mouth-as well as an oral spray (Zolpimist)these latter three preparations apparently are more rapidly absorbed avoiding first pass effects of the liver, have shorter half-lives, and allow patients to not have to deal with swallowing a tablet or pill. Swallowing issues can be a problem, particularly in the elderly, a population representing the majority of insomniacs and hypnotic users [bib_ref] Alternative formulations, delivery methods, and administration options for psychotropic medications in elderly..., Muramatsu [/bib_ref]. The two sublingual preparations have been tweaked for different unique sleep disturbances. The sublingual preparation, Edluar was developed and FDA approved for sleep onset insomnia in 2009. The other sublingual preparation, Intermezzo was specifically developed and FDA approved (2011) for a subtype of sleep maintenance insomnia, i.e., middle-of-the-night-wakefullness with difficulty returning to sleep. The dose is particularly small, 1.75-3.5 mg, and should be taken only if 4 h of bedtime remain prior to the time one must awaken. The Zolpimist preparation is an oral spray preparation with each metered spray containing 5 mg of zolpidem. The drug was approved for sleep onset insomnia in 2008.
In 2005, the FDA approved the first melatonin agonist, ramelteon (Rozerem), which is effective for sleep-onset problems (see [fig_ref] Table 1: The Food and Drug Administration [/fig_ref]. It has a short half-life (1-1.5 h). Its mechanism of action is as a melatonin receptor agonist acting via promoting drowsiness via MT1 receptor stimulation and synchronizing of the circadian clock via MT2 receptor stimulation. It has no effect on the benzodiazepine-GABA-A receptor [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref]. Therefore, it appears to be free of possible drug abuse, dependence, and next-day cognitive dysfunction although one recent report suggests otherwise [bib_ref] Next-day effects of ramelteon (8 mg), zopiclone (7.5 mg), and placebo on..., Mets [/bib_ref]. It is one of two prescribed hypnotics that is not a scheduled drug. In 2010, the FDA approved the first H 1 antagonist and tricyclic antidepressant (TCA), doxepin (Silenor, 3 and 6 mg) for insomnia (see [fig_ref] Table 1: The Food and Drug Administration [/fig_ref]. At these small doses (in contrast, the antidepressant dose is 150-300 mg/day), doxepin (Silenor) was found to be effective for maintenance sleep problems without any significant side effects in both younger and older populations for periods up to 3-6 months. At these low doses, doxepin (Silenor) is preferentially a histaminic H 1 receptor antagonist which is believed to be its main mechanism of action underlying its effect on insomnia [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref] [bib_ref] Zolpidem for insomnia, Greenblatt [/bib_ref] [bib_ref] Efficacy and safety of doxepin 1 mg and 3 mg in a..., Krystal [/bib_ref]. Interestingly, doxepin (Silenor) is not effective for sleep-onset problems which is probably related to a long T max of approximately 3.5 h (see [fig_ref] Table 1: The Food and Drug Administration [/fig_ref] Although doxepin (Silenor) has minimal anti-cholinergic effects, out of caution, the PI states that it should be avoided in the presence of untreated narrow angle glaucoma or severe urinary retention. Doxepin does not effect the GABA-A receptor and does not have any associated complications of abuse, tolerance, withdrawal, or complex sleep behavior. It is not a scheduled hypnotic, similar to ramelteon (all other hypnotics in [fig_ref] Table 1: The Food and Drug Administration [/fig_ref] are schedule 1V drugs). Doxepin (Silenor) has minimal associated next-day residual effects (sedation, 6%-9% for Silenor and 4% for placebo)which may relate to an early morning rise of histamine which is an "alerting neurotransmitter" [bib_ref] Review of the histamine system and the clinical effects of H1 antagonists:..., Krystal [/bib_ref]. Recently, Wu, Chang and Zu demonstrated that low dose doxepin (12.5 mg), the generic formulation, was effective in insomnia without inducing significant side effects (this study was not placebo-controlled) [bib_ref] Efficacy and safety evaluation of citalopram and doxepin on sleep quality in..., Wu [/bib_ref]. It may be that 10 mg doxepin capsules, the smallest generic capsule in the United States, would also be as effective and comparable to Silenor 3 or 6 mg. Comparative studies have not been performed. In 2014, the FDA approved suvorexant (Belsomra), the first orexin receptor antagonist (for orexin 1 and orexin 2 receptor) for the treatment of insomnia with sleep onset and/or sleep maintenance difficulties (see [fig_ref] Table 1: The Food and Drug Administration [/fig_ref] ; since orexin is a peptide that promotes wakefulness and effects the sleep wake cycle, suvorexant blocks these effects and induces sleep by being a dual orexin antagonist. It is approved for geriatric (ě65 years old) and non-geriatric populations. The dose range is 10-20 mg/day with a half-life of 12.2 h. In trials where suvorexant was given up to I year, there was no evidence of withdrawal, or rebound effects upon discontinuation of the medication. The main side effect was somnolence seen in 6.7% of patients on drug vs. 3% of patients on placebo. This side effect usually resolved with continued usage. Rarely, complex sleep-related behavior was observed for suvorexant (0.2%) vs. placebo (0%) [bib_ref] Safety and efficacy of suvorexant during 1-year treatment of insomna with subsequent..., Michelson [/bib_ref] [bib_ref] Suvorexant for insomnia: A systematic review of the efficacy and safety profile..., Citrome [/bib_ref]. Cataplexy was not observed in patients administered a therapeutic dose although it has occurred at higher doses; the latter is of theoretical interest since patients with narcolepsy are orexin deficient. Therefore, patients treated with a dual orexin antagonist might be expected to be associated with cases of cataplexy [bib_ref] Safety and efficacy of suvorexant during 1-year treatment of insomna with subsequent..., Michelson [/bib_ref] [bib_ref] Suvorexant for insomnia: A systematic review of the efficacy and safety profile..., Citrome [/bib_ref]. On a precautionary note, the PI does warn against administering suvorexant in patients with narcolepsy [bib_ref] Suvorexant for insomnia: A systematic review of the efficacy and safety profile..., Citrome [/bib_ref]. In general, suvorexant appears to have a more benign side effect profile than the benzodiazepines and non-benzodiazepines.
Clinicians frequently administer off-label medications for insomnia, particularly sedating antidepressants as a treatment of choice for insomnia (see [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref] [bib_ref] Clinical pharmacology of other drugs used as hypnotics, Buysse [/bib_ref] [bib_ref] Pharmacological treatment: Other medications, Krystal [/bib_ref]. . Off-label medications for insomnia.
## Drug class gerneric name trade name dose (mg) eliminations half life (h) t max (h)
Sedating Antidepressants Resources used for data-see references [bib_ref] Clinical pharmacology of other drugs used as hypnotics, Buysse [/bib_ref] [bib_ref] Pharmacological treatment: Other medications, Krystal [/bib_ref] ; * these 2 trade names are no longer available in USA.
Other than doxepin (Silenor), antidepressants are not FDA approved for insomnia. Sedating antidepressants such as trazodone and amitriptyline are not only routinely prescribed by clinicians but they are the most prescribed treatments for insomnia. The NIH State of Science Conference on insomnia treatments reviewed the status of antidepressants reporting minimal scientific evidence supporting their use. Of particular concern in using antidepressants for insomnia are a number of unique potential side effects. TCA's can have cardiovascular complications; they block α-1 adrenoceptors leading to orthostatic hypotension. They also slow intraventricular conduction and can lead to bundle-branch block and arrhythmias [bib_ref] Review of cardiovascular effects of heterocyclic antidepressants, Glassman [/bib_ref]. Trazodone, a heterocyclic antidepressant, has similar cardiovascular side effects as TCA's [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref] [bib_ref] Clinical pharmacology of other drugs used as hypnotics, Buysse [/bib_ref] [bib_ref] Pharmacological treatment: Other medications, Krystal [/bib_ref]. Furthermore, trazodone is associated with a rare but serious side effect, priaprism, a sustained erection which can result in a urological emergency; this was recently reported after a single 100 mg dose [bib_ref] Safety of trazodone as a sleep agent for inpatients, Jayaram [/bib_ref] , well within the dose range used for insomnia. Lastly, overdoses with sedating antidepressants, particularly TCA's, (most have half-lives over 24 h) can lead to a successful suicide. For example, a 30 day prescription of 100 mg/day of amitriptyline (the dose range for insomnia ranges from 10-100 mg at bedtime)falls within the lethal dose [bib_ref] Tricyclic antidepressant poisoning: An evidence-based consensus guideline for out-of-hospital management, Woolf [/bib_ref].
Other off-label hypnotics widely used by clinicians are sedating atypical antipsychotics, antihistamines, and anticonvulsants [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref] [bib_ref] Clinical pharmacology of other drugs used as hypnotics, Buysse [/bib_ref] [bib_ref] Pharmacological treatment: Other medications, Krystal [/bib_ref]. One of the most widely used is an atypical antipsychotic, quetiapine. Approved for schizophrenia and bipolar disorder, it is effective at lower doses for insomnia (25-100 mg/day). Unfortunately, it poses many medical risks including glucose dysregulation, tardive dyskinesia and an increased risk of stroke in those with dementia.
As recommended by the American Academy of Sleep Medicine (AASM) [bib_ref] Clinical guideline for the evaluation and management of chronic insomnia in adults, Schutte-Rodin [/bib_ref] , off-label hypnotics may be considered in at least two situations: When FDA approved drugs are not efficacious for a particular patient (as many as 40% of insomniacs fail to respond) [bib_ref] Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: A..., Morin [/bib_ref] and when an insomnia patient has a co-morbid condition that may actually benefit from this off-label drug which is FDA approved for the co-morbid condition. An example of the latter is in an insomnia patient with schizophrenia or bipolar disorder in which quetiapine might be tried or in a patient with a seizure disorder where anticonvulsants (e.g., gabapentin) might be appropriate, or an insomnia patient with severe allergies where antihistamines might be helpful.
## Hypnotics in the elderly
All of the FDA approved hypnotics have been found to be effective in the elderly. Dose reductions (starting with half the dose) are required for zolpidem, zaleplon and eszopiclone due to increased sensitivity in the elderly [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref].
## Short-term vs. long-term
Prior to 2005, hypnotics, particularly benzodiazepines have been recommended for short-term use, 7-14 days, predominantly due to concerns of their side effects [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref]. For example, benzodiazepines were only studied in short-term studies mainly focusing on a maximum of 2-4 weeks duration [bib_ref] A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for..., Krystal [/bib_ref]. Unfortunately, insomnia frequently becomes chronic in many patients, lasting over 2 years [bib_ref] Clinical correlates of insomnia in patients with chronic illness, Katz [/bib_ref]. Therefore, what are clinicians to do? The FDA has realized the need for long-term use of hypnotics as demonstrated by the fact that all hypnotics since 2005 have been studied long-term and approved with no limitation on duration of usage on the labeling [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref]. Continued long-term efficacy and safety studies (both placebo-controlled, double-blind and open-label) ranging from 3 to 12 months have demonstrated that zolpidem, zaleplon, ezsopiclone, remelteon, doxepin, and suvorexant retain their efficacy without tolerance, abuse, withdrawal effects or any new adverse events developing [bib_ref] Chronic insomnia: Clinical and research challenges-An agenda, Riemann [/bib_ref] [bib_ref] Efficacy and safety of doxepin 1 mg and 3 mg in a..., Krystal [/bib_ref] [bib_ref] Safety and efficacy of suvorexant during 1-year treatment of insomna with subsequent..., Michelson [/bib_ref] [bib_ref] Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic..., Mayer [/bib_ref] [bib_ref] Twelve months of nightly zolpidem does not lead to dose escalation: A..., Roehrs [/bib_ref] [bib_ref] An evaluation of the efficacy and safety of eszopiclone over 12 months..., Roth [/bib_ref] [bib_ref] Long-term use of sedative hypnotics in older patients with insomnia, Ancoli-Israel [/bib_ref]. Thus, clinicians may use hypnotics long-term if necessary; the need for continued use should be reassessed periodically.
If long-term use is necessary, one useful strategy is to administer hypnotics on an as needed basis-a few times a week vs. nightly. This would cut down on total medication exposure and minimize costs and possible side effects. This strategy was also based on the fact that insomnia frequently is not a nightly phenomenon. Interestingly, no matter whether medications were taken nightly or intermittently, there were no differences in efficacy, tolerance, or abuse.
## Treatment strategy based on specific sleep disturbances and clinical situations
Which sleep disturbance is actually present may help to determine which hypnotic medication to use. Patients with a sleep-onset disturbance might be best treated with a hypnotic with a short half-life (e.g., zaleplon, remelteon, triazolam, zolpidem IR, zolpidem oral spray, zolpidem sublingual-Edular); those with a sleep disturbance later in the evening or early in the morning might require a hypnotic that has a longer half-life (e.g., zolpidem ER, eszopiclone, temazepam, doxepin, or suvorexant). Patients who suffer from sleep awakenings in the middle of the night and cannot get back to sleep might best be treated with zolpidem sublingual (Intermezzo). Zaleplon (which is only FDA approved for sleep-onset difficulties) can also be used off-label for this indication since it has a very short half-life (1 h) and as long as the patient plans to remain in bed or be sleeping for another 4 h.
Unfortunately, insomniacs frequently have multiple sleep disturbances [bib_ref] Daytime consequences of insomnia symptoms among outpatients in primary care practice: EQUINOX..., Leger [/bib_ref] and therefore, may need hypnotics with longer half-lives ranging from 2.5 to 8 h to treat both sleep onset and sleep maintenance problems (e.g., temazolam, zolpidem ER, eszopiclone, or suvorexant). Hypnotics with particular long half-lives in general should be avoided due to an increased likelihood of next-day sedation (e.g., flurazepam). One exception to avoiding longer acting hypnotics is when a patient with insomnia has significant daytime agitation and anxiety where daytime anxiolytic effects from the hypnotic might be helpful.
Clinical situations that guide clinicians to use one treatment vs. others are numerous. A patient may have severe pulmonary disease where CNS sedating medications should be avoided. Here, ramelteon or doxepin are favorable choices as well as a non-pharmacological approach-CBT-I. If pregnancy or breast feeding is foreseeable, pharmacotherapy should be avoided; CBT-I might be the treatment of choice. If there is a history of drug or alcohol problems, avoiding benzodiazepines and non-benzodiazepines and utilizing doxepin, remelteon or possibly CBT-I are recommended. Recently, ramelteon was used successfully in alcohol dependent insomniacs [bib_ref] Ramelteon and improved insomnia in alcohol-dependent patients: A case series, Brower [/bib_ref].
Insomnia patients with a co-morbid anxiety disorder may respond best to specific hypnotic treatments. For example, patients with insomnia who have co-morbid generalized anxiety disorder (GAD) appear to do well when eszopiclone is added to the anti-anxiety treatment of escitalopram; both insomnia and anxiety improved more significantly with the addition of eszopiclone vs. placebo [bib_ref] Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety..., Pollack [/bib_ref]. Interestingly, when zolpidem was used in insomnia patients with GAD being treated with escitalopram, zolpidem (vs. placebo) had no added effect on reducing anxiety [bib_ref] Zolpidem extended-release improves sleep and next-day symptoms in comorbid insomnia and generalized..., Fava [/bib_ref]. In addition, insomnia patients with GAD might be treated with benzodiazepines with or without a SSRI which might give relief of both insomnia and anxiety. Patients with insomnia co-morbid with PTSD appear to have a therapeutic response to both their insomnia and PTSD symptoms when treated with eszopiclone or an α-1 antagonist, prazosin as reported in double-blind, placebo-controlled studies [bib_ref] Sleep disturbances in patients with post-traumatic stress disorder: Epidemiology, impact and approaches..., Maher [/bib_ref] [bib_ref] Eszopiclone for the treatment of posttraumatic stress disorder and associated insomnia: A..., Pollack [/bib_ref]. The latter drug was particularly effective for PTSD nightmares [bib_ref] Sleep disturbances in patients with post-traumatic stress disorder: Epidemiology, impact and approaches..., Maher [/bib_ref]. Here again, zolpidem, when given to patients with insomnia co-morbid with PTSD, improved insomnia but PTSD symptoms failed to respond [bib_ref] Zolpidem for insomnia related to PTSD, Dieperink [/bib_ref]. Furthermore, caution should be applied in administering benzodiazepine hypnotics in insomnia co-morbid with PTSD; they appear to be relatively ineffective for both insomnia and PTSD symptoms and may be abused in this vulnerable population which has a frequent co-morbid history of drug abuse) [bib_ref] Sleep disturbances in patients with post-traumatic stress disorder: Epidemiology, impact and approaches..., Maher [/bib_ref] [bib_ref] Declining benzodiazepine use in veterans with posttraumatic stress disorder, Lund [/bib_ref] [bib_ref] Benzodiazepine prescribing variation and clinical uncertainty in treating posttraumatic stress disorder, Lund [/bib_ref] ; some investigators have even recommended that benzodiazepine use be contraindicated for this population [bib_ref] Benzodiazepine prescribing variation and clinical uncertainty in treating posttraumatic stress disorder, Lund [/bib_ref].
Patients with insomnia and a co-morbid major depressive disorder (MDD) also seem to have preferential responses regarding their insomnia and mood disorder. Benzodiazepines when added to an antidepressant course are clearly helpful for insomnia. Evidence also suggests that depression may also be more responsive with the combination but the advantage may fade over time [bib_ref] Short-term augmentation of fluoxetine with clonazepam in te treatment of depression: A..., Smith [/bib_ref] [bib_ref] Summit research network. Is extended clonazepam cotherapy of fluoxetine effective for outpatients..., Smith [/bib_ref]. Eszopiclone (vs. placebo) when added to fluoxetine antidepressant treatment not only improved insomnia but also increased the speed and magnitude of the antidepressant response to fluoxetine [bib_ref] Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive..., Fava [/bib_ref]. When zolpidem was used as the hypnotic in another study of insomnia with co-morbid MDD being treated with the SSRI, escitalopram, zolpidem (vs. placebo) significantly improved insomnia without any additional effect on depression responsiveness [bib_ref] Improved insomnia symptoms and sleep-related next-day functioning in patients with comorbid major..., Fava [/bib_ref]. The beneficial effect of eszopiclone on anxiety and depression in contrast to a negligible effect of zolpidem seen in the above studies in insomnia co-morbid with GAD and MDD is most interesting. It may be that the differences of these drugs on the GABA-A α subunits contribute to these specific findings; the specificity of eszopiclone for the α-2 and α-3 subtypes may contribute to anxiolytic and antidepressant properties as proposed in the animal literature [bib_ref] Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABA(A)..., Sanna [/bib_ref] [bib_ref] The modulation of synaptic GABA A receptors in the thalamus by eszopiclone..., Jia [/bib_ref] [bib_ref] GABAA receptors: Subtypes, regional distribution, and function, Nutt [/bib_ref] ].
## New concerns
As a result of anecdotal reports received by the Medwatch system that hypnotics occasionally caused "sleep-related complex behaviors", the FDA in 2007 required a label change, warning of this for all hypnotics. These behaviors included "sleep driving", "sleep-walking", "sleep-eating" and "sleep-violence" occurring in the middle of the night without any memory of the activity [bib_ref] Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: Fluorine-18-flourodeoxyglucose positron emission tomography..., Hoque [/bib_ref].
Recently, the FDA required pharmacokinetic studies on various preparations of zolpidem after receiving complaints of carry-over effects the next morning involving driving and sedation; significantly high blood levels 8 h after ingesting zolpidem were found, particularly in women (15% of women and 3% of men). The FDA (2013) mandated a lowered starting dose (half the usual dose) in women and suggested a similar lower dose for men (many men will respond to a lower dose); they recommended similar caution for all hypnotic medications [bib_ref] FDA warning: Driving may be impaired the morning following sleeping pill use, Kuehn [/bib_ref].
Some epidemiological studies have suggested that the use of hypnotic medications were associated with increased mortality [bib_ref] Mortality associated with sleep duration and insomnia, Kripke [/bib_ref] [bib_ref] Use of benzodiazepines or benzodiazepine related drugs and the risk of cancer:..., Kripke [/bib_ref]. Interestingly, this was recently confirmed in another study but after controlling for baseline characteristics and lifestyle issues, there was no longer an association of hypnotic use and increased mortality [bib_ref] Hypnotics and mortality in an elderly general population: A 12-year prospective study, Jaussent [/bib_ref]. Since this potential association is so alarming, further studies must prospectively examine this.
# Conclusions
Chronic insomnia is a prevalent disorder that must be treated. Clinicians can use either pharmacotherapy or CBT-I. Pros and cons of each are discussed, as well as the use of off-label hypnotic medications.
[table] Table 1: The Food and Drug Administration (FDA) approved hypnotics for insomnia. [/table]
[table] Table 2: Zolpidem and its derivatives. [/table]
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https://www.mdpi.com/1422-0067/17/1/50/pdf?version=1451478567
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Insomnia is a prevalent disorder with deleterious effects such as decreased quality of life, and a predisposition to a number of psychiatric disorders. Fortunately, numerous approved hypnotic treatments are available. This report reviews the state of the art of pharmacotherapy with a reference to cognitive behavioral therapy for insomnia (CBT-I) as well. It provides the clinician with a guide to all the Food and Drug Administration (FDA) approved hypnotics (benzodiazepines, nonbenzodiazepines, ramelteon, low dose sinequan, and suvorexant) including potential side effects. Frequently, chronic insomnia lasts longer than 2 years. Cognizant of this and as a result of longer-term studies, the FDA has approved all hypnotics since 2005 without restricting the duration of use. Our manuscript also reviews off-label hypnotics (sedating antidepressants, atypical antipsychotics, anticonvulsants and antihistamines) which in reality, are more often prescribed than approved hypnotics. The choice of which hypnotic to choose is discussed partially being based on which segment of sleep is disturbed and whether co-morbid illnesses exist. Lastly, we discuss recent label changes required by the FDA inserting a warning about “sleep-related complex behaviors”, e.g., sleep-driving for all hypnotics. In addition, we discuss FDA mandated dose reductions for most zolpidem preparations in women due to high zolpidem levels in the morning hours potentially causing daytime carry-over effects.
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b24eebba09829d24118c4f73097ea7159088b476
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pubmed
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Guidance for Rebooting Electrophysiology Through the COVID-19 Pandemic From the Heart Rhythm Society and the American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology
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Guidance for Rebooting Electrophysiology Through the COVID-19 Pandemic From the Heart Rhythm Society and the American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology
Coronavirus disease 2019 has presented substantial challenges to patient care and impacted health care delivery, including cardiac electrophysiology practice throughout the globe. Based upon the undetermined course and regional variability of the pandemic, there is uncertainty as to how and when to resume and deliver electrophysiology services for arrhythmia patients. This joint document from representatives of the Heart Rhythm Society, American Heart Association, and American College of Cardiology seeks to provide guidance for clinicians and institutions reestablishing safe electrophysiological care. To achieve this aim, we address regional and local COVID-19 disease status, the role of viral screening and serologic testing, return-to-work considerations for exposed or infected health care workers, risk stratification and management strategies based on COVID-19 disease burden, institutional preparedness for resumption of elective procedures, patient preparation and communication, prioritization of procedures, and development of outpatient and periprocedural care pathways. (J Am Coll Cardiol EP 2020;6:1053-66)
which has seen great regional variability in surge volumes, incidence curve flattening, and outcomes. As stay-at-home orders are lifted and businesses reopen, concerns remain regarding the prospect of secondary peaks in disease incidence and the possibility of a continuation or expansion of existing restrictions of clinical services. It is likely that the global pandemic will continue to exert significant effects until resistance to the pathogen is developed through vaccination, herd immunity, or discovery of definitive therapy.
The degree to which patient outcomes have been adversely impacted by delaying the delivery of usual cardiac care, due to resource limitations and/or patient reluctance, is not fully understood. Early data have suggested that cardiac patients presenting with a myocardial infarction or experiencing heart failure may be suffering worse outcomes due to delayed presentations [bib_ref] Secondary impact of the COVID-19 pandemic on patients with heart failure, Reza [/bib_ref] [bib_ref] Heart failure in the COVID-19 pandemic: where has all New York's congestion..., Barghash [/bib_ref]. Many chronic diseases and acute medical conditions often require a nonurgent, but time-sensitive, intervention to prevent them from becoming emergencies or having long-term sequelae.
Questions remain as to how long one can delay these nonurgent medical interventions to prevent patients from developing undesirable outcomes. Given these remaining shortcomings and the still undetermined course of the pandemic, there is uncertainty as to how to resume effectively and deliver much-needed electrophysiology (EP) services for non-COVID-19 arrhythmia patients. COVID-19 will continue to coexist and present significant health care delivery challenges. Many patients remain fearful about exposure in health care settings [bib_ref] Secondary impact of the COVID-19 pandemic on patients with heart failure, Reza [/bib_ref].
Creating a relatively COVID-19 safe clinical care continuum and environment is an important strategy that can regain patient confidence and enable health care institutions to start providing elective cardiovascular (7) and EP procedures. "Rebooting" EP at many institutions may be more challenging than
## Covid-19 ep reboot
A U G U S T 2 0 2 0 : 1 0 5 3 - severely affected, where entire hospitals were converted into COVID-19 care units, will likely require a longer time before they will have capacity to provide care for non-COVID-19, nonurgent cases. However, this may be quite different for regions that are less affected and have a significantly lower prevalence and incidence of COVID-19 cases. In general, a significant and sustained drop in local incidence should be observed before health care organizations in areas experiencing a high case level should increase elective medical interventions. The timing and rollout of this process will be dictated by governmental and health system policies. In areas fortunate enough to have avoided a high COVID-19 burden, assiduous attention to ongoing local COVID-19 incidence will be essential to managing the reboot process and the need to respond rapidly if a second wave occurs.
Accordingly, resumption of nonurgent EP services should be approached in a measured and cautious manner. Contingency plans and specific criteria to limit or stop elective cases in the event of a second wave should be predefined in advance of reopening in compliance with local regulations.
## Role of screening and
## Diagnostic viral testing
Testing for COVID-19 infection is a critical tool as we embark on safely restarting elective and semi-elective procedures. Patient screening and diagnostic testing are important tools to limit patient and staff exposure.
However, lack of widespread access to timely and accurate viral testing has been a major limitation from the onset of the pandemic [bib_ref] Overcoming the bottleneck to widespread testing: A rapid review of nucleic acid..., Esbin [/bib_ref] , and there will likely be persistent variations in regional availability of testing, greatly affecting our ability to identify infected individuals, schedule cases, prevent disease transmission, and clarify policies that will minimize the risk of restarting elective procedures. DEVELOPING TESTING POLICIES FOR EP CARE. A major concern inhibiting patients from coming to hospitals is the fear of contracting COVID-19, as both patients and HCWs can be asymptomatic carriers with the potential to infect other patients and health care staff [bib_ref] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV-2), Li [/bib_ref]. The availability and implementation of universal testing policies for patients prior to procedures and for HCWs, as well as universal masking, sanitization, and hand hygiene, can favorably impact confidence.
Institutions will need to define standardized and comprehensive protocols for testing, including testing prior to planned procedures. Electrophysiologists, laboratory managers, and outpatient clinical team leaders should define workflow processes for preprocedure testing and operational plans concordant with hospital and local policies. For many institutions, testing policies will be extensive and include multiple locations, such as clinics, procedural areas (eg, cardiac catheterization laboratory, endoscopy suite, interventional radiology suite, etc), and off-site locations (including drive-through testing). Accommodations to testing will need to be based on a patient's clinical condition, geographic location, inpatient versus outpatient status, type and urgency of intervention, test capability, and local conditions.
Ideally, viral PCR testing should be performed
## Covid-19 ep reboot
A U G U S T 2 0 2 0 : 1 0 5 3 - Postoperative or postprocedure COVID-19 testing may need to be considered in patients who develop symptoms after the procedure is performed. Atelectasis, fever, and volume overload are not uncommon in the postoperative period. Establishing operational guidelines for COVID-19 testing in these patients and management of testing results should be determined.
## Testing and return to work for health care workers
Transmission of COVID-19 to exposed HCWs has been documented. Since a negative test does not preclude subsequent infection, even soon after testing, periodic viral testing for asymptomatic HCWs is not currently a standard approach, but enhanced surveillance of IgG serology. Where available, viral testing should be performed to help determine whether the HCW is in true convalescence without active viral shedding. Some institutions offer serology testing for HCWs, which may suggest exposure to coronavirus, but whether antibodies confer immunity to recurrent infection is unproven.
## Risk stratification and
## Management strategies based on
## Covid-19 disease burden
The ability to perform elective or semi-elective cases is highly dependent on the COVID-19 burden in each region. Regional risk can be categorized based on the severity of disease burden, the state of resource utilization, and projections [fig_ref] FIGURE 3: Framework [/fig_ref] , as follows: 1) high prevalence and incidence, 2) medium prevalence and incidence, and 3) low prevalence and incidence.
These factors could impact whether the health care systems in a region have the capacity to start engaging in elective procedural or medical care. Type of procedures to be restarted (see
[formula] - Urgent/emergent - Urgent/emergent - PrioriƟzed semi-elecƟve, Ɵme- sensiƟve - Urgent/emergent - PrioriƟzed semi-elecƟve, Ɵme-sensiƟve - Semi-elecƟve, [/formula]
## In-person cied interrogation
Depending on the regional stage of the pandemic, local, hospital, and departmental guidance may vary.
In regions with continuing concern for pandemic spread, in order to minimize exposure of EP staff and device manufacturer representatives to patients with
## Covid-19 ep reboot
A U G U S T 2 0 2 0 : 1 0 5 3 - Potential strategies to maintain social distancing include reconfiguring waiting areas and/or notifying patients when it is time for them to be seen. Importantly, device interrogation programmers, cables, and wands should be disinfected between all patients.
Plastic sleeves to cover the cable and wand may also be considered. It may be helpful to inform patients of the disinfecting procedures being systematically performed between visits.
## Remote device monitoring
A current expert consensus statement gives remote monitoring a class I recommendation for routine use in patients with CIEDs (22) based on multiple studies demonstrating reduction of unnecessary ICD therapies and mortality [bib_ref] HRS Expert Consensus Statement on remote interrogation and monitoring for cardiovascular implantable..., Slotwiner [/bib_ref] [bib_ref] Use of remote monitoring of newly implanted cardioverterdefibrillators: Insights from the patient..., Akar [/bib_ref] [bib_ref] Impact of remote monitoring on clinical events and associated health care utilization:..., Piccini [/bib_ref]. Despite its effectiveness, prior to the pandemic, remote monitoring was significantly underutilized due to a variety of patientand system-based issues [bib_ref] Use of remote monitoring of newly implanted cardioverterdefibrillators: Insights from the patient..., Akar [/bib_ref]. During the pandemic, use of remote monitoring is even more important and should be used in most circumstances to reduce the need for nonurgent clinic visits. When feasible, remote monitoring should be reconsidered in patients who are currently not enrolled.
## Creating relatively covid-19 safe ep care pathways
Quality improvement programs and care pathways can help to standardize and support safe, highquality, high-value patient care. Risk-adjusted data can be used to evaluate patient care outcomes. Based on principles discussed, an example of a stepwise care pathway is summarized as follows :
Step 1: Initial consultation for an intervention
## -post-discharge period
Update the workflow based on tes ng availability and na onal, regional, and ins tu onal guidelines
- Preauthoriza on consent and documenta on
## -preopera ve period
## Covid-19 ep reboot
A U G U S T 2 0 2 0 : 1 0 5 3 -6 6
Step 5: Post-discharge period
[fig] Figure 1: illustrates a model for the evolution of detectable virus and virus-specific immunoglobulin during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our current understanding regarding the limitations of these tests and how the timing of results over the course of exposure or infection impacts the interpretation of test results are shown in Figure 2. [/fig]
[fig] FIGURE 2: The Differences Between Polymerase Chain Reaction (PCR) and Serologic Testing as Well as Features and Limitations That Need to Be Understood Prior to Using Them and Incorporating Them Into the Reboot Testing and Workflow [/fig]
[fig] FIGURE 3: Framework [/fig]
[fig] •: Obtain proper consent with paƟents understanding the medical necessity and the risks of COVID-19 infecƟon; this may require documentaƟon in the medical record Be facile to adjust prioriƟzaƟon if incidence rates indicate a second wave(s) High Severity of disease burden Medium Low The ultimate decision regarding the time sensitivity of a procedure is based on clinical judgment and individual patient factors. AF ¼ atrial fibrillation; AFL ¼ atrial flutter; AV ¼ atrioventricular; AVB ¼ atrioventricular block; CHB ¼ complete heart block; CIED ¼ cardiac implantable electronic device; CRT ¼ cardiac resynchronization therapy; CT ¼ computed tomography; EOS ¼ end of service; EP ¼ electrophysiology; ERI ¼ elective replacement indicator; HF ¼ heart failure; ICD ¼ implantable cardioverter defibrillator; LAA ¼ left atrial appendage; PM ¼ pacemaker; PVC ¼ premature ventricular contractions; RVR ¼ rapid ventricular response; SND ¼ sinus node dysfunction; SVT ¼ supraventricular tachycardia; TEE ¼ transesophageal echocardiography; VT ¼ ventricular tachycardia; WPW ¼ Wolff-Parkinson-White. [/fig]
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5ca44ab10012471563476b30b192b37d4fed3187
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pubmed
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Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines☆
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Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines☆
# Introduction
Cachexia remains an underdiagnosed and undertreated, complex condition which includes 'objective' components (e.g. inadequate food intake, weight loss, inactivity, loss of muscle mass and metabolic derangements, inducing catabolism) 1,2 and 'subjective' components (e.g. anorexia, early satiety, taste alterations, chronic nausea, distress, fatigue and loss of concentration). Approximately half of all patients with advanced cancer experience cachexia.
Comprehensive treatment requires a multitargeted and multidisciplinary approach aimed at evaluating the objective signs and relieving the symptoms. The primary goal is to meet the physiological and psychological needs of the patient. This includes providing energy, nutritional substrates and anabolic stimuli, as well as compassionate support to address dysfunctions associated with the emotional and social aspects of eating. Nutritional and metabolic interventions range from dietary counselling to pharmacological agents and parenteral nutrition (PN). The invasiveness of an intervention needs to be chosen and tailored, weighing the benefits and risks for each individual patient. This is of increasing importance with advancing disease and when approaching end of life. In this sense, nutrition is an essential component of supportive, rehabilitative and palliative care. During the patient's trajectory towards end of life, however, the focus of nutritional care needs to change. During anticancer treatment, patients should be offered all available nutritional therapeutic options, if required, whereas during the last weeks of life, care should focus increasingly on immediate symptomatic relief [fig_ref] Figure 1: Invasiveness of interventions relative to expected survival [/fig_ref].
In general, if anticancer treatment is effective, this often results in an improvement in cachectic signs and symptoms, [bib_ref] Effect of chemotherapy on quality of life in patients with non-small cell..., Mannion [/bib_ref] while ineffective anticancer treatment may increase catabolism and aggravate cachexia. [bib_ref] Chemotherapy use, performance status, and quality of life at the end of..., Prigerson [/bib_ref] This European Society for Medical Oncology (ESMO) Clinical Practice Guideline (CPG) on cancer cachexia has been designed for medical oncologists who frequently care for patients with cancer cachexia in their clinical practice. The goal is to provide answers to questions regarding the diagnosis and treatment of cachexia-related physical and psychological problems, relying on evidence-based information whenever possible. A similar approach has recently been published by the American Society of Clinical Oncology (ASCO). [bib_ref] Management of cancer cachexia: ASCO guideline, Roeland [/bib_ref] This CPG provides recommendations on overt cachexia as well as at-risk settings. Evidence to support these recommendations has been derived from trials studying the evolution of the signs and symptoms of cachexia. Whereas today we define cachexia on a pathophysiological basis to be malnutrition in the presence of disease-related metabolic alterations, [bib_ref] Definition and classification of cancer cachexia: an international consensus, Fearon [/bib_ref] [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] [bib_ref] GLIM criteria for the diagnosis of malnutrition e a consensus report from..., Cederholm [/bib_ref] historically, clinical trials used varying and inconsistent combinations of inclusion criteria. A summary of inclusion criteria for all clinical trials, guidelines and systematic review articles reported in this CPG is therefore provided for reference in Supplementary Tables S1, S2 and Supplementary Figures S1AeS1C, available at https://doi. org/10.1016/j.esmoop.2021.100092.
## Recommendations
Regular nutritional screening and nutritional support, including (if necessary) enteral nutrition or PN, is recommended in all patients receiving anticancer treatment and in those with an expected survival of more than a few months . In patients with an expected survival of less than a few months, a decrease in the invasiveness of nutritional interventions is recommended, with dietary counselling and oral supplements preferred, if possible . In patients with an expected survival of less than a few weeks, comfort-directed care is the recommended approach, including alleviating thirst, eating-related distress and other debilitating symptoms .
## Definition and impact of cachexia
Weight loss with depletion of fat stores and muscle mass frequently develop in patients with advanced cancer and may be the first signs leading to the diagnosis of a malignancy. A number of pathophysiological derangements may result in weight loss and several factors often occur at the same time, including impaired food intake, reduction in physical activity and its associated anabolic effects as well as metabolic changes leading to systemic inflammation and activation of catabolism (see [fig_ref] Figure 2: The complexity of causes contributing to weight loss in patients with cancer [/fig_ref]. Patients with depleted resources are at an increased risk of anticancer treatment-related toxicity and a lower quality of life (QoL); toxicity results in shorter treatment times, lower dose intensity, lower response rates, increased surgical complications and higher mortality. [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] Although used since the 19th century, a disconcerting number of definitions have been proposed for the term 'malnutrition'. To avoid confusion, we recommend following the recent suggestion of the Global Leadership Initiative in Malnutrition (GLIM) [bib_ref] GLIM criteria for the diagnosis of malnutrition e a consensus report from..., Cederholm [/bib_ref] that defines malnutrition by the presence of a positive malnutrition screening test, one of a list of phenotypical and one of two aetiological criteria (see [fig_ref] Table 1: Definitions of major terms [/fig_ref]. Aetiological criteria are used to differentiate starvation-type (with protein-sparing metabolism [bib_ref] Starvation in man, Cahill [/bib_ref] from cachexia-type or disease-associated malnutrition, characterised by accelerated protein breakdown and the hallmark of muscle loss driven by metabolic changes, most notably systemic inflammation. [bib_ref] Definition and classification of cancer cachexia: an international consensus, Fearon [/bib_ref] [bib_ref] Adult starvation and diseaserelated malnutrition: a proposal for etiology-based diagnosis in the..., Jensen [/bib_ref] Tissue injury induces inflammation; 12 in cancer, malignant and stromal immune cells may contribute to a chronic inflammatory state 13 leading to complex catabolic sequelae. [bib_ref] Evolutionary medicine and chronic inflammatory state e known and new concepts in..., Straub [/bib_ref] Systemic inflammation has been extensively and reliably associated with poor clinical outcome. A widely validated and simple score to categorise systemic inflammation is the modified Glasgow Prognostic Score, based on C-reactive protein and serum albumin (C-reactive protein normal: 0; raised C-reactive protein and normal albumin: 1; raised C-reactive protein and low albumin: 2). This score is highly prognostic of clinical outcome. [bib_ref] The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients..., Mcmillan [/bib_ref] Thus, the pathophysiology of cachexia is currently understood as host-tumour interactions redirecting metabolism and driving the brain to reduce appetite, cause alterations in taste and smell, impact gastrointestinal (GI) autonomic function, induce fatigue and decrease daily physical activity (see Section 2 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2021.100092). While inadequate food intake is a major driver of weight loss, 7 metabolic changes and reduced activity contribute to loss of muscle mass. [bib_ref] Cancer cachexia: mediators, signaling, and metabolic pathways, Fearon [/bib_ref] More than a few (3-6) months
## Probability of survival focus of care
Less than a few (3-6) months
Less than a few (3-6) weeks During the last decade, low muscle mass (sarcopenia; see definition in [fig_ref] Table 1: Definitions of major terms [/fig_ref] [bib_ref] Sarcopenia: revised European consensus on definition and diagnosis, Cruz-Jentoft [/bib_ref] has been identified as a central factor impacting clinical outcome, and anticancer agents have been recognised as an important cause of sarcopenia. [bib_ref] Chemotherapy-induced sarcopenia, Bozzetti [/bib_ref] In clinical practice, it is highly relevant that loss of muscle strength and muscle mass may appear early and before the occurrence of a clinically apparent weight loss and that it may coexist with obesity and hence be present in patients with a high body mass index (sarcopenic obesity). [bib_ref] Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours..., Prado [/bib_ref] Cachexia may evolve over time and it has been proposed to differentiate early phases without discernible weight loss (pre-cachexia) from advanced or refractory stages 6 (see [fig_ref] Figure 3: Evolution of cancer cachexia [/fig_ref]. In cachectic patients, the most common GI symptoms are anorexia and early satiety, nausea, bloating, taste alterations, xerostomia, dysphagia and constipation. In addition, other secondary nutrition impact symptoms may occur, such as breathlessness, severe fatigue, etc. Nutrition impact symptoms are commonly experienced and are associated with a poor QoL and performance status (PS). 20
## Recommendation
Defining cachexia as disease-related malnutrition based on the GLIM definition of malnutrition and the presence of systemic inflammation is recommended [V, A].
## Screening and assessment of cachexia
To ensure access to adequate nutritional and metabolic care for all patients, it is important to:
Detect at-risk patients by routinely implementing a standardised screening procedure. Assess all at-risk patients for their nutritional and metabolic status as well as all impairments endangering this status. 7
## Malnutrition risk screening
Nutritional risk screening should be carried out regularly in all cancer patients undergoing anticancer treatment and in those with an expected survival of more than a few (i.e. [bib_ref] Effect of chemotherapy on quality of life in patients with non-small cell..., Mannion [/bib_ref] [bib_ref] Chemotherapy use, performance status, and quality of life at the end of..., Prigerson [/bib_ref] [bib_ref] Management of cancer cachexia: ASCO guideline, Roeland [/bib_ref] [bib_ref] Definition and classification of cancer cachexia: an international consensus, Fearon [/bib_ref] months. In patients with an expected survival of less than a few months, screening for eating-related distress should be carried out [fig_ref] Figure 4: Screening and assessment of nutritional and metabolic risk for cachexia [/fig_ref].
While there is no general agreement on the 'best' screening tool, [bib_ref] Nutrition screening tools: does one size fit all? A systematic review of..., Van Bokhorst-De Van Der Schueren [/bib_ref]
## Assessment of nutritional status
All patients diagnosed as being at-risk following malnutrition screening should be referred to a nutrition expert for assessment of nutritional and metabolic status and evaluation of food intake impairment and GI function. [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] Assessing nutritional status should include objective assessment of the following (see [fig_ref] Table 2: Parameters of comprehensive cachexia assessment and recommended tools ADL, activities of daily... [/fig_ref] An assessment of factors that are impeding or that might interfere with maintaining nutritional status should include evaluation of:
Nutrition impact symptoms, such as anorexia, nausea, taste and smell alterations, mucositis, constipation, dysphagia, chronic pain, abdominal pain (e.g. cramping) and diarrhoea, as well as aspects of GI function potentially responsible for these symptoms. Fatigue, physical activity, shortness of breath and psychosocial distress. [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] Assessment should focus on modifiable factors that can be addressed by an intervention. The systematic use of a nutritional impact checklist has been shown to trigger more therapeutic interventions, leading to better symptom control and subsequently to a better nutritional intake. [bib_ref] Nutrition impact symptoms in advanced cancer patients: frequency and specific interventions, a..., Omlin [/bib_ref] Based on these findings, a tailored intervention can be started, including nutritional advice, alleviating nutritional impact factors and targeting any other factors that may hinder an adequate nutritional intake (such as social support or financial difficulties).
## Recommendations
Standardised screening for nutritional risk at regular intervals is recommended for all patients undergoing anticancer treatment and those with a life expectancy of at least a few (i.e. 3-6) months; a validated screening tool should be applied [V, B]. Offering supportive nutritional advice and education about cachexia, as well as psychological and palliative support, is recommended for all patients experiencing eating-related distress [V, B]. Patients found to be at no immediate risk of malnutrition by screening should be re-screened at regular intervals (typically every 3 months or at staging for anticancer treatment) or, in cases where anticancer treatment with a high risk of inducing malnutrition is planned (e.g. combined-modality treatments, high-dose chemotherapy, highly emetogenic agents), prophylactic nutritional support should be considered . For patients identified as being at nutritional risk, an objective assessment of nutritional and metabolic status (including weight, weight loss, body composition, inflammatory state, nutritional intake and physical activity) and examination for the presence of factors interfering with the maintenance or improvement of this status (including nutrition impact symptoms, GI dysfunction, chronic pain and psychosocial distress) is recommended. Repeating nutritional assessments at regular intervals, typically monthly, is also recommended to guide multicomponent anti-cachexia treatment .
## Deciding on cachexia treatment
The relative importance of cachexia-related subjective and objective signs and symptoms may change during the trajectory of the disease; changes in body resources and metabolic pattern as well as impairment of physical performance are essential targets in patients undergoing anticancer treatment, but they lose their importance near end of life. Debilitating symptoms, however, need to be treated
## Esmo open
and alleviated as much as possible throughout the life of every patient with the involvement of his/her family members and caregivers.
Predicting the overall survival (OS) and end of life of individual patients is inherently difficult, inaccurate and often overly optimistic. [bib_ref] Predicting life expectancy in patients with advanced incurable cancer: a review, Krishnan [/bib_ref] Probability estimates (i.e. prediction of
## Is the patient and/or family members experiencing eating-related distress?
Consider a preventive/prophylactic supportive approach Re-screen at least every 3 months
## Is the patient at nutritional risk?
Perform a comprehensive assessment (see [fig_ref] Table 2: Parameters of comprehensive cachexia assessment and recommended tools ADL, activities of daily... [/fig_ref]
## Start a tailored intervention
Individualised nutritional intervention by a nutritionally-trained professional team, alleviation/treatment of nutrition impact symptoms, psychological/social support, (supervised) physical exercise (strength, endurance), consider anticancer treatment
## Yes no
Is the patient planned for anticancer treatment with a high risk of inducing malnutrition?
Nutritional advice, education about cachexia, treat symptoms, offer psychological and palliative support Reassess at weekly intervals the chances of a patient being alive at a certain time point) are more accurate, [bib_ref] Prognostication in advanced cancer: update and directions for future research, Hui [/bib_ref] as are simple scores based on inflammatory markers. [bib_ref] Prognostic tools in patients with advanced cancer: a systematic review, Simmons [/bib_ref] Dealing with uncertainties in prognosis requires continuous, honest and empathic communication with the patient and his/her caregivers as well as comprehensive discussions among all members of the medical team to recognise and repeatedly re-evaluate the indication for individual anticachexia interventions, given that each intervention is associated with different risks and burdens. [fig_ref] Table 3: Criteria to consider when deciding on nutritional and metabolic interventions Ongoing anticancer... [/fig_ref] provides a summary of key criteria to consider when discussing the initiation of nutritional interventions with the patient and family/caregivers.
## Choosing anti-cachexia treatment options: prioritising multimodal care
Given the complex and multifaceted contributors to cachexia, anti-cachexia treatment must be based on a comprehensive assessment of the patient's situation and an evaluation of reasonable, available treatment options, resulting in a personalised, multitargeted and multimodal approach. [bib_ref] Struggling with nutrition in patients with advanced cancer: nutrition and nourishment-focusing on..., Arends [/bib_ref] Food intake may be compromised by many factors and secondary to nutrition impact symptoms, some of which may be amenable to treatment. If, after alleviating these factors, food intake is still inadequate, nutrition-based interventions should be initiated.
Compared with providing energy and nutrients by nutritional interventions, modulating metabolic derangements is more complex. The evolution of insulin resistance [bib_ref] Insulin resistance and body composition in cancer patients, Dev [/bib_ref] and anabolic resistance [bib_ref] Role and potential mechanisms of anabolic resistance in sarcopenia, Haran [/bib_ref] impair the maintenance of wholebody muscle mass. Thus, interventions to decrease catabolism and increase anabolic pathways include the provision of adequate amounts of energy and proteins; muscle training; pharmacological agents to increase appetite, diminish systemic inflammation and stimulate muscle growth; and psychosocial interactions to alleviate distress.
When anticancer treatment is offered to a cachectic patient, in addition to carefully adjusting the dosing, the intensity of multimodal supportive management needs to be enhanced, encompassing nutrition, physical exercise, anti-catabolic and anti-inflammatory treatment, as well as psychological and social support. In the cachectic cancer patient who is physically unfit for further oncological therapy, a key challenge is to decide whether to maintain or reduce the intensity of multimodal supportive management. Nutritional support and physiotherapy may be offered on an individual basis while carefully monitoring individual goals and QoL. During the last weeks of life, it is essential to provide relief from eating-related distress and weight loss-related distress, strategies to cope with impending death and compassionate communication with patients and family.
## Nutritional interventions
In patients undergoing anticancer therapy and/or with an expected survival of at least a few months, ensuring an adequate energy and nutrient intake should be pursued vigorously (see section on nutritional requirements). Cancer patients who cannot eat adequate amounts of food should receive nutritional support as an essential component of best supportive care to improve food intake, BW and QoL. [bib_ref] Oral nutritional interventions in malnourished patients with cancer: a systematic review and..., Baldwin [/bib_ref] [bib_ref] Nutritional advice in older patients at risk of malnutrition during treatment for..., Bourdel-Marchasson [/bib_ref] [bib_ref] Systematic review and meta-analysis of the evidence for oral nutritional intervention on..., De Van Der Schueren [/bib_ref] Nutritional support in patients able to eat should be based on dietary counselling, guidance on choosing highenergy, high-protein foods, enriching foods (e.g. by adding fat/oils, protein powder) and use of oral nutritional supplements (ONSs). If this proves inadequate, tube feeding should be offered if the lower GI tract is working, otherwise PN is the method of choice. Separate routes of feeding may be combined for optimal effect 7 [fig_ref] Figure 5: Choosing nutritional intervention options [/fig_ref]. In patients not receiving anticancer therapy with an expected survival of less than a few months, nutritional interventions with low risks/burdens for the patient (e.g. counselling and ONSs) are preferred. Very few trials have compared different modes or amounts of nutritional support. In one trial, which randomised patients with severely compromised food intake and a limited survival of 1-4 months to supplemental PN or oral feeding, PN did not improve QoL or survival but increased adverse events. [bib_ref] Impact on health-related quality of life of parenteral nutrition for patients with..., Bouleuc [/bib_ref] Similarly, another trial which randomised patients in the end-of-life setting to PN or fluids only showed that PN did not affect median survival. [bib_ref] A randomized phase II study to assess the effectiveness of fluid therapy..., Oh [/bib_ref] During the last weeks of life, nutritional interventions are rarely indicated. [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] Given the potential risks of enteral nutrition and PN (see sections on tube feeding and PN), these interventions should be considered as high-risk compared with low-risk interventions such as counselling and ONSs.
## Nutritional requirements
The aim of nutritional support is to ensure adequate intake of energy and nutrients by enabling the patient to eat normal food, enjoy eating and participate in meals with others as a component of social life. 7 It may be difficult or even impossible to achieve tissue accretion without physical activity and within the context of active systemic inflammation; therefore, these problems need to be addressed simultaneously.
While resting energy expenditure may be increased in cachexia, total energy expenditure is often normal (25-30 kcal/kg BW/day) because of corresponding reductions in physical activity, 7 but may be unpredictably low or high in some patients. [bib_ref] Total energy expenditure in patients with colorectal cancer: associations with body composition,..., Purcell [/bib_ref] Even increased energy and protein intake may not be able to attenuate weight loss in all patients. Given the presence of anabolic resistance in older subjects and in chronic diseases, higher than normal amounts of protein (at least 1.2 and possibly up to 2 g/kg BW/day) may be required to balance protein synthesis. [bib_ref] Is the intravenous supplementation of amino acid to cancer patients adequate? A..., Bozzetti [/bib_ref] [bib_ref] Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer..., Winter [/bib_ref] [bib_ref] Sir David P Cuthbertson lecture. Amino acids and muscle protein metabolism in..., Wolfe [/bib_ref] Fat utilisation in weight-losing cancer patients is very efficient and may cover a major part of resting energy expenditure, [bib_ref] Resting energy expenditure and body composition in patients with newly detected cancer, Cao [/bib_ref] [bib_ref] Increased lipid utilization in weight losing and weight stable cancer patients with..., Körber [/bib_ref] whereas carbohydrate utilisation is impaired in the presence of systemic inflammation and insulin resistance. In addition, fats are energy-dense and allow for feeding of smaller volumes. Compared with standard food, an isonitrogenous, isocaloric, ketogenic diet low in carbohydrates maintains nitrogen balance and whole-body protein turnover rates. [bib_ref] Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism, Fearon [/bib_ref] In a randomised controlled trial (RCT) carried out in malnourished cancer patients, a high-fat diet improved weight control, fat-free mass and body mass compared with normal food. [bib_ref] Effects of a high-fat diet on body composition in cancer patients receiving..., Breitkreutz [/bib_ref]
## Dietary counselling and onss
It is unreasonable to expect an increase or stabilisation in weight if nutritional needs are not met. As a good example, two systematic reviews have shown that dietary counselling is generally effective in increasing dietary intake, BW and QoL in patients undergoing radiotherapy, with some suggestion that dietary counselling may also improve nutrition impact symptoms, complications, response to anticancer treatment and survival. [bib_ref] Nutritional support for head and neck cancer patients receiving radiotherapy: a systematic..., Garg [/bib_ref] [bib_ref] Effect of nutritional interventions on nutritional status, quality of life and mortality..., Langius [/bib_ref] ONSs are a balanced mixture of macro-and micronutrients available as liquid feeds, puddings and powdered formulations reconstituted with milk or water. They are available in a range of different presentations, flavours and formulations, including fibre-containing and milk-, juice-or yoghurt-like products. In general, dietary counselling with ONSs, when necessary, is effective for inducing weight gain and increasing dietary intake. However, most trials on this topic were hampered by poor methodological quality, specifically from inadequate reporting of actual dietary intake and not reaching recommended dietary intakes. [bib_ref] Systematic review and meta-analysis of the evidence for oral nutritional intervention on..., De Van Der Schueren [/bib_ref] [bib_ref] Dietary treatment of weight loss in patients with advanced cancer and cachexia:..., Balstad [/bib_ref] Three systematic reviews reported that providing standard ONSs without dietary counselling was not effective. [bib_ref] Nutritional support for head and neck cancer patients receiving radiotherapy: a systematic..., Garg [/bib_ref] [bib_ref] Effect of nutritional interventions on nutritional status, quality of life and mortality..., Langius [/bib_ref] As such, ONSs are best used as an adjunct to a therapeutic diet and counselling by a professional dietician.A meta-analysis of patients undergoing chemotherapy showed positive effects of dietary counselling on weight gain with or without ONSs. [bib_ref] Systematic review and meta-analysis of the evidence for oral nutritional intervention on..., De Van Der Schueren [/bib_ref] Two systematic reviews focusing on dietary counselling and ONSs in malnourished patients reported positive effects on energy intake, weight gain and some aspects of QoL (e.g. emotional functioning, loss of appetite and global QoL) but noted that evidence was weak due to the poor methodological quality of included trials. [bib_ref] Oral nutritional interventions in malnourished patients with cancer: a systematic review and..., Baldwin [/bib_ref] [bib_ref] A systematic review examining nutrition support interventions in patients with incurable cancer, Blackwood [/bib_ref] In cancer cachexia, n-3 fatty acids have been studied, particularly for their anti-inflammatory properties, and are available as a component of specialised ONSs, usually also enriched in protein (N3P-ONSs). Several randomised trials have been published on the effects of N3P-ONSs in cancer patients. [bib_ref] Systematic review and meta-analysis of the evidence for oral nutritional intervention on..., De Van Der Schueren [/bib_ref] [bib_ref] A systematic review examining nutrition support interventions in patients with incurable cancer, Blackwood [/bib_ref] [bib_ref] Omega-3 supplements for patients in chemotherapy and/or radiotherapy: a systematic review, De Aguiar Pastore Silva [/bib_ref] [bib_ref] Nutritional counseling with or without systematic use of oral nutritional supplements in..., Cereda [/bib_ref] [bib_ref] n-3 PUFAs in cancer, surgery, and critical care: a systematic review on..., Van Der Meij [/bib_ref] Overall, studies were heterogeneous and inadequately powered to show effects on treatment toxicity or survival. No negative effects of the supplements were reported. Most trials suggested benefits of N3P-ONSs on weight, lean body mass and some aspects of QoL when given to patients receiving radiotherapy, chemotherapy or chemoradiotherapy. However, when given to patients not receiving anticancer therapy, no benefit of N3P-ONSs was detected. 51
## Tube feeding
Dysphagia due to obstruction, motility dysfunction or mucosal inflammation may compromise or prevent normal food intake and thus is an indication for tube feeding to circumvent the defect. Patients with head and neck or upper GI cancers are at particular risk of dysphagia due to obstructing tumours as well as severe mucositis induced by aggressive treatment (e.g. combined-modality treatment). It is critical to recognise the emergence of dysphagia early and to respond in a timely and individually appropriate way to safeguard adequate feeding. This may include diagnostic procedures to classify and grade swallowing deficits, involving a speech therapist, specialised dietary counselling and products either via nasogastric tube feeding (NTF) or percutaneous tube feeding [e.g. percutaneous endoscopic gastrostomy (PEG)]. [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] [bib_ref] Nutritional interventions in head and neck cancer patients undergoing chemoradiotherapy: a narrative..., Bossola [/bib_ref] Tube feeding may be associated with potentially serious complications, including mechanical (e.g. tube blockage), GI (e.g. diarrhoea), infectious (e.g. aspiration pneumonia) and metabolic (e.g. refeeding syndrome) complications. [bib_ref] Gastroenteric tube feeding: techniques, problems and solutions, Blumenstein [/bib_ref] Short-term RCTs have shown that the metabolic efficacy and complication rates of enteral nutrition and PN are similar. [bib_ref] Effect of enteral versus parenteral nutrition on outcome of medical patients requiring..., Altintas [/bib_ref] [bib_ref] Enteral and parenteral nutrition in cancer patients, a comparison of complication rates:..., Chow [/bib_ref] As the enteral route is more physiological, safer and less expensive, it represents the first option if there is no severe impairment of GI function [fig_ref] Figure 5: Choosing nutritional intervention options [/fig_ref]. In some
## Esmo open
settings, supplemental PN should be preferred over tube feeding; for example, if patients are suffering from nausea, vomiting, abdominal discomfort or severe diarrhoea. Tube feeding may be ineffective due to frequent dislodging; in particular, tube feeding may not prevent aspirations in patients with dysphagia. Given the lack of reliable clinical evidence of superior outcome for either method, it has been proposed that patient preference be considered when deciding on the feeding method. [bib_ref] Enteral versus parenteral nutrition: the patient's preference, Scolapio [/bib_ref] Some patients strongly prefer an intravenous route over tube feeding, [bib_ref] Enteral versus parenteral nutrition: the patient's preference, Scolapio [/bib_ref] ,57 especially if a patient has already had a central venous catheter inserted.
Results from observational trials and RCTs comparing early tube feeding to oral nutrition in patients with head and neck cancer are heterogeneous, possibly due to the different oral nutrition regimens used in the control groups as well as a lack of stratification of patients by risk scores for malnutrition and dysphagia. [bib_ref] Nutritional support of the oncology patient, Bozzetti [/bib_ref] Appropriate prediction and careful monitoring of food intake in order to identify the need for initiation of enteral feeding are recommended by European and Canadian guidelines. [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] Several RCTs have compared NTF and PEG in head and neck cancer patients requiring nutritional support for 1 month. PEG resulted in better nutritional parameters after 6 weeks of treatment but not later. [bib_ref] Nasogastric and percutaneous endoscopic gastrostomy tube use in advanced head and neck..., Sadasivan [/bib_ref] Meta-analyses have also reported no significant differences in the overall complication rates between NTF and PEG, 62 even though tube dislodgement was more frequent with NTF and dysphagia was more frequent with PEG. [bib_ref] Percutaneous endoscopic gastrostomy versus nasogastric tube feeding for patients with head and..., Wang [/bib_ref] Resolution of dysphagia is impaired with long-term tube feeding.
## Pn
In patients with severely compromised GI function, it may be impossible to ensure adequate nutrition by the oral or enteral route. PN and home PN are being widely used in patients with advanced cancer, both in patients still receiving or no longer receiving anticancer treatments, although evidence to support PN in patients with advanced cancer is weak. 33,64-66 It appears obvious that a prolonged, severely reduced tolerance of food may compromise clinical outcome, and in these settings, PN might improve QoL and possibly survival. A recent systematic review assessing the effectiveness of home PN in people with malignant bowel obstruction included only observational studies, reported a high risk of bias and graded the certainty of evidence to be very low for improving survival and QoL. [bib_ref] Home parenteral nutrition for people with inoperable malignant bowel obstruction, Sowerbutts [/bib_ref] Another systematic review found that PN in patients with advanced cancer was understudied and that the level of evidence was weak. [bib_ref] Effects of current parenteral nutrition treatment on health-related quality of life, physical..., Tobberup [/bib_ref] The PS and Glasgow Prognostic Score impact strongly on survival in patients with advanced cancer receiving home PN. [bib_ref] Performance status, prognostic scoring, and parenteral nutrition requirements predict survival in patients..., Keane [/bib_ref] From this, it has been suggested that PN should be avoided if the ECOG/WHO PS is 3 or 4. [bib_ref] Quality of life and length of survival in advanced cancer patients on..., Bozzetti [/bib_ref] More complex scores and nomograms have been developed to estimate the probability of survival in patients with advanced cancer receiving home PN, e.g. based on Glasgow Prognostic Score, PS, presence of metastatic disease and cancer entity. [bib_ref] Development and validation of a nomogram to predict survival in incurable cachectic..., Bozzetti [/bib_ref] While these tools may separate groups of patients with similar survival, predictions for individual patients are imprecise.
However, absence of evidence is not identical to evidence of absence of an effect, [bib_ref] Absence of evidence is not evidence of absence, Altman [/bib_ref] and a decision to forego the option of intravenous nutrition should not only be based on the lack of high-quality trials. Rather, the decision to initiate PN should be individualised based on the extent of disease, physical and psychological resources of the patient and on a case-by-case risk/benefit assessment (see [fig_ref] Table 3: Criteria to consider when deciding on nutritional and metabolic interventions Ongoing anticancer... [/fig_ref].
PN carries the risk of potentially severe complications, including (but not limited to) catheter-related infection, occlusion and thrombosis, derangements of substrate and electrolyte levels, refeeding syndrome, exsiccosis, fluid overload and chronic hepatopathy and osteopathy. [bib_ref] ESPEN guidelines on chronic intestinal failure in adults, Pironi [/bib_ref] PN may be offered to patients who do not tolerate any oral food or those who still tolerate some but inadequate amounts of oral food. The latter has been termed 'supplemental PN', although there is no agreement on the amount of food tolerated to justify this designation. A number of prospective observational studies have reported the effects of PN in patients with advanced cancer suffering from either severe GI obstruction or malnutrition. [bib_ref] Longitudinal study of quality of life in advanced cancer patients on home..., Cotogni [/bib_ref] [bib_ref] Home parenteral nutrition improves quality of life and nutritional status in patients..., Culine [/bib_ref] [bib_ref] Quality of life and nutrition condition of patients improve under home parenteral..., Girke [/bib_ref] [bib_ref] A longitudinal study investigating quality of life and nutritional outcomes in advanced..., Vashi [/bib_ref] OS was reported as 57%-75% after 1 month, 34%-67% after 3 months and 12%-34% after 6 months, but this was dependent on the type of patients included. [bib_ref] Longitudinal study of quality of life in advanced cancer patients on home..., Cotogni [/bib_ref] [bib_ref] Home parenteral nutrition improves quality of life and nutritional status in patients..., Culine [/bib_ref] [bib_ref] A longitudinal study investigating quality of life and nutritional outcomes in advanced..., Vashi [/bib_ref] Only one of these observational trials reported a small, but not clinically relevant, improvement in QoL. [bib_ref] Home parenteral nutrition improves quality of life and nutritional status in patients..., Culine [/bib_ref] Obling et al. [bib_ref] Home parenteral nutrition increases fat free mass in patients with incurable gastrointestinal..., Obling [/bib_ref] randomised 47 patients with incurable GI cancer to dietary counselling plus either ONSs or supplemental PN. The authors observed improvements in fat-free mass and QoL in favour of the supplemental PN group at 12 weeks but no difference in 6-month survival; however, the statistical analysis was flawed by the very large number of statistical tests carried out. [bib_ref] Home parenteral nutrition increases fat free mass in patients with incurable gastrointestinal..., Obling [/bib_ref] Bouleuc et al. [bib_ref] Impact on health-related quality of life of parenteral nutrition for patients with..., Bouleuc [/bib_ref] randomised 111 patients with advanced cancer to optimised nutritional care with or without additional supplemental PN for several months; supplemental PN did not improve either QoL or survival but increased severe adverse events. Thus, the potential clinical benefit of PN needs to be balanced against relevant risks (e.g. metabolic derangements, septic complications) and burdens (e.g. connection to an intravenous line for up to 14 hours per day). [bib_ref] Impact on health-related quality of life of parenteral nutrition for patients with..., Bouleuc [/bib_ref] None of the published trials reported whether patients were aware of their prognosis or the uncertainty about the benefits of PN.
An open question is how to manage the withdrawal of home PN at end of life. Although there has been no formal study on this issue, clinical experience shows that general criteria to withhold home PN when deemed no longer helpful should be considered early at the time when home PN is first offered and thereafter be discussed repeatedly to minimise distress when it is required to phase out PN at end of life.
## Recommendations
## Nutritional interventions
In patients with inadequate food intake, nutritional interventions are recommended. In patients with an expected survival of more than several months and in those receiving anticancer therapy, these interventions should be escalated, as required. In other situations, low-risk interventions (e.g. counselling and ONSs) are preferred [II, A]. If safe, the oral route should be the first option for nutritional support. Enteral tube feeding may be used in cases of dysphagia if the small bowel function is preserved. PN should be considered if oral intake and tube feeding are not tolerated or remain inadequate [II, A].
## Nutritional requirements
## Dietary counselling and onss
Dietary counselling should be the first choice of nutritional support offered to improve oral intake and possibly weight gain in cachectic or at-risk patients who are able to eat. Dietary counselling should emphasise protein intake, an increased number of meals per day, treatment of nutrition impact symptoms and offering nutritional supplements when necessary. An adequately trained professional should guide this advice . ONSs can be supplied as part of dietary counselling to improve energy intake and induce weight gain [II, B]. Patients receiving chemotherapy, radiotherapy or chemoradiotherapy may be offered N3P-ONSs to increase BW, attenuate loss of lean body mass and improve QoL [II, C].
## Tube feeding
For patients with head and neck or upper GI cancers, especially those undergoing anticancer treatment, tube feeding to maintain BW or to reduce weight loss is recommended if oral feeding including ONSs is expected to remain inadequate for more than a few days [I, A]. In patients requiring >4 weeks of enteral feeding, PEG rather than NTF is recommended [II, C]. In patients requiring tube feeding, screening for and management of dysphagia is recommended along with encouragement and education to patients regarding how to maintain their swallowing function .
## Muscle strength and endurance training to support anabolism
Current evidence shows that physical exercise is safe and provides benefit in QoL and in muscular and aerobic fitness for people with cancer, both during and after treatment. [bib_ref] Exercise for people with cancer: a systematic review, Segal [/bib_ref] However, so far, reviews on exercise in cancer cachexia have generally been narrative or based on animal models. A systematic review and meta-analysis of RCTs focusing on exercise training in cachexia found no trials which met the inclusion criteria. [bib_ref] Exercise for cancer cachexia in adults: executive summary of a Cochrane Collaboration..., Grande [/bib_ref] An RCT comparing 8 weeks of exercise training with usual care in 231 patients with advanced cancer reported improved physical performance but no effect on subjective fatigue. [bib_ref] Physical exercise for cancer patients with advanced disease: a randomized controlled trial, Oldervoll [/bib_ref] However, despite limited robust data, multimodal rehabilitation programmes incorporating exercise and nutritional interventions have been reported to improve many outcomes, most notably those relating to physical endurance and depression scores. [bib_ref] Combined exercise and nutritional rehabilitation in outpatients with incurable cancer: a systematic..., Hall [/bib_ref] While many patients with advanced cancer may drop out of exercise programmes due to progressive disease, when carefully supervised, the intervention appears safe for patients with advanced cancer, even in the hospice setting. [bib_ref] Physical exercise for cancer patients with advanced disease: a randomized controlled trial, Oldervoll [/bib_ref] [bib_ref] Strength in numbers: patient experiences of group exercise within hospice palliative care, Malcolm [/bib_ref] [bib_ref] A randomized phase II feasibility trial of a multimodal intervention for the..., Solheim [/bib_ref] It is suggested that exercise techniques be chosen based on the individual risk of falls and of skeletal instabilities, and to suspend training when patients experience a fever >38 C, infection, platelet count <20 000 g/l, haemoglobin <8 g/dl or if they display other contraindications to exercising. [bib_ref] Multimodal exercise training during myeloablative chemotherapy: a prospective randomized pilot trial, Oechsle [/bib_ref] Exercise has been hypothesised to attenuate the effects of cancer cachexia by modulating muscle metabolism, insulin sensitivity, anaemia, hypogonadism and systemic inflammation. [bib_ref] Understanding the role of exercise in cancer cachexia therapy, Hardee [/bib_ref] Physical activity may increase muscle ESMO Open strength and maintain a patient's functional ability, especially when a combination of moderate-to high-intensity resistance and aerobic exercise is undertaken. [bib_ref] Understanding the role of exercise in cancer cachexia therapy, Hardee [/bib_ref] Exercises of moderate intensity are described as those which fall in between 5-8 metabolic equivalents (METS; a procedure to quantify the energy cost of activities). These include activities that take as much effort as brisk walking (5 km/h), a stationary bike with light effort and home-based exercises. [bib_ref] Metabolic equivalents (METS) in exercise testing, exercise prescription, and evaluation of functional..., Jetté [/bib_ref] Resistance exercises should alternate between upper and lower limbs, focus on movement quality and use defined sets of repetitions. Aerobic training should be accompanied by continuous or intermittent heart rate monitoring.
## Recommendations
When guided by professional experts, moderate physical exercise is safe in patients with cancer cachexia and is recommended to maintain and improve muscle mass . Resistance exercise two to three times per week as well as moderate aerobic (endurance) training should be offered to all patients with cachexia. The exercise prescription should involve a physiotherapist or an adequately trained professional and comprise a structured approach, including mode (aerobic, resistance, flexibility), frequency, intensity and duration as well as defined time points for reassessment [II, B].
## Pharmacological interventions
Several drugs have been investigated for their potential use to treat or ameliorate the consequences of cancer cachexia. However, only corticosteroids and progestins have consistently shown beneficial effects on appetite and/or BW, though at the expense of substantial side-effects, while for other agents, the data are heterogeneous or disappointing.
The following section presents drugs that are approved for clinical use and have shown some anti-cachexia effect in clinical trials.
## Corticosteroids
Corticosteroids include several agents with variable glucocorticoid, mineralocorticoid and anti-inflammatory potency. Prednisolone, methylprednisolone and dexamethasone are used most frequently. Symptomatic relief appears to be mainly achieved by their potent anti-inflammatory activity. [bib_ref] The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights, Coutinho [/bib_ref] Toxicity is usually minor when used for only a few weeks, whereas during prolonged intake, corticosteroids cause a rapid loss of muscle mass, insulin resistance and increased likelihood of infections, such as candida and stomatitis, contributing to a deterioration of cachectic patients. [bib_ref] Glucocorticoid-induced skeletal muscle atrophy, Schakman [/bib_ref] Corticosteroids are recommended for the control of cancer-related fatigue. [bib_ref] Cancer-related fatigue: ESMO Clinical Practice Guidelines for diagnosis and treatment, Fabi [/bib_ref] Several RCTs investigating the effects of corticosteroids on appetite in patients with advanced cancer have been published. Most trials reported a temporary benefit in appetite and well-being, whereas there were no effects on BW or survival. [bib_ref] ESPEN guidelines on nutrition in cancer patients, Arends [/bib_ref] [bib_ref] Systematic review of the treatment of cancer-associated anorexia and weight loss, Yavuzsen [/bib_ref] The antianorectic effect of corticosteroids is transient and often disappears after a few weeks. [bib_ref] Corticosteroid therapy of preterminal gastrointestinal cancer, Moertel [/bib_ref] There are limited data available to recommend one corticosteroid over another.
## Progestins
Medroxyprogesterone acetate and megestrol acetate (MA) have been studied widely to treat weight loss and anorexia in cancer patients. In preclinical models, progestins stimulate appetite and inhibit the synthesis of pro-inflammatory cytokines. A Cochrane review 91 including 23 RCTs on the use of MA in patients with cancer (median duration of 8 weeks) found a significant improvement in appetite (relative risk 2.57) and weight gain (relative risk 1.55). However, no consistent improvement in QoL was observed and no data on muscle mass or physical function were reported. In the analysed trials, MA was used in doses of 160-800 mg/day and weight improvement appeared higher for doses >160 mg/day, while no dose effect was observed for appetite.
Treatment with MA is associated with an increased risk of thromboembolism, fluid retention, adrenal insufficiency and hypogonadism in male patients. [bib_ref] Association between megestrol acetate treatment and symptomatic adrenal insufficiency with hypogonadism in..., Dev [/bib_ref] While the aforementioned Cochrane review reported that MA treatment was associated with an increased mortality rate, [bib_ref] Megestrol acetate for treatment of anorexia-cachexia syndrome, Garcia [/bib_ref] an update concluded that MA does not increase the rates of adverse events or death. [bib_ref] Megestrol acetate for cachexia-anorexia syndrome. A systematic review, Ruiz-García [/bib_ref] Although progestins have been studied in many RCTs, confirming modest stimulation of appetite, their clinical use is limited because of the significant risk of potentially serious side-effects.
## Cannabinoids
Cannabis sativa is a medical plant containing multiple cannabinoids, including tetrahydrocannabinol (THC). Medical cannabis is available in various formulations, e.g. tablets/capsules, vaporiser or mouth spray.
In patients with cancer cachexia, when studied in small trials and case series, THC appeared to improve appetite and attenuate weight loss. However, larger randomised trials comparing THC with either MA 94 or placebo 95 could not detect a significant effect on appetite or QoL; in these trials, toxicity was low. In a small, placebo-controlled, 8week RCT in 47 anorectic patients with advanced nonsmall-cell lung cancer, the synthetic THC derivative, nabilone, resulted in low toxicity but no significant effects on appetite or QoL.Current safety data for medical cannabis in cancer cachexia is based on only a few trials that likely under-dosed patients and so safety concerns remain.
## Androgens
In cancer patients, hypogonadism is related to advanced cancer status, weight loss and, most likely, the use of opioid therapy. Anabolic-androgenic steroids have been shown to ameliorate loss of muscle mass and strength in patients with wasting associated with acquired immune deficiency syndrome. The use of androgens has not been studied extensively in patients with cancer cachexia. In an RCT of 37 lung cancer patients, the analogue nandrolone did not improve BW compared with placebo. [bib_ref] Influence of nandrolone decanoate on weight loss in advanced non-small cell lung..., Chlebowski [/bib_ref] In a three-armed RCT including 496 patients with cachexia, fluoxymesterone 10 mg b.i.d. was significantly inferior to MA 800 mg/day in terms of appetite improvement. [bib_ref] Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment..., Loprinzi [/bib_ref] Olanzapine Olanzapine is an atypical antipsychotic drug acting on multiple receptors, including dopamine and serotonin receptors, both of which are potentially relevant in cachexia. [bib_ref] Treatment of cancer-related anorexia with olanzapine and megestrol acetate: a randomized trial, Navari [/bib_ref] In clinical use, olanzapine causes more weight gain than other antipsychotic drugs. [bib_ref] Weight effects associated with antipsychotics: a comprehensive database analysis, Parsons [/bib_ref] In a single arm, dose escalation study in 39 weight-losing patients with advanced cancer, olanzapine could not attenuate weight loss. [bib_ref] Olanzapine for cachexia in patients with advanced cancer: an exploratory study of..., Naing [/bib_ref] However, in a trial randomising 80 patients with advanced cancer to receive MA or MA and olanzapine, the combination arm yielded significant improvements in appetite and BW. [bib_ref] Treatment of cancer-related anorexia with olanzapine and megestrol acetate: a randomized trial, Navari [/bib_ref] In a recent RCT, olanzapine significantly reduced non-chemotherapy-induced nausea in 30 patients with advanced cancer compared with placebo. [bib_ref] Olanzapine for the treatment of advanced cancer-related chronic nausea and/or vomiting: a..., Navari [/bib_ref] Thus, olanzapine may be considered for treating chronic nausea in patients with advanced cancer.
## Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) block the cyclooxygenase pathways and reduce inflammation by inhibiting prostaglandin production. NSAIDs have been studied to reduce the catabolic drive of systemic inflammation in patients with advanced cancer and cachexia. In a systematic review including six controlled trials and seven observational trials, [bib_ref] Non-steroidal anti-inflammatory treatment in cancer cachexia: a systematic literature review, Solheim [/bib_ref] 11 of these trials reported an increase or stabilisation of BW or lean body mass with few side-effects reported. The cumulative evidence, however, was weak due to the low methodological quality of the analysed trials. Thus, in cachectic patients requiring pain control, NSAIDs could be considered with the potential additional benefit of improving BW.
## Prokinetics
Metoclopramide and domperidone are widely used to treat early satiety and chronic nausea 104 as well as dyspepsia syndrome and gastroparesis. [bib_ref] Clinical guideline: management of gastroparesis, Camilleri [/bib_ref] However, no large RCT has investigated the role of prokinetic agents in cachexia. While one RCT in patients with advanced cancer showed that metoclopramide may improve nausea but not appetite, [bib_ref] A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic..., Bruera [/bib_ref] there are no similar studies with domperidone.
Metoclopramide and domperidone can cause serious, mainly neurological, side-effects, e.g. tardive dyskinesia, spasms, depression, dizziness and urinary retention.
## Ghrelin receptor agonists
Anamorelin has recently been approved in Japan for cancer cachexia in patients with non-small-cell lung cancer, gastric cancer, pancreatic cancer and colorectal cancer, but it is not approved in Europe based on findings from the ROMANO studies which showed a more modest improvement in lean body mass compared with that seen in the Japanese trials.
## Combination therapy
Published trials investigating potential synergies among pharmacological agents like progestins, antioxidants, Lcarnitine, thalidomide, n-3 fatty acids and NSAIDs were unsuccessful or unreliable due to methodological deficiencies. [bib_ref] Randomized phase III clinical trial of five different arms of treatment in..., Mantovani [/bib_ref] [bib_ref] Cancer cachexia: medical management, Mantovani [/bib_ref] Recommendations Corticosteroids may be used to increase appetite for a short period of up to 2-3 weeks. Effects on appetite usually disappear with longer treatment . Progestins may be used to increase appetite and BW, but not muscle mass, QoL or physical function in patients with cancer cachexia . The risk of serious sideeffects, including thromboembolic events, must be considered.
There is insufficient evidence to support the use of medical cannabis or its derivatives to alleviate anorexia or early satiety in patients with cancer cachexia [II, C]. As there is evidence of no beneficial effect in terms of improvement in muscle mass, androgens are not recommended [II, D]. There is moderate evidence to suggest considering the use of olanzapine to treat appetite and nausea in patients with advanced cancer [II, B]. There is insufficient evidence to recommend the use of NSAIDs alone to treat cancer cachexia [III, C]. There is insufficient evidence to recommend the use of metoclopramide or domperidone alone to treat cancer cachexia [II, C]. There is insufficient evidence to recommend specific combination regimens due to the lack of evidence from large, well-designed, randomised trials [II, C].
## Communication with patients and their families
## Addressing cachexia-related psychosocial distress
In the presence of cachexia-related symptoms such as anorexia and fatigue, patients and their families experience stressful changes in eating habits and challenging social interactions. [bib_ref] Psychosocial effects of cancer cachexia: a systematic literature search and qualitative analysis, Oberholzer [/bib_ref] [bib_ref] Fighting a losing battle: eatingrelated distress of men with advanced cancer and..., Strasser [/bib_ref] Patients report wanting and trying to eat but being unable to do so, while family members often misunderstand the complex and powerful derangements responsible for anorexia and food aversion in cachexia and pressure their relative to eat, thus increasing tension and conflict in the patientefamily unit. [bib_ref] The path from oral nutrition to home parenteral nutrition: a qualitative interview..., Orrevall [/bib_ref] [bib_ref] The experience of cancer cachexia: a qualitative study of advanced cancer patients..., Reid [/bib_ref] In addition, continued loss of weight and function alters the patient's appearance with consequences on their self-image and selfesteem. [bib_ref] The experience of cancer cachexia: a qualitative study of advanced cancer patients..., Reid [/bib_ref]
## Esmo open
Early identification of psychosocial distress and the impact of cachexia allows for timely interventions to manage distressing symptoms and improve QoL. [bib_ref] educational and communicative interventions for patients with cachexia and their family carers, Psychosocial [/bib_ref]
## Cachexia-centred communication
Focus groups and semi-structured interviews with 34 Irish health care professionals revealed that doctors, nurses and dieticians tend to avoid the problem of cancer cachexia because of difficulties in communicating its complex and often irreversible nature and negative prognosis, and for fear of lowering the patient's hope. [bib_ref] Healthcare professionals' response to cachexia in advanced cancer: a qualitative study, Millar [/bib_ref] A missed acknowledgement, however, has made family members feel misinformed and isolated. [bib_ref] An exploration of the experience of cancer cachexia: what patients and their..., Reid [/bib_ref] Poor communication by health care professionals may weaken the confidence of patients and families in their knowledge and understanding of cachexia; thus, transparent information is clearly preferred. [bib_ref] An exploration of the experience of cancer cachexia: what patients and their..., Reid [/bib_ref] A large survey (response rate 76%) of 702 bereaved family members of cancer patients in Japan suggested that health care professionals may relieve psychological and emotional distress by explaining the mechanisms of cancer cachexia as simply as possible. [bib_ref] Eating-related distress and need for nutritional support of families of advanced cancer..., Amano [/bib_ref] Tailored information about the role of nutritional support according to the stage of cachexia (see [fig_ref] Figure 3: Evolution of cancer cachexia [/fig_ref] is fundamental to achieving agreement between health care professionals, patients and families on treatment goals. A systematic review including 19 studies investigating eatingrelated distress in patients with cachexia found that the main causes of negative psychosocial effects are a lack of knowledge regarding the nature of cancer cachexia and unsuccessful attempts to increase BW. A structured and informative intervention prevents families from feeling overwhelmed by their loved one's disease and alone in managing weight and eating problems. [bib_ref] The deliverability, acceptability, and perceived effect of the Macmillan approach to weight..., Hopkinson [/bib_ref] These findings suggest that patients and their families need honest and problem-centred communication tailored to the disease stage.
## Psychosocial interventions
The aim of psychosocial interventions is to reduce the emotional burden associated with cancer cachexia by empowering patients and families to cope with the dysfunctions and derangements of cachexia, thus improving QoL. [bib_ref] The deliverability, acceptability, and perceived effect of the Macmillan approach to weight..., Hopkinson [/bib_ref] [bib_ref] Outcomes of a nurse-delivered psychosocial intervention for weight-and eating-related distress in family..., Hopkinson [/bib_ref] [bib_ref] A mixed-methods qualitative research study to develop a complex intervention for weight..., Hopkinson [/bib_ref] Health care professionals can adopt different strategies (e.g. DVDs, stories, open questions) to help patients and families to share their perspectives about foodrelated issues. [bib_ref] A mixed-methods qualitative research study to develop a complex intervention for weight..., Hopkinson [/bib_ref] A small, randomised, exploratory trial evaluating psychosocial intervention on weight and eating-related distress in 50 patients with advanced cancer found that treated patients reported lower levels of distress compared with the control group. [bib_ref] The deliverability, acceptability, and perceived effect of the Macmillan approach to weight..., Hopkinson [/bib_ref] Qualitative analysis suggested that psychosocial intervention was helpful for carers as it provided information, reassurance and support for self-management. [bib_ref] Outcomes of a nurse-delivered psychosocial intervention for weight-and eating-related distress in family..., Hopkinson [/bib_ref] In a small, mixed-methods, qualitative research study, a family-centred psychosocial intervention was developed and delivered by a single nurse researcher to help patients with advanced cancer and their families/caregivers to cope with the patient's involuntary weight loss and worsening appetite. The intervention was delivered during face-to-face consultations and 15 out of 16 patientecaregiver dyads reported benefits. [bib_ref] A mixed-methods qualitative research study to develop a complex intervention for weight..., Hopkinson [/bib_ref]
## Recommendations
Health care professionals should routinely assess patients and their families to permit timely identification of any psychosocial distress [V, B]. Health care professionals should provide tailored information according to the stage of cachexia and empower patients and their families to understand its nature, course and biological mechanisms, and to acknowledge its negative effects (e.g. weight loss, reduced appetite, early satiety), thereby promoting greater awareness about the clinical condition and the need for early multidisciplinary intervention [IV, B]. Psychosocial interventions should be considered as early as possible in cachexia management. They should be conducted by trained health care professionals and aim to help patients and their families to cope with involuntary weight loss and to strengthen the dyadic coping resources [III, B].
## Multimodal treatment
Multimodal interventions against cancer cachexia have been advocated for more than a decade based on the complex underlying pathophysiology [see Section 2 (text and Supplementary [fig_ref] Figure 2: The complexity of causes contributing to weight loss in patients with cancer [/fig_ref] of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop. 2021.100092] and the wealth of contributing factors impacting on BW, muscle mass, food intake and physical function. [bib_ref] Cancer cachexia: developing multimodal therapy for a multidimensional problem, Fearon [/bib_ref] Components of such multimodal support may target calorific intake, physical activity, psychosocial and spiritual functions, as well as key factors in cachexia pathophysiology, such as inflammation. The concept of using synergies of supportive interventions has been described to achieve 'anabolic competence'. [bib_ref] Anabolic competence: assessment and integration of the multimodality interventional approach in disease-related..., Reckman [/bib_ref] Examples of multimodal care in daily clinical practice have been assembled by Maddocks et al. [bib_ref] Practical multimodal care for cancer cachexia, Maddocks [/bib_ref] However, so far, few trials combining separate treatment modalities have been reported; ongoing investigations primarily focus on simultaneously targeting nutritional support, muscle training and anti-inflammatory concepts. Importantly, in healthy subjects, bouts of physical exercise significantly prolong the increase in muscle protein synthesis induced by feeding. [bib_ref] Muscle protein synthesis in response to nutrition and exercise, Atherton [/bib_ref] The randomised, 6-week, MENAC pilot trial compared a multimodal combination of NSAIDs, nutritional advice, oral supplements enriched in eicosapentaenoic acid and physical exercise to standard treatment in 46 patients with solid tumours starting chemotherapy. [bib_ref] A randomized phase II feasibility trial of a multimodal intervention for the..., Solheim [/bib_ref] This trial showed that the intervention improved BW and is now being followed by a phase III trial recruiting patients with lung and pancreatic cancer. Another small trial, randomising 58 patients with advanced cancer to usual care or 12 weeks of an exercise training programme combined with repeated nutritional counselling, showed a significant increase in protein intake and a decrease in nausea and vomiting. [bib_ref] Effects of nutrition and physical exercise intervention in palliative cancer patients: a..., Uster [/bib_ref] Recently, a large RCT including 328 patients with previously untreated metastatic oesophago-gastric cancer received either standard care or additional nutritional and psychological interventions; combined-modality support resulted in improved OS in the intention-to-treat analysis. [bib_ref] Early interdisciplinary supportive care in patients with previously untreated metastatic esophagogastric cancer:..., Lu [/bib_ref]
## Recommendation
In patients with cachexia, combining nutritional support with exercise training and psychological support is proposed . Anti-inflammatory interventions should also be considered [V, C].
## Organising successful cachexia care in modern oncology
Critical points for cachexia care are to implement screening, assessment and treatment in routine cancer care. Initiating and maintaining these efforts, including a quality control process, requires support by the institutional leadership. Evidence for the effectiveness of cachexia clinics is scarce due to a lack of RCTs. [bib_ref] Hypermetabolism and symptom burden in advanced cancer patients evaluated in a cachexia..., Dev [/bib_ref] Extrapolation from pain interventions [bib_ref] Pain management in cancer center inpatients: a cluster randomized trial to evaluate..., Fallon [/bib_ref] or specialised palliative care 129 suggests its potential effectiveness. Typically, a registered dietician, physiotherapist, palliative care nurse, psychologist and a palliative/supportive/rehabilitative care specialistdwho ideally would also be a medical oncologist [bib_ref] Palliative oncologists: specialists in the science and art of patient care, Hui [/bib_ref] dcould build the 'inner circle' of a cachexia clinic or team . A close integration of these professionals within the cancer clinic (e.g. case discussions, tumour boards, clinical rounds, education, clinical trials), as well as access to specialised professionals such as gastroenterologists (e.g. for vent, stent, gastrostomy, jejunostomy), head and neck specialists, logopaedic experts and invasive pain specialists, is highly recommended.
## Recommendations
Screening for cachexia should be integrated into routine cancer care, supported by accountable professionals and
[fig] Figure 1: Invasiveness of interventions relative to expected survival. ONS, oral nutritional supplement. [/fig]
[fig] Figure 2: The complexity of causes contributing to weight loss in patients with cancer. GI, gastrointestinal. [/fig]
[fig] Figure 4: Screening and assessment of nutritional and metabolic risk for cachexia. GI, gastrointestinal; MNA-sf, Mini Nutritional Assessment short form; MST, Malnutrition Screening Tool; MUST, Malnutrition Universal Screening Tool; NRS-2002, Nutrition Risk Screening 2002; PG-SGA, Patient-Generated Subjective Global Assessment; SNAQ, Short Nutritional Assessment Questionnaire. [/fig]
[fig] Figure 3: Evolution of cancer cachexia. Adapted from Fearon et al.6 [/fig]
[fig] Figure 5: Choosing nutritional intervention options. Purple: symptom; turquoise: nutritional interventions; white: other aspects of management. EN, enteral nutrition; GI gastrointestinal; NTF, nasogastric tube feeding; ONS, oral nutritional supplement; PEG, percutaneous endoscopic gastrostomy; PN, parenteral nutrition. [/fig]
[fig] PN: Home should be offered to patients if their QoL and/ or length of survival is expected to be severely compromised by progressive malnutrition. Indicators of a potential benefit are ECOG/WHO PS 0-2, a low level of systemic inflammation (normal levels of serum albumin, modified Glasgow Prognostic Score <2) and the absence of metastatic disease [V, B]. There is insufficient evidence to routinely recommend supplemental in hypophagic, malnourished patients receiving chemotherapy to improve QoL and nutrition parameters [V, B]. [/fig]
[table] Table 1: Definitions of major terms [/table]
[table] Table 2: Parameters of comprehensive cachexia assessment and recommended tools ADL, activities of daily living; BIA, bioelectrical impedance analysis; BW, body weight; CT, computed tomography; DEXA, dual X-ray absorptiometry; ECOG, Eastern Cooperative Oncology Group; ESAS, Edmonton Symptom Assessment System; EORTC, European Organisation for Research and Treatment of Cancer; FAACT, Functional Assessment of Anorexia/Cachexia Treatment; GI, gastrointestinal; PG-SGA, Patient-Generated Subjective Global Assessment; PS, performance status; QLQ-CAX24, cachexia-specific quality of life questionnaire; WHO, World Health Organization. a If available and appropriate, depending on resources available and the patient's capability. [/table]
[table] Table 3: Criteria to consider when deciding on nutritional and metabolic interventions Ongoing anticancer treatment Approaching end of life No or only minimal inflammation or inflammation responsive to treatment Persistent, severe and unresponsive inflammation No or only slow and mild weight loss Rapid and severe weight loss refractory to anticancer treatment Stable or only slowly progressing cancer Rapidly progressing cancer without reasonable treatment options Good chance of intervention to improve the patient's well-being No realistic chance that the intervention will improve the situation of the patient Patient is aware of the prognosis and of the positive/negative effects of the intervention Patient is not fully aware of the prognosis or the positive/negative effects of the intervention Strong wish of the patient to accomplish or reach an individual goal Patient is preparing for dying Patient is motivated and feels very little inconvenience considering the planned nutritional intervention Patient feels the nutritional intervention to be burdensome and is unmotivated/unwilling to start the intervention Patient is able and motivated to be physically active Immobilised patient without urge to be or to become active Severely impaired food tolerance Only mildly impaired food intake ESMO Open Every patient with cachexia should be offered interventions with the goal of either improving or alleviating the consequences of cachexia [II, B]. Cachexia treatment requires a multimodal approach aimed at relieving symptoms impacting on food intake, ensuring adequate energy and nutrient intake, minimising catabolic alterations, supporting muscle training and offering psychological and social support [II, B]. During anticancer treatment and in patients with a life expectancy of more than a few (i.e. 3-6) months, interventions to both antagonise deterioration of body resources and metabolism, and to alleviate debilitating symptoms, are recommended [IV, B]. If expected survival is less than a few (i.e. 3-6) weeks, focussing on anti-cachexia interventions aimed at alleviating distressing symptoms like thirst, nausea, vomiting and dysphagia, and psychological and existential distress, as well as distress to family members, is recommended [IV, B]. In situations where it is difficult to decide on appropriate anti-cachexia intervention strategies, a tentative intervention for a limited period may be considered to evaluate the likelihood of improvement [IV, C]. [/table]
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American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS–CoV‐2 and Hyperinflammation in Pediatric COVID‐19: Version 1
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American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS–CoV‐2 and Hyperinflammation in Pediatric COVID‐19: Version 1
Objective. To provide guidance on the management of multisystem inflammatory syndrome in children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. Methods. A multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting.Results. The ACR task force approved a total of 128 guidance statements addressing the management of MIS-C and hyperinflammation in pediatric COVID-19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS-C.Conclusion. Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The guidance provided in this "living document" reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available.
# Introduction
Since its initial description in December 2019 in Wuhan, China, coronavirus disease 2019 , caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly evolved into a worldwide pandemic affecting millions of lives [bib_ref] An interactive web-based dashboard to track COVID-19 in real time, Dong [/bib_ref]. Unlike adults, the vast majority of children with COVID-19 have mild symptoms. However, there are children who have significant respiratory disease, and some children may develop a hyperinflammatory response similar to what has been observed in adults with COVID-19. Furthermore, in late April 2020, reports emerged of children with a different clinical syndrome resembling Kawasaki disease (KD) and toxic shock syndrome; these patients frequently had evidence of prior exposure to SARS-CoV-2. Subsequent to these initial reports from Italy and the United Kingdom, multiple case series from Europe and the United States have surfaced describing a similar phenomenon [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref]. While this constellation of symptoms has been given many names, for the purposes of this discussion we refer to it as "multisystem inflammatory syndrome in children" (MIS-C).
For a number of reasons, there is an urgent need to provide guidance to healthcare providers in the evaluation of patients in whom MIS-C is a diagnostic consideration. These reasons include the fact that 1) case definitions for MIS-C are variable, 2) clinical descriptions of MIS-C are limited to case series,clinical features of MIS-C may also be seen in other infections and malignant entities and in other rheumatic diseases in childhood, 4) suggested treatment strategies have relied on extrapolation from other inflammatory or rheumatic conditions with similar clinical presentations, and 5) myocardial dysfunction may present insidiously but is a major source of morbidity and mortality in MIS-C. In addition, pediatric rheumatologists are often asked to recommend immunomodulatory therapy for patients developing hyperinflammation as a result of acute SARS-CoV-2 infection. Therefore, the American College of Rheumatology (ACR) convened the MIS-C and COVID-19-Related Hyperinflamma-tion Task Force on May 22, 2020, which was charged by ACR leadership to provide guidance to clinicians in the evaluation and management of MIS-C and COVID-19-related hyperinflammatory syndromes in children. Clinical guidance generated from this effort is intended to aid in the care of individual patients, but it is not meant to supplant clinical decision-making. Modifications to treatment plans, particularly in patients with complex conditions, are highly disease-, patient-, geography-, and time-specific, and therefore must be individualized as part of a shared decision-making process.
# Methods
Task force. Panelists were selected by the task force leadership (LAH and JJM) based on their clinical expertise in rheumatology, infectious diseases, cardiology, cytokine storm-related syndromes, and KD, as well as experience in managing MIS-C and hyperinflammation in acute SARS-CoV-2 infection. The multidisciplinary task force was composed of clinicians from the United States and Canada and included 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. All individuals who were approached to develop this guidance agreed to participate.
Prior to the first meeting, task force members were subdivided into 4 work groups to address the following clinical topics related to MIS-C and hyperinflammation in COVID-19: 1) diagnostic evaluation of MIS-C (led by SKL); 2) cardiac management of MIS-C (led by KGF); 3) treatment of MIS-C (led by MG); and 4) management of hyperinflammation in COVID-19 (led by SWC). During the first webinar on May 22, 2020, participants agreed with the importance of addressing these 4 overarching topics and the structure of the work groups. The first webinar was used to confirm the target audience for the guidance, which focuses on clinicians in North America managing inflammatory syndromes in children related to recent or concurrent infections with SARS-CoV-2. Notably, the task force deliberately did not attempt to create a new case definition for MIS-C, as several already exist [fig_ref] Table 1: Case definitions of MIS-C* [/fig_ref]. Instead, the task force elected to leverage consensus building to identify the most appropriate diagnostic and therapeutic steps that providers should consider at the present time. All panelists agreed to develop consensus through a modified Delphi process, which involved 2 rounds of asynchronous, anonymous voting and 2 webinars to discuss voting results.
Evidence review. From May 22 to May 29, 2020, the work groups developed preliminary recommendation statements within their assigned topic, based on expert opinion and evidence reviewed from publications listed in PubMed, scientific briefings from the World Health Organization, health alerts from the Centers for Disease Control and Prevention (CDC), and guidance provided by the Royal College of Paediatrics and Child Health. Each work group generated an evidence report supporting the recommendations, which was shared with the entire task force.
Voting. Round 1. The task force voted virtually and anonymously using the RAND/University of California at Los Angeles (UCLA) Appropriateness Method [bib_ref] US Agency for Health Care Policy and Research Office of the Forum..., Brook [/bib_ref]. A 9-point scale was used by panelists to rate the appropriateness of each of the statements. A score of 9 was considered to be the highest level of appropriateness, while a score of 1 indicated that the statement was entirely inappropriate. Prior to voting, median scores of 1-3 were defined as inappropriate, 4-6 as uncertain, and 7-9 as appropriate. Consensus was prespecified as high if all 16 votes coalesced within the same tertile, while low consensus was recognized when voting was dispersed widely along the 9-point scale (with ≥5 votes in the 1-3 score range and ≥5 votes in the 7-9 score range). Moderate consensus encompassed all other scenarios. The votes of each task force member were counted equally and tallied. The results of the initial voting were distributed to the task force and reviewed during a 90-minute webinar on June 4, 2020. Statements that were rated as uncertain (median score 4-6) and/or characterized by moderate or low consensus were addressed first. The panelists were then encouraged to discuss the remaining statements. Round 2. Input from the initial voting and discussion was incorporated (by LAH and JJM) into the draft guidance statements, and the document was redistributed to the entire task force for a second round of voting. Voting in this phase was conducted in the same manner as described above, and results were reviewed at a third webinar on June 10, 2020. Guidance statements that earned a median score of 7-9 with moderate or high levels of consensus were approved by the panel.
Guidance approval. Following the final webinar, approved statements were refined and, in some instances, combined to reduce redundancy. A preliminary guidance document was generated, and the entire task force was given an opportunity to review and edit the document. Approval was obtained from each panelist on June 14, 2020 and by the ACR Board of Directors on June 17, 2020. After further review, the authors decided to include measurement of C-reactive protein (CRP) levels in the laboratory evaluation of hyperinflammation in severe COVID-19 , and the entire task force then voted again on the guidance statements and approved the modifications to this recommendation statement.
# Results
In the first round of voting, the task force evaluated a total of 125 statements that addressed the management of MIS-C and hyperinflammation in pediatric patients with COVID-19. Of these, 112 statements met the criteria for approval, with a median score for appropriateness of 7-9 and with moderate or high consensus, while 13 statements were rated as uncertain (median score. After refining the statements based on the input from the initial phase, 128 guidance statements were approved in the second round of voting (see [fig_ref] Table 1: Case definitions of MIS-C* [/fig_ref] the Arthritis & Rheumatology website at http://onlin elibr ary.wiley. com/doi/10.1002/art.41454/ abstract). These statements were organized into 40 final guidance statements as well as a flow diagram depicting the diagnostic pathway for MIS-C [fig_ref] Figure 1: Diagnostic pathway for multisystem inflammatory syndrome in children [/fig_ref] , which were approved by the entire task force and the ACR Board of Directors. Topics covered in the guidance include the following: 1) diagnostic evaluation of MIS-C (Table 2 and [fig_ref] Figure 1: Diagnostic pathway for multisystem inflammatory syndrome in children [/fig_ref] ; 2) comparing and contrasting features of MIS-C and KD ; 3) cardiac management of MIS-C ; 4) treatment of MIS-C ; and 5) hyperinflammation in COVID-19 .
Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The recommendations provided by the task force reflect expert opinion and currently available evidence, which is of low quality and based on a limited number of case series and retrospective cohort studies. Thus, this guidance is meant to be a "living document" and will be modified as additional data become available. The recommendations provided in the guidance document do not replace the importance of clinical judgment tailored to the unique circumstances of an individual patient. . Diagnostic evaluation of MIS-C*
# Guidance statement
Level of consensus
The vast majority of children with COVID-19 present with mild symptoms and have excellent outcomes. MIS-C remains a rare complication of SARS-CoV-2 infections.
High MIS-C is temporally associated with SARS-CoV-2 infections. Therefore, the prevalence of the virus in a given geographic location, which may change over time, should inform management decisions.
## Moderate
A child "under investigation" for MIS-C should also be evaluated for other possible infections and non-infectionrelated conditions (e.g., malignancy) that may explain the clinical presentation.
## High
Patients "under investigation" for MIS-C may require additional diagnostic studies (not described in [fig_ref] Figure 1: Diagnostic pathway for multisystem inflammatory syndrome in children [/fig_ref] , including, but not limited to, imaging of the chest, abdomen, and/or central nervous system and lumbar puncture.
## High
Outpatient evaluation for MIS-C may be appropriate for assessing well-appearing children with stable vital signs and for ensuring that physical examinations provide close clinical follow-up.
## Moderate
Patients "under investigation" for MIS-C should be considered for admission to the hospital for further observation while the diagnostic evaluation is completed, especially if the patient displays any of the following symptoms: 1. abnormal vital signs (tachycardia, tachypnea); 2. respiratory distress of any severity; 3. neurologic deficits or change in mental status (including subtle manifestations); 4. evidence of even mild renal or hepatic injury; 5. marked elevations in inflammation markers (CRP ≥10 mg/dl); 6. abnormal EKG findings or abnormal levels of BNP or troponin T.
## Moderate to high
Patients presenting with shock, significant respiratory distress, neurologic changes (altered mental status, encephalopathy, focal neurologic deficits, meningismus, papilledema), dehydration, or features of KD should be admitted for further evaluation, regardless of MIS-C status, in accordance with standard of care.
## High
Children admitted to the hospital with MIS-C should be managed by a multidisciplinary team that includes pediatric rheumatologists, cardiologists, infectious disease specialists, and hematologists. Depending on the clinical manifestations, other subspecialties may need to be consulted as well; these include, but are not limited to, pediatric neurology, nephrology, hepatology, and gastroenterology. Diagnostic evaluation of MIS-C. Maintaining a broad differential diagnosis. Multiple case definitions of MIS-C have been proposed (4-6), some of which are broader than others [fig_ref] Table 1: Case definitions of MIS-C* [/fig_ref]. Common clinical features of MIS-C include fever, mucocutaneous findings (rash, conjunctivitis, edema of the hands/feet, red/cracked lips, and strawberry tongue), myocardial dysfunction, cardiac conduction abnormalities, shock, gastrointestinal symptoms, and lymphadenopathy [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] COVID-19 associated pediatric multi-system inflammatory syndrome, Leon [/bib_ref] [bib_ref] Septic shock presentation in adolescents with COVID-19 [letter, Dallan [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref] [bib_ref] SARS-CoV-2-induced Kawasaki-like hyperinflammatory syndrome: a novel COVID phenotype in children, Licciardi [/bib_ref]. There are also increasing reports of neurologic involvement, manifesting as severe headache, altered mental status, cranial nerve palsies, or meningismus, in select patients [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref]. These findings are nonspecific and can also occur in other types of infections and in noninfection-related conditions such as malignancy or inflammatory conditions. Therefore, it is imperative that a diagnostic evaluation for MIS-C include investigation for other possible causes, as would be deemed appropriate by the treating provider. MIS-C is temporally associated with SARS-CoV-2 infections, and clusters of cases have been reported in geographic areas with dense COVID-19 disease burden, typically being found to emerge within 2-6 weeks after the peak incidence of acute, infectious COVID-19 [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. Thus, the prevalence and chronology of SARS-CoV-2 infection in a given location, which may change over time, should also inform the diagnostic evaluation.
The incidence of MIS-C is unknown; however, it appears to be a rare complication of SARS-CoV-2 infection, with some estimates indicating that MIS-C occurs in 2 of 200,000 individuals <21 years old [bib_ref] Multisystem inflammatory syndrome in children in New York State, Dufort [/bib_ref]. The relative rarity of MIS-C should also be considered in the diagnostic approach. . Moderate-to-high consensus was reached by the task force in the development of this diagnostic pathway for MIS-C associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). [bib_ref] An interactive web-based dashboard to track COVID-19 in real time, Dong [/bib_ref] An epidemiologic link to SARS-CoV-2 infection is defined as a child with any of the following criteria: positive for SARS-CoV-2 by polymerase chain reaction (PCR), positive for SARS-CoV-2 by serology, preceding illness resembling coronavirus disease 2019 (COVD- [bib_ref] Multisystem inflammatory syndrome in children in New York State, Dufort [/bib_ref] or close contact with an individual with confirmed or suspected COVID-19 in the past 4 weeks. [bib_ref] Hyperinflammatory shock in children during COVID-19 pandemic, Riphagen [/bib_ref] Suggestive clinical features include rash (polymorphic, maculopapular, or petechial, but not vesicular), gastrointestinal symptoms (diarrhea, abdominal pain, or vomiting), oral mucosal changes (red and/or cracked lips, strawberry tongue, or erythema of the oropharyngeal mucosa), conjunctivitis (bilateral conjunctival infection without exudate), and neurologic symptoms (altered mental status, encephalopathy, focal neurologic deficits, meningismus, or papilledema).The complete metabolic panel (CMP) includes measurement of sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, glucose, calcium, albumin, total protein, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin.Procalcitonin and cytokine panel results should be sent, if available.Serologic test results should be sent if not sent in tier 1 evaluation, and if possible, SARS-CoV-2 IgG, IgM, and IgA test results should be sent. CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; ALC = absolute lymphocyte count; CBC = complete blood cell count; BNP = B-type natriuretic peptide; PT = prothrombin time; PTT = partial thromboplastin time; LDH = lactate dehydrogenase; u/a = urinalysis; EKG = electrocardiogram.
Tier 1 screening. Based on our review of the literature and diagnostic algorithms that are publicly available, the task force chose to cast a broad net with respect to the evaluation of patients with possible MIS-C, while simultaneously balancing the need to reduce indiscriminate overtesting and to prevent unnecessary use of resources in the treatment of pediatric patients who have unrelated causes of fever [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] COVID-19 associated pediatric multi-system inflammatory syndrome, Leon [/bib_ref] [bib_ref] Septic shock presentation in adolescents with COVID-19 [letter, Dallan [/bib_ref] [bib_ref] COVID-19 associated multisystem inflammatory syndrome in children (MIS-C) guidelines: a western New..., Hennon [/bib_ref]. To date, there are no clear data indicating the pretest positive predictive or negative predictive probabilities for each clinical symptom or laboratory value in diagnosing MIS-C. It should be noted that due to the paucity of data, our recommendations reflect a multidisciplinary consensus that is likely to be revised as novel data become available.
Children with fever and epidemiologic link to SARS-CoV-2 and whose clinical symptoms are suggestive of SARS-CoV-2 infection should be considered "under investigation" for MIS-C, while alternative diagnoses that could explain the patient's clinical presentation are also explored [fig_ref] Figure 1: Diagnostic pathway for multisystem inflammatory syndrome in children [/fig_ref]. A tiered diagnostic approach is recommended in patients without life-threatening manifestations; this includes performing an initial screening evaluation (tier 1), and thereafter proceeding to a complete diagnostic evaluation (tier 2) only in patients with laboratory results from the tier 1 screening that are concerning. Tier 1 consists of laboratory studies that are easily obtained at most clinical facilities (complete blood cell count with manual differential, complete metabolic panel, erythrocyte sedimentation rate [ESR], CRP measurement, and testing for SARS-CoV-2 by polymerase chain reaction or serology). The overwhelming majority of MIS-C cases reported in the literature display elevations in inflammation markers, particularly the CRP level as values higher than 10 mg/dl or even 20 mg/dl are common [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. Thus, to enter the second stage of testing, children should have elevated ESR and/or CRP and at least 1 other suggestive laboratory feature: lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, or hypoalbuminemia [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. . Comparing and contrasting features of MIS-C and KD*
# Guidance statement
Level of consensus
Patients with KD that is unrelated to SARS-CoV-2 will continue to require evaluation, diagnosis, and treatment during the SARS-CoV-2 pandemic.
High MIS-C and KD unrelated to SARS-CoV-2 infections may share overlapping clinical features, including conjunctival infection, oropharyngeal findings (red and/or cracked lips, strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy.
## Moderate to high
Several epidemiologic, clinical, and laboratory features of MIS-C may differ from KD unrelated to SARS-CoV-2 in the following ways: 1. There is an increased incidence of MIS-C in patients of African, Afro-Caribbean, and possibly Hispanic descent, but a lower incidence in those of East Asian descent. 2. Patients with MIS-C encompass a broader age range, have more prominent GI and neurologic symptoms, present more frequently in a state of shock, and are more likely to display cardiac dysfunction (arrhythmias and ventricular dysfunction) than children with KD. 3. At presentation, patients with MIS-C tend to have lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels than patients with KD.
## Moderate to high
It is unknown if the incidence of CAAs is different in MIS-C compared to KD; however, MIS-C patients without KD features can develop CAAs.
Moderate to high * MIS-C = multisystem inflammatory syndrome in children; KD = Kawasaki disease; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; GI = gastrointestinal; CRP = C-reactive protein; CAAs = coronary artery aneurysms. . Cardiac management of MIS-C*
## Guidance statement level of consensus
Patients with MIS-C and abnormal BNP and/or troponin T levels at diagnosis should have these laboratory parameters trended over time until they normalize.
## High
EKGs should be performed at a minimum of every 48 hours in MIS-C patients who are hospitalized and during follow-up visits. If conduction abnormalities are present, patients should be placed on continuous telemetry while in the hospital, and Holter monitors should be considered during follow-up.
## Moderate to high
Echocardiograms conducted at diagnosis and during clinical follow-up should include evaluation of ventricular/valvar function, pericardial effusion, and coronary artery dimensions with measurements indexed to body surface area using z-scores.
## High
Echocardiograms should be repeated at a minimum of 7-14 days and 4-6 weeks after presentation. For those patients with cardiac abnormalities occurring in the acute phase of their illness, an echocardiogram 1 year after MIS-C diagnosis could be considered. Patients with LV dysfunction and/or CAAs will require more frequent echocardiograms.
## Moderate to high
Cardiac MRI may be indicated 2-6 months after MIS-C diagnosis in patients who presented with significant transient LV dysfunction in the acute phase of illness (LV ejection fraction <50%) or persistent LV dysfunction. Cardiac MRI should focus on myocardial characterization, including functional assessment, T1/T2-weighted imaging, T1 mapping and extracellular volume quantification, and late gadolinium enhancement.
## High
Cardiac CT should be performed in patients with suspected presence of distal CAAs that are not well seen on echocardiogram.
Moderate * MIS-C = multisystem inflammatory syndrome in children; BNP = B-type natriuretic peptide; EKG = electrocardiogram; LV = left ventricular; CAAs = coronary artery aneurysms; MRI = magnetic resonance imaging; CT = computed tomography.
## | 1797
Tier 2 evaluation. Tier 2 encompasses more complex testing that typically requires additional time to complete. Reports in the literature and unpublished observations by members of the panel both note that some patients with MIS-C can decompensate rapidly; however, the risk factors that predispose patients to such severe and progressive illness have not been identified [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref]. Accordingly, children with abnormal vital signs, concerning physical examination findings, significantly elevated levels of inflammation markers, or signs of cardiac involvement will need to be admitted to the hospital for supportive care, during which time tier 2 testing should be completed.
The panel also noted that MIS-C appears to be a continuum of disease that encompasses milder phenotypes, none of which have been fully described in the published literature. Some patients present with fever, rash, and systemic inflammation and no other organ damage. While these children require close monitoring, they do not always need to be hospitalized. Thus, in some cases, well-appearing children with reassuring vital signs and physical examination findings may be suitable for outpatient diagnostic evaluations, as long as close clinical follow-up can be ensured.
Prominent cardiac involvement has been reported in a proportion of MIS-C patients in every retrospective cohort study published to date [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. These include left ventricular (LV) dysfunction, coronary artery dilation or coronary artery aneurysm (CAA), and electrical conduction abnormalities. Valvular dysfunction and pericardial effusion are less frequently described. Among the initial descriptions of MIS-C, LV dysfunction was present in 20-55% of cases, and coronary artery dilation or CAA in ~20% [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref]. Although the early reports may overestimate the incidence of cardiac features-as they likely represent the most severe component of the MIS-C spectrum-these numbers . Immunomodulatory treatment in MIS-C*
# Guidance statement
Level of consensus
Patients "under investigation" for MIS-C without life-threatening manifestations should undergo diagnostic evaluation for MIS-C, as well as other possible infections and non-infection-related conditions, before immunomodulatory treatment is initiated.
## Moderate
Patients "under investigation" for MIS-C with life-threatening manifestations may require immunomodulatory treatment for MIS-C before the full diagnostic evaluation can be completed.
## High
After evaluation by specialists with expertise in MIS-C, some patients with mild symptoms may only require close monitoring without immunomodulatory treatment. The panel noted uncertainty around the empiric use of IVIG to prevent CAAs in this setting.
## Moderate
A stepwise progression of immunomodulatory therapies should be used to treat MIS-C with IVIG and/or glucocorticoids considered as first-tier treatments.
## Moderate to high
High-dose IVIG (typically 1-2 gm/kg) may be considered for treatment of MIS-C. Cardiac function and fluid status should be assessed in MIS-C patients with shock before IVIG treatment is provided, and IVIG should be administered when cardiac function is restored.
## Moderate to high
Low-to-moderate doses of glucocorticoids may be considered for treatment of MIS-C. High-dose IV pulse glucocorticoids may be considered to treat patients with life-threatening complications, such as shock, and specifically, if a patient requires high-dose or multiple inotropes and/or vasopressors.
## Moderate to high
Anakinra (IV or SC) may be considered for treatment of MIS-C refractory to IVIG and glucocorticoids or in patients with contraindications to these treatments.
## Moderate to high
Serial laboratory testing and cardiac assessment should guide the immunomodulatory treatment response and tapering. Patients will often require a 2-3-week taper of immunomodulatory medications.
## High
* MIS-C = multisystem inflammatory syndrome in children; IVIG = intravenous immunoglobulin; CAAs = coronary artery aneurysms; SC = subcutaneous. . Antiplatelet and anticoagulation therapy in MIS-C*
## Guidance statement level of consensus
Low-dose aspirin (3-5 mg/kg/day; maximum 81 mg/day) should be used in patients with MIS-C and KD-like features and/or thrombocytosis (platelet count ≥450,000/μl) and should be continued until the platelet count is normalized and normal coronary arteries are confirmed at ≥4 weeks after diagnosis. Treatment with aspirin should be avoided in patients with a platelet count of ≤80,000/μl.
Moderate MIS-C patients with CAAs and a maximal z-score of 2.5-10.0 should be treated with low-dose aspirin. Patients with a z-score of ≥10.0 should be treated with low-dose aspirin and therapeutic anticoagulation with enoxaparin (factor Xa level 0.5-1.0) or warfarin.
## Moderate to high
Patients with MIS-C and documented thrombosis or an EF of <35% should receive therapeutic anticoagulation with enoxaparin until at least 2 weeks after discharge from the hospital.
## High
Indications for longer outpatient therapeutic enoxaparin dosing include the following: CAAs with a z-score of >10.0 (indefinite treatment), documented thrombosis (treatment for ≥3 months pending thrombus resolution), or ongoing moderate-to-severe LV dysfunction.
## High
For MIS-C patients who do not meet the above criteria, the approach to antiplatelet and anticoagulation therapeutic management should be tailored to the patient's risk for thrombosis. nonetheless highlight the significant risk of cardiac involvement in MIS-C. For these reasons, electrocardiogram (EKG) and echocardiogram are key testing components of the full diagnostic evaluation. The echocardiogram should include quantification of LV size and systolic function using end-diastolic volume (and z-score) and ejection fraction (EF) [bib_ref] Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for..., Mccrindle [/bib_ref]. Detailed evaluation of all coronary artery segments and normalization of coronary artery measurements to body surface area using z-scores is necessary [bib_ref] Recommendations for quantification methods during the performance of a pediatric echocardiogram: a..., Lopez [/bib_ref]. Cardiac laboratory values at the time of diagnosis, specifically levels of troponin T and B-type natriuretic peptide (BNP)/N-terminal proBNP (NT-proBNP), may help identify patients with cardiac sequelae resulting from MIS-C (7-9,13,14,17). In particular, highly elevated BNP/NT-proBNP levels may be helpful in distinguishing between MIS-C patients with and those without LV dysfunction; however, mild and transient elevations in these laboratory parameters are likely nonspecific and not necessarily indicative of cardiac involvement [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Assessment of B-type natriuretic peptide in patients with pneumonia, Yetkin [/bib_ref] [bib_ref] A pilot study of the association of amino-terminal pro-B-type natriuretic peptide and..., Melendez [/bib_ref]. BNP, in particular, is an acute-phase reactant, and may therefore be elevated in inflammatory conditions without cardiac involvement [bib_ref] Assessment of B-type natriuretic peptide in patients with pneumonia, Yetkin [/bib_ref].
Tier 2 testing should also include further assessment for systemic inflammation. In addition to the ESR and CRP level, MIS-C patients typically demonstrate other markers of inflammation, including high d-dimer levels, moderately elevated ferritin levels (often ranging from 500 to 2,000 ng/dl), profoundly increased procalcitonin levels in the absence of bacterial infection, and increased lactate dehydrogenase (LDH) levels [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. Cytokine panels, when available, can assist in the diagnostic evaluation, since levels of interleukin-6 (IL-6), tumor necrosis factor (TNF), or IL-10 are often increased; however, cytokine levels measured in this manner should not dictate treatment choices and are not required to determine treatment plans [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref]. In addition, serologic tests can be used. Serologic testing for SARS-CoV-2 has yielded positive results in a greater proportion of MIS-C patients (80-90%) as compared to the results of PCR testing in MIS-C patients (20-40%), and therefore both serology and PCR should be used to evaluate the epidemiologic link to the infection (7-9,13,17).
## Comparing and contrasting features of mis-c and kd.
In an early sentinel report from Bergamo, the Italian epicenter of the COVID-19 pandemic, KD and KD-like illnesses were observed at a rate 30 times higher than that observed in the prepandemic era [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref]. Since this observation, the clinical symptoms of MIS-C have frequently been compared to those of KD, given their similarity in profiles, including fevers, mucocutaneous features, and cardiac sequelae [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] COVID-19 associated pediatric multi-system inflammatory syndrome, Leon [/bib_ref] [bib_ref] Septic shock presentation in adolescents with COVID-19 [letter, Dallan [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref] [bib_ref] Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for..., Mccrindle [/bib_ref] [bib_ref] A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in..., Kawasaki [/bib_ref]. However, a closer examination of the literature shows that only about one-quarter to one-half of reported MIS-C patients meet the full diagnostic criteria for KD [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref].
Several epidemiologic, clinical, and laboratory features of MIS-C that differ from KD unrelated to SARS-CoV-2 are worthy of mention. First, whereas the incidence of KD is highest in Japan, MIS-C appears to be frequent in patients of African descent and possibly those of Hispanic descent [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Nationwide epidemiologic survey of Kawasaki disease in Japan, Makino [/bib_ref]. It is unclear whether this racial/ethnic distribution of MIS-C is due to genetic or biologic factors or whether it might be attributed to socioeconomic status and risk of SARS-CoV-2 exposure. . Hyperinflammation in COVID-19*
# Guidance statement
Level of consensus
Children with a complex medical history and those taking immunosuppressive medications, including moderateto-high-dose glucocorticoids, may be at higher risk for severe outcomes in COVID-19.
## Moderate to high
Children and adults admitted to the hospital with COVID-19 present with similar symptoms, including fever, upper respiratory tract symptoms, abdominal pain, and diarrhea.
## Moderate
Children with severe respiratory symptoms due to COVID-19 should be considered for immunomodulatory therapy if any of the following are present: ARDS, shock/cardiac dysfunction, substantially elevated LDH, d-dimer, IL-6, IL-2R, CRP, and/or ferritin levels, and depressed lymphocyte count, albumin levels, and/or platelet count.
## Moderate to high
Glucocorticoids may be considered for use as immunomodulatory therapy in patients with COVID-19 and hyperinflammation (as outlined in the above statement).
Moderate Anakinra treatment appears safe in severe infections and in children with hyperinflammatory syndromes. In children with COVID-19 and hyperinflammation, anakinra (>4 mg/kg/day IV or SC) should be considered for immunomodulatory therapy. Initiation of anakinra before invasive mechanical ventilation may be beneficial.
## High
Children with COVID-19 treated with anakinra should be monitored for LFT abnormalities. Moderate Compared to standard care, tocilizumab may be effective in reducing mortality and ICU admission in patients with severe COVID-19 pneumonia and signs of hyperinflammation; however, patients treated with tocilizumab may be at higher risk for bacterial and fungal infections.
## Moderate
When tocilizumab is used to treat children with COVID-19, weight-based dosing should be employed (body weight <30 kg, 12 mg/kg IV; body weight ≥30 kg, 8 mg/kg IV, maximum 800 mg). Children treated with tocilizumab should be monitored for LFT abnormalities and elevated triglyceride levels.
## Moderate to high
In the absence of randomized controlled trials or comparative effectiveness studies, if immunomodulation is to be used at all, the balance of risks and benefits suggests that anakinra be used as first-line immunomodulatory treatment of children with COVID-19 and hyperinflammation. There is insufficient evidence to support the use of other immunomodulatory agents, unless glucocorticoids, IL-1-blocking therapies, and/or IL-6-blocking therapies are contraindicated or have failed.
## | 1799
Second, the age distribution of MIS-C is broad, with reports of MIS-C found in children ranging from age 3 months to age 17 years [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. In contrast, the majority of children with KD are diagnosed before age 5 years [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Kawasaki syndrome hospitalizations in the United States, Holman [/bib_ref] [bib_ref] Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from, Son [/bib_ref].
Third, as discussed above, the clinical presentation of LV dysfunction and shock that is characteristic of patients with MIS-C is considerably less common in patients with KD, with fewer than 10% of KD patients presenting with KD shock syndrome [bib_ref] Recognition of a Kawasaki disease shock syndrome, Kanegaye [/bib_ref]. Close to one-quarter of untreated KD patients develop CAAs [bib_ref] The treatment of Kawasaki syndrome with intravenous γ globulin, Newburger [/bib_ref]. Coronary artery dilation or CAAs have been documented in up to 20% of MIS-C patients, and at least 3 patients have developed giant CAAs [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. It is unknown if the incidence or progression of CAAs differ between MIS-C and KD patients. Importantly, it is clear that MIS-C patients without KD symptoms can develop CAAs, highlighting the need for cardiac evaluation in all patients with MIS-C regardless of phenotypic features, and providing support for the treatment rationale discussed below [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref].
Fourth, although gastrointestinal and neurologic symptoms are reported to occur in KD patients, the panel agreed that these findings are more frequently encountered in the MIS-C patient population.
Finally, the laboratory parameters that have been found to differ between retrospective cohorts of MIS-C patients and historical cohorts of KD patients include a lower platelet count, lower absolute lymphocyte count, and higher CRP levels in MIS-C patients [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref].
## Cardiac management of mis-c.
Children with MIS-C will need close clinical follow-up with cardiology. Extrapolating data from KD, another condition that can be complicated by CAA, the panel recommended that repeat echocardiograms be obtained from all children with MIS-C at a minimum of 7-14 days and then 4-6 weeks after the initial presentation [bib_ref] Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for..., Mccrindle [/bib_ref]. For those patients with cardiac involvement noted during the acute phase of illness, another echocardiogram at 1 year after MIS-C diagnosis could be considered. Children with LV dysfunction and CAAs will require more frequent echocardiograms.
Although LV function improves rapidly in most MIS-C patients, the long-term complications of myocardial inflammation in this syndrome are not known, and may include myocardial fibrosis and scarring, features that have been seen in other forms of pediatric myocarditis [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Cardiovascular magnetic resonance techniques and findings in children with myocarditis: a multicenter..., Banka [/bib_ref]. Cardiac magnetic resonance imaging at 2-6 months post-acute illness in those patients who had moderate-to-severe LV dysfunction will allow for evaluation of fibrosis and scarring. Electrical conduction abnormalities are increasingly noted in MIS-C patients and may develop after the initial presentation; therefore, EKG should be performed at a minimum of every 48 hours in patients who are hospitalized and at each follow-up visit [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref]. If conduction abnormalities are present, the patient should be placed on telemetry while in the hospital and may need Holter monitoring at clinical follow-up.
## Treatment of mis-c. immunomodulatory treatment in mis-c.
Goals of treatment in the MIS-C population are to stabilize patients with life-threatening manifestations such as shock, and to prevent long-term sequelae, which may include CAAs, myocardial fibrosis/scarring, and fixed cardiac conduction abnormalities. There is no available literature that directly compares therapeutic approaches in MIS-C. Recommendations approved by the task force are derived from experience in managing MIS-C and from higher quality data in other pediatric conditions with similar features. Initiation of treatment will often depend on the severity of the patient's presentation. There was consensus among the panelists that patients under investigation for MIS-C without life-threatening manifestations should undergo a diagnostic evaluation for MIS-C as well as for other possible infections and noninfection-related conditions before immunomodulatory treatment is initiated. This is to prevent the use of therapies that could be potentially harmful in patients who do not have MIS-C.
Further, a subgroup of patients with MIS-C will develop progressive cardiac involvement rapidly; therefore, hospital admission and sequential monitoring of inflammation markers, BNP/ NT-proBNP levels, and troponin T levels without instituting treatment can sometimes inform the diagnostic evaluation [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref]. Children with a life-threatening presentation such as shock will clearly require supportive care and may benefit from early initiation of immunomodulatory treatment, sometimes before a full diagnostic evaluation can be completed. In such cases, ongoing diagnostic evaluation should be pursued with a multidisciplinary team, in parallel with treatment.
Finally, the current recommendations address the treatment of MIS-C that is uncomplicated by macrophage activation syndrome (MAS). Importantly, there is a subgroup of patients with MIS-C who may also develop overt MAS. The treatment of those patients may need to deviate from the recommendations presented herein [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref].
A stepwise approach to immunomodulatory treatment in MIS-C is recommended, with intravenous immunoglobulin (IVIG) and/or glucocorticoids considered as first-tier agents. Both IVIG and glucocorticoids, either alone or in combination, are the most commonly used immunomodulatory medications reported to date in MIS-C patients [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] COVID-19 associated pediatric multi-system inflammatory syndrome, Leon [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref]. There are insufficient data available to compare the efficacy of IVIG and glucocorticoids in MIS-C or to determine whether these treatments should be provided individually or as dual therapy. Accordingly, the task force recommended that IVIG and glucocorticoids could be used alone or in combination to treat MIS-C.
Evidence for the use of IVIG and glucocorticoids to treat MIS-C is also based on the use of these treatments in patients with KD and fulminant myocarditis, both of which are conditions that resemble MIS-C in some aspects. IVIG at a dose of 2 gm/kg prevents CAAs in KD, while the benefit of IVIG in myocarditis remains unclear; however, case reports of successful use of IVIG in coronavirus-associated myocarditis have been published [bib_ref] Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for..., Mccrindle [/bib_ref] [bib_ref] The treatment of Kawasaki syndrome with intravenous γ globulin, Newburger [/bib_ref] [bib_ref] High-dose intravenous γ globulin for Kawasaki disease, Furusho [/bib_ref] [bib_ref] Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health..., Newburger [/bib_ref] [bib_ref] Recognition and initial management of fulminant myocarditis: a scientific statement from the, Kociol [/bib_ref] [bib_ref] Intravenous immunoglobulin therapy for patients with idiopathic cardiomyopathy and endomyocardial biopsy-proven high..., Dennert [/bib_ref] [bib_ref] Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients..., Goland [/bib_ref] [bib_ref] Role of intravenous immunoglobulin therapy in the survival rate of pediatric patients..., Yen [/bib_ref]. Before IVIG is given, cardiac function and fluid status should be assessed. If these parameters are abnormal, the rate of IVIG infusion may be slowed or treatment delayed until cardiac function is restored.
Glucocorticoids reduce the rates of CAA development when used in KD patients at high risk of being resistant to IVIG treatment [bib_ref] Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in..., Kobayashi [/bib_ref]. Verdoni and colleagues (7) reported a high rate of IVIG resistance in KD patients who presented during the COVID-19 pandemic, as compared to that in a historical cohort of KD patients, which may suggest a role for glucocorticoids in MIS-C. Panelists reported that low-to-moderate doses (1-2 mg/kg/day) of glucocorticoids were sufficient to treat many MIS-C patients. Some children with shock requiring multiple inotropes and/or vasopressors have responded best to high doses of intravenous glucocorticoids. High-dose intravenous glucocorticoids have been used safely in patients with KD and have been used successfully in small numbers of patients with MIS-C and shock [bib_ref] Multisystem inflammatory syndrome in children during the COVID-19 pandemic: a case series, Chiotos [/bib_ref] [bib_ref] Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease, Newburger [/bib_ref] [bib_ref] A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki..., Inoue [/bib_ref] [bib_ref] Corticosteroid pulse combination therapy for refractory Kawasaki disease: a randomized trial, Ogata [/bib_ref]. Adjunctive glucocorticoids have also been shown to shorten the duration of shock in patients with sepsis [bib_ref] Adjunctive glucocorticoid therapy in patients with septic shock, Venkatesh [/bib_ref]. Panelists agreed that MIS-C patients who are treated with steroids, regardless of the dose, often require a 2-3-week taper to avoid rebound inflammation.
Anakinra is a recommended treatment for MIS-C patients who are refractory to IVIG and/or glucocorticoids. This recommendation is based on the relative safety of anakinra in pediatric patients with hyperinflammatory syndromes and active infection, the experience of panel members in using anakinra to treat MIS-C patients, and the findings in a small number of MIS-C patients reported in the literature [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref] [bib_ref] Characteristics, cardiac involvement, and outcomes of multisystem inflammatory disease of childhood (MIS-C)..., Capone [/bib_ref] [bib_ref] A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra..., Quartier [/bib_ref] [bib_ref] Treatment to target using recombinant interleukin-1 receptor antagonist as first-line monotherapy in..., Haar [/bib_ref] [bib_ref] for the Phase III rhIL-1ra Sepsis Syndrome Study Group. Recombinant human interleukin..., Fisher [/bib_ref] [bib_ref] Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis, Eloseily [/bib_ref]. Similarly, anakinra has been used successfully in a small number of patients with IVIG-resistant KD [bib_ref] The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: a..., Kone-Paut [/bib_ref] [bib_ref] High-dose anakinra as treatment for macrophage activation syndrome caused by refractory Kawasaki..., Lind-Holst [/bib_ref] [bib_ref] Usefulness and safety of anakinra in refractory Kawasaki disease complicated by coronary..., Guillaume [/bib_ref].
Treatment with immunomodulatory agents may not always be required in MIS-C. Whittaker et al reported that 22% of MIS-C patients recovered with supportive care [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref]. In close coordination with specialists who have expertise in MIS-C, some patients with mild symptoms may require only close monitoring, without the use of IVIG and/or glucocorticoids. The panel noted uncertainty around the empiric use of IVIG in this setting to prevent CAAs.
Antiplatelet and anticoagulation therapy in MIS-C. Published reports of patients with MIS-C describe marked abnormalities in the coagulation cascade, including prominent elevations in d-dimer and fibrinogen levels, a variable effect on the platelet count, and a high clot strength as determined by thromboelastography [bib_ref] An outbreak of severe Kawasaki-like disease at the Italian epicentre of the..., Verdoni [/bib_ref] [bib_ref] Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic, Toubiana [/bib_ref] [bib_ref] Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents, Cheung [/bib_ref] [bib_ref] Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the..., Belhadjer [/bib_ref] [bib_ref] Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally..., Whittaker [/bib_ref]. An increased risk of thrombosis is a concern in patients with MIS-C, based on the data outlined above as well as the hypercoagulability noted in adults with COVID-19 [bib_ref] Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy:..., Carsana [/bib_ref] [bib_ref] Thromboinflammation and the hypercoagulability of COVID-19, Connors [/bib_ref] [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] [bib_ref] Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe..., Zhou [/bib_ref]. A recent report also described a small number of MIS-C patients with deep vein thrombosis or pulmonary embolism, but the overall risk of thrombosis in this population is not known [bib_ref] Multisystem inflammatory syndrome in US children and adolescents, Feldstein [/bib_ref]. Therefore, these recommendations are based on experience in analogous pediatric conditions, specifically KD and myocarditis, and the emerging data from adults with COVID-19.
Antiplatelet agents such as aspirin are recommended in patients with KD, because of the presence of platelet activation, thrombocytosis, altered flow dynamics in the affected coronary arteries, and endothelial damage characteristic of this disease [bib_ref] Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for..., Mccrindle [/bib_ref]. Accordingly, low-dose aspirin (3-5 mg/kg/day up to 81 mg once daily) is recommended in all MIS-C patients with KD features, CAAs, and thrombocytosis. Anti-acid treatments should be used to prevent gastrointestinal complications in MIS-C patients who are taking steroids and aspirin. The risk of coronary artery thrombosis is directly related to the size of the CAA, with the probability of thrombosis occurring in the coronary arteries being exponentially increased with artery dimensions above a z-score of 10.0 [bib_ref] Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for..., Mccrindle [/bib_ref] [bib_ref] Coronary artery aneurysms in Kawasaki disease: risk factors for progressive disease and..., Friedman [/bib_ref] [bib_ref] Stenotic lesions and the maximum diameter of coronary artery aneurysms in Kawasaki..., Tsuda [/bib_ref]. Thus, anticoagulation with enoxaparin (factor Xa level 0.5-1.0) or warfarin in MIS-C patients with a coronary artery z-score of greater than 10.0 is advised. Patients with more-thanmild LV dysfunction are at risk for intracardiac thrombosis [bib_ref] Thrombosis and embolism in pediatric cardiomyopathy, Chen [/bib_ref] [bib_ref] Prevention and treatment of thrombosis in pediatric and congenital heart disease: a..., Giglia [/bib_ref]. Given the lack of clarity about the exact risk of hypercoagulability in MIS-C, the task force recommended considering anticoagulation therapy for MIS-C patients who have moderate or severe LV dysfunction (EF <35%).
## Hyperinflammation in children with covid-19.
Severe COVID-19 in children. The task force also addressed immunomodulatory treatment in children with severe COVID-19, a condition that panelists (given the current information) deemed to be readily distinguishable from MIS-C. The vast majority of children with COVID-19 have mild symptoms in the acute, infectious phase of the disease, but a small minority of children become severely ill [bib_ref] Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted..., Shekerdemian [/bib_ref] [bib_ref] Severe COVID-19 in children and young adults in the Washington, DC metropolitan..., Debiasi [/bib_ref] [bib_ref] Epidemiology of COVID-19 among children in China, Dong [/bib_ref]. MIS-C patients are often previously healthy and will present with symptoms of fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS-CoV-2 infection (most are positive for SARS-CoV-2 IgG antibodies). In contrast, children who develop severe COVID-19 during their initial infection often have a complex medical history [bib_ref] Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted..., Shekerdemian [/bib_ref] [bib_ref] Severe COVID-19 in children and young adults in the Washington, DC metropolitan..., Debiasi [/bib_ref]. Shekerdemian and colleagues reported that 40% of patients admitted to the intensive care unit (ICU) for COVID-19 had developmental delay or a genetic anomaly, or were dependent on technological support (e.g., tracheostomy) for survival [bib_ref] Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted..., Shekerdemian [/bib_ref]. There is no definitive evidence suggesting that children with rheumatic diseases treated with immunosuppression are also at risk of developing poor outcomes from COVID-19. Shekerdemian et al also observed that 23% of pediatric patients with COVID-19 who were admitted to the ICU were either immunosuppressed or had cancer, but they did not specify whether any of these patients had a rheumatic condition [bib_ref] Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted..., Shekerdemian [/bib_ref]. Extrapolating from adults with inflammatory bowel disease and rheumatic conditions, glucocorticoid use may be associated with worse outcomes in COVID-19, while treatment with TNF inhibitors may actually be protective against severe COVID-19 [bib_ref] but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients..., Brenner [/bib_ref] [bib_ref] Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data..., Gianfrancesco [/bib_ref]. In addition, in cohorts of pediatric patients receiving immunosuppressive | 1801 medications, an increased risk of severe COVID-19 has not been identified [bib_ref] The severity of COVID-19 in children on immunosuppressive medication, Marlais [/bib_ref] [bib_ref] ) from the Paediatric IBD Porto Group of European Society of Paediatric..., Turner [/bib_ref] [bib_ref] Incidence of COVID-19 in a cohort of adult and paediatric patients with..., Michelena [/bib_ref].
Immunomodulatory treatment in children with hyperinflammation and COVID-19. Data to guide the treatment of pediatric patients with severe illness during the early phase of SARS-CoV-2 infection are limited. In adults, certain laboratory parameters associated with an exaggerated inflammatory response (hyperinflammation) portend worse outcomes in COVID-19, including elevated levels of LDH, d-dimer, IL-6, IL-2 receptor, CRP, and ferritin and a decreased lymphocyte count, albumin level, and platelet count [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Risk factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref] [bib_ref] Clinical and immunologic features in severe and moderate coronavirus disease 2019, Chen [/bib_ref] [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Huang [/bib_ref]. In at least one case series of pediatric patients with COVID-19, increased CRP levels, elevated procalcitonin levels, and decreased platelet counts were significantly more common in children requiring ICU admission as compared to those cared for on the floor; however, further studies are needed to identify laboratory parameters that would be predictive of poor outcomes in the pediatric population [bib_ref] Clinical characteristics and outcomes of hospitalized and critically ill children and adolescents..., Chao [/bib_ref]. These results suggest that patients with COVID-19 and hyperinflammation have poor outcomes, and that the host immune response to SARS-CoV-2 may contribute to disease severity. The panel agreed that children with severe COVID-19, manifesting as acute respiratory distress syndrome (ARDS), shock, or signs of hyperinflammation as measured by the laboratory parameters discussed above, should be considered for immunomodulatory therapy in addition to supportive care and antiviral medications.
Glucocorticoids are a readily available and inexpensive option for immunomodulation; however, their use in adults with COVID-19 is controversial. Prior experience with adjunctive glucocorticoid therapy in ARDS unrelated to COVID-19 has been equivocal [bib_ref] Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled..., Villar [/bib_ref] [bib_ref] Effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in..., Seam [/bib_ref] [bib_ref] Corticosteroid exposure in pediatric acute respiratory distress syndrome, Yehya [/bib_ref]. Observational studies evaluating glucocorticoid treatment in other respiratory viral infections, such as influenza, suggest that it is associated with increased mortality; however, these studies are difficult to interpret, due to confounding by indication [bib_ref] The effect of corticosteroids on mortality of patients with influenza pneumonia: a..., Ni [/bib_ref] [bib_ref] Corticosteroids as adjunctive therapy in the treatment of influenza: an updated Cochrane..., Lansbury [/bib_ref]. There are concerns that glucocorticoids given at high doses or early in the course of infection delay viral clearance [bib_ref] Adjuvant corticosteroid treatment in adults with influenza A (H7N9) viral pneumonia, Cao [/bib_ref] [bib_ref] Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in..., Lee [/bib_ref]. Glucocorticoid use in critically ill patients is also associated with increased neuropathy and myopathy [bib_ref] Corticosteroid use and intensive care unit-acquired weakness: a systematic review and meta-analysis, Yang [/bib_ref]. In SARS-CoV-2 infections, there is conflicting evidence about the impact of glucocorticoids on viral clearance [bib_ref] Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation..., Ling [/bib_ref] [bib_ref] Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19, Fang [/bib_ref]. A small number of cohort studies suggest a benefit in patients with severe COVID-19 pneumonia who are treated with glucocorticoids [bib_ref] Risk factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref] [bib_ref] Early short course corticosteroids in hospitalized patients with COVID-19, Fadel [/bib_ref]. Importantly, preliminary results from a large randomized controlled trial (the RECOVERY trial) indicated that low-to-moderate doses of dexa methasone significantly reduced mortality in COVID-19 patients requiring mechanical ventilation [bib_ref] Dexamethasone in hospitalized patients with COVID-19: preliminary report, Horby [/bib_ref] ; however, those results were reported after the task force had already voted on this guidance. Based on these studies that suggest that patients with severe COVID-19 pneumonia may benefit from immunomodulation with glucocorticoids, the task force achieved moderate consensus that glucocorticoid treatment could be considered in pediatric patients with severe COVID-19 and signs of hyperinflammation.
Targeted neutralization of inflammatory cytokines is another approach that can be employed to reduce pathologic inflammation in COVID-19. In contrast to glucocorticoids, the panel was able to achieve high consensus with regard to the statement that anakinra (recombinant human IL-1 receptor antagonist) can be used to treat pediatric patients with COVID-19 and hyperinflammation. Anakinra appears to be safe in patients with severe infections, based on the results of a randomized controlled trial in patients with sepsis in whom there was no difference in the frequency of adverse events in the anakinra group compared to the placebo group [bib_ref] for the Phase III rhIL-1ra Sepsis Syndrome Study Group. Recombinant human interleukin..., Fisher [/bib_ref]. Furthermore, a re-analysis of the data from this trial in sepsis showed increased survival in patients treated with anakinra who also had excessive inflammation, manifested as hepatobiliary dysfunction and coagulopathy, which is commonly seen in COVID-19 [bib_ref] Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with..., Shakoory [/bib_ref]. IL-1 blockade has also been used safely in children with inflammatory syndromes, including those with systemic juvenile idiopathic arthritis and those with MAS [bib_ref] A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra..., Quartier [/bib_ref] [bib_ref] Treatment to target using recombinant interleukin-1 receptor antagonist as first-line monotherapy in..., Haar [/bib_ref] [bib_ref] Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis, Eloseily [/bib_ref]. In COVID-19, observations from case series provide evidence of the safety and efficacy of anakinra in patients with elevated inflammation marker levels and moderate-to-severe disease; however, most of those studies do not have a comparison group [bib_ref] Interleukin-1 receptor antagonist anakinra in association with remdesivir in severe coronavirus disease..., Franzetti [/bib_ref] [bib_ref] Use of anakinra in severe COVID-19: a case report, Filocamo [/bib_ref] [bib_ref] Favorable anakinra responses in severe covid-19 patients with secondary hemophagocytic lymphohistiocytosis, Dimopoulos [/bib_ref] [bib_ref] Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung..., Pontali [/bib_ref]. In one retrospective cohort of patients with COVID-19-related moderate-to-severe ARDS, treatment with anakinra in addition to usual care significantly reduced mortality when compared to patients treated at the same center a week prior [bib_ref] Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress..., Cavalli [/bib_ref]. The patients in this cohort received high-dose anakinra (10 mg/kg/day) and were not yet mechanically ventilated, suggesting that treatment administered before intubation is beneficial.
Given the association between increased IL-6 levels and negative outcomes in COVID-19, IL-6 neutralization with tocilizumab may be an appealing potential therapy [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Risk factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref] [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Huang [/bib_ref]. In some case series (reported without a comparison group), clinical improvement with tocilizumab treatment was demonstrated, while others have not shown any clinical improvement or have noted a high rate of bacterial and fungal infections after treatment with tocilizumab [bib_ref] Tocilizumab treatment in COVID-19: a single center experience, Luo [/bib_ref] [bib_ref] Effective treatment of severe COVID-19 patients with tocilizumab, Xu [/bib_ref] [bib_ref] Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in, Morena [/bib_ref]. Cohort studies with comparison groups have demonstrated conflicting results with one study reporting safety and efficacy of tocilizumab while another found no improvement in clinical outcomes [bib_ref] Impact of low dose tocilizumab on mortality rate in patients with COVID-19..., Capra [/bib_ref]. In a study by Capra and colleagues, treatment with tocilizumab showed some benefit in COVID-19 patients who had not yet been mechanically ventilated [bib_ref] Impact of low dose tocilizumab on mortality rate in patients with COVID-19..., Capra [/bib_ref].
The task force agreed that the features of severe COVID-19 were sufficiently similar between the described adult cases and pediatric cases to cautiously extrapolate from adult studies. Overall, the consensus among panelists was that immunomodulatory treatment should be considered in pediatric patients with hyperinflammation and severe symptoms in the acute phase of illness. While the data are still too sparse to make definitive recommendations based on high-quality evidence, the panel favored the use of anakinra in this setting.
# Discussion
There has been an evolution in our understanding of SARS-CoV-2 infections in children. Initially, it was believed that COVID-19 was almost entirely benign and of little consequence in the pediatric population. There has been a sudden reversal from this stance in the context of the emergence of MIS-C cases. The goals of this ACR task force were to synthesize available data and expert opinion to provide a resource for clinicians on the frontlines caring for children with inflammatory syndromes due to recent or concurrent infections with SARS-CoV-2.
Recognizing the need to address the unique challenges facing children with inflammatory conditions triggered by SARS-CoV-2 infections, the ACR convened the task force to provide guidance in a short period of time. To accomplish this charge, a multidisciplinary panel was assembled that included clinicians from North America with expertise encompassing pediatric rheumatology, cardiology, infectious disease, and critical care. Well-established methodology in the form of the RAND/UCLA Appropriateness Method was used to achieve consensus. There are limitations inherent in our approach. Given the need for expedited decision-making, we were unable to provide guidance on all topics of interest. In particular, the task force focused its efforts on providing diagnostic and treatment recommendations for MIS-C instead of developing a new case definition for this condition. This choice was made because several case definitions for MIS-C exist, and the data needed to develop a sensitive and specific set of criteria are not yet available. The guidance provided in this document is targeted to clinicians with access to complex diagnostic tools and biologic treatments. Thus, some of the recommendations are not practical in less resource-rich settings. The task force may consider providing additional recommendations for these settings in subsequent versions of this guidance. In addition, the work product of the task force is considered guidance instead of formal treatment guidelines that must adhere to the strict methodology endorsed by the ACR.
The guidance provided in this document is supported by reports from the scientific literature and recommendations from public health institutions. Yet, the available data remain restricted to low-quality evidence that often must be extrapolated from the experience in adults. This approach is particularly problematic when confronting clinical questions regarding MIS-C, which, to date, has been reported primarily in children. This unique manifestation of COVID-19 in children and adolescents highlights the need to prioritize and fund rigorous research in the pediatric population. For now, our understanding of pediatric SARS-CoV-2 infections is rudimentary and will continue to change as higher quality evidence becomes available. Thus, the recommendations contained in this document should be interpreted in the setting of this shifting landscape and will be modified prospectively as our understanding of COVID-19 improves. For these reasons, this guidance does not replace the critical role of clinical judgment that is essential to address the unique needs of individual patients.
As the SARS-CoV-2 pandemic continues to unfold, the ACR will support clinicians caring for children with COVID-19 by enabling this task force to continue the work of reviewing evidence and providing expert opinion through revised versions of this guidance document. It is the ultimate goal of both the ACR and the task force panelists to disseminate knowledge quickly in an effort to improve outcomes for children with SARS-CoV-2 infections.
[fig] *: MIS-C = multisystem inflammatory syndrome in children; COVID-19 = coronavirus disease 2019; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; CRP = C-reactive protein; EKG = electrocardiogram; BNP = B-type natriuretic peptide; KD = Kawasaki disease. [/fig]
[fig] Figure 1: Diagnostic pathway for multisystem inflammatory syndrome in children (MIS-C) [/fig]
[table] Table 1: Case definitions of MIS-C* [/table]
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https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/art.41454
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To provide guidance on the management of multisystem inflammatory syndrome in children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS–CoV‐2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID‐19), the acute, infectious phase of SARS–CoV‐2 infection.
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87602b64966855995a5ba0422f9ffdb1b451fbd0
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pubmed
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Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines
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Oropharyngeal cancer: United Kingdom National Multidisciplinary Guidelines
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. There has been significant debate in the management of oropharyngeal cancer in the last decade, especially in light of the increased incidence, clarity on the role of the human papilloma virus in this disease and the treatment responsiveness of the human papilloma virus positive cancers. This paper discusses the evidence base pertaining to the management of oropharyngeal cancer and provides recommendations on management for this group of patients receiving cancer care. - Where possible, patients should be offered the opportunity to enrol in clinical trials in the field. (G)
## Recommendations
- Cross-sectional imaging is required in all cases to complete assessment and staging. (R)
- Magnetic resonance imaging is recommended for primary site and computed tomography scan for neck and chest. (R) - Positron emission tomography combined with computed tomography scanning is recommended for the assessment of response after chemoradiotherapy, and has a role in assessing recurrence. (R) - Examination under anaesthetic is strongly recommended, but not mandatory.
# Introduction and epidemiology
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing significantly in developed countries. [bib_ref] Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an..., Nasman [/bib_ref] In the USA, the incidence increased by 22 per cent from 1.53 per 100 000 to 1.87 per 100 000 between 1999 and 2006, after showing no change between 1975 and 1999. The UK has seen a doubling of incidence between 1990 and 2006. There has been a further doubling in incidence between 2006 and 2010. The increasing incidence of OPSCC is due to human papilloma virus (HPV) infection, with HPV-16 being the predominant subtype responsible. The proportion of cases with evidence of HPV infection has risen rapidly and HPV is now responsible for over 70 per cent of OPSCCs in Europe and the USA. [bib_ref] Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an..., Nasman [/bib_ref] [bib_ref] Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer..., Mehanna [/bib_ref] The rise in HPV-related OPSCC has been called an 'epidemic' and is expected to continue.
## Clinical presentation
Patients often present with a painless neck lump, with few other symptoms. They may also complain of a sore throat or tongue, otalgia, pain and/or difficulty swallowing and/or a change in voice quality (hot potato voice).
## Assessment and staging
Clinical examination Flexible direct endoscopy of the upper aerodigestive tract is now available in virtually all ear, nose and throat clinics in the UK. It is vital for assessing the limits of spread, such as direct through and through invasion of the soft palate from anterior to posterior surfaces, the inferior extent of lateral pharyngeal wall tumours into the vallecula and pyriform fossa, and the superior extension of tonsillar cancers into the postnasal space and skull base.
## Imaging considerations
Cross-sectional imaging is required in all cases to complete assessment and staging. Magnetic resonance imaging (MRI) scanning with contrast is optimal for staging the primary tumour, particularly when assessing soft tissue spread, such as in the tongue base and/or body of the tongue. [bib_ref] Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines, Lewis-Jones [/bib_ref] Computed tomography (CT) scanning may also be required, particularly to assess the extent of nodal disease and bony invasion, e.g. body of the mandible and skull base in tonsillar tumours and cervical spine in posterior pharyngeal wall tumours.
The presence of nodal metastases should be evaluated by CT or MRI in all patients. Ultrasound with or without needle biopsy should be carried out for all patients presenting with a neck lump and is an accurate method of staging nodal disease in experienced hands.
Distant metastases should be assessed by CT scanning of the chest and upper abdomen, to exclude metastatic disease to the lungs and liver. [bib_ref] Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines, Lewis-Jones [/bib_ref] Magnetic resonance imaging scanning is not suitable for this due to the relatively slow acquisition process leading to movement artefact caused by breathing.
Fluoro-deoxy-glucose positron emission tomography combined with computed tomography (F-FDG PET-CT) scanning may be used to give additional staging information when it is available, particularly where staging is difficult clinically (e.g. patient with trismus) or where there is uncertainty on other imaging and/or equivocal findings that would preclude radical treatment. Positron emission tomography (PET) also has a role in the assessment of recurrent tumours and can detect recurrence at primary sites, neck nodes and/or distant metastases.
Supported by the results of the UK PET-Neck randomised controlled trial (RCT) study, 5 F-FDG PET-CT scanning is now also recommended for the assessment of response approximately three months post-chemoradiotherapy, particularly in patients with advanced nodal disease. PET-CT guided active surveillance showed similar survival outcomes to the planned neck dissection arm, but resulted in considerably fewer neck dissections, and fewer complications, and was cost effective, supporting its use in routine practice. [bib_ref] PETCT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer, Mehanna [/bib_ref] Examination under anaesthetic and panendoscopy Examination under anaesthetic and panendoscopy is strongly recommended to assess the extent and resectability of the primary tumour and to exclude second primaries, especially in hypopharynx and oesophagus. Examination under anaesthetic is mandatory if thorough endoscopic examination is not possible in the clinic as above and/or if no biopsy can be obtained.
## Recommendations
- Cross-sectional imaging is required in all cases to complete assessment and staging (R) - Magnetic resonance imaging is recommended for primary site and CT scan for neck and chest (R) - Positron emission tomography combined with computed tomography scanning is recommended for the assessment of response after chemoradiotherapy, and has a role in assessing recurrence (R) - Examination under anaesthetic is strongly recommended, but not mandatory (R)
Pre-treatment staging Pre-treatment staging for the primary tumour based on the tumour-node-metastasis classification (7th edition) for oropharyngeal tumours is shown in Box I. Pathology Formal tissue biopsy of the primary cancer is one of the cornerstones of the management pathway in oropharyngeal cancer. Tumours can be biopsied under local or no anaesthetic in the clinic. Otherwise, direct biopsy and staging under general anaesthetic is necessary. In very few circumstances, a positive cancer diagnosis from fine needle aspiration (FNA) of involved nodes may suffice, provided the cytology result has been considered in conjunction with the clinical presentation and appropriate imaging at a head and neck cancer multidisciplinary team meeting. Such circumstances may arise in a person who is unfit to have an anaesthetic for an open biopsy and in whom local anaesthetic biopsies have not been successful. There is limited information on the reliability of p16 and HPV tests on FNA material and HPV testing is not currently routinely recommended on FNA samples.
The majority of oropharyngeal cancers are squamous cell carcinomas. It is recommended that they are reported according to The Royal College of Pathologists UK Guidelines for the histopathology reporting of mucosal malignancies of the pharynx (2013). Human papilloma virus testing is a core item for OPSCC to allow the stratification of treatment outcomes. Human papilloma virus status should be assessed using validated methods with appropriate controls. Human papilloma virus testing for oropharyngeal cancer should be performed within a diagnostic service where the laboratory procedures and reporting standards are quality assured. The immunohistochemical identification of over-expression of p16 protein is a useful screening method for HPV infection as HPV-associated carcinomas show strong nuclear and cytoplasmic expression of p16 in over 70 per cent malignant cells and p16-negative cases are almost certainly not HPV associated. Carcinomas showing p16 over-expression should have the presence of HPV confirmed by highrisk HPV DNA in situ hybridisation, if possible. Polymerase chain reaction analysis for HPV is not currently recommended in clinical practice as there is a risk of false positive results from formalin-fixed tissues. [bib_ref] A novel algorithm for reliable detection of human papillomavirus in paraffin embedded..., Smeets [/bib_ref]
## Recommendations
## Prognosis
Prognosis is dependent on stage at presentation as well as HPV status. [bib_ref] The increasing clinical relevance of human papillomavirus type 16 (HPV-16) infection in..., Shaw [/bib_ref] The status of human papilloma virus is a strong and independent prognostic factor for survival, and HPV-positive OPSCC has a 58 per cent reduction in the risk of death compared with HPV-negative OPSCC (hazard ratio 0.42, 95 per cent; confidence interval 0.27-0.66), with 3 year overall survival rates of 82.4 per cent for HPV-positive disease compared with 57.1 per cent ( p < 0.001) for HPV-negative disease. [bib_ref] Human papillomavirus and survival of patients with oropharyngeal cancer, Ang [/bib_ref] Factors including smoking, particularly current smoking, 9,10 which may be a surrogate of genetic instability, and nodal stage, may influence prognosis in HPV-positive OPSCC. Several immunological markers have also been shown to correlate with prognosis and a UK study showed significant associations between the presence of tumour infiltrating lymphocytes and improved survival. [bib_ref] Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer, Ward [/bib_ref] Although there are no head-to-head comparisons of primary surgical vs nonsurgical management for OPSCC, similar survival outcomes have been reported in studies of primary chemoradiotherapy and of surgery followed by postoperative radiotherapy (RT) and/or chemoradiotherapy, albeit there is a lack of prospective randomised trials of surgical management. [bib_ref] Human papillomavirus and survival of patients with oropharyngeal cancer, Ang [/bib_ref] [bib_ref] High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous..., Licitra [/bib_ref] [bib_ref] Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United..., Haughey [/bib_ref] [bib_ref] Improved survival of patients with human papillomavirus-positive head and neck squamous cell..., Fakhry [/bib_ref] To date, there is no evidence that patients with HPVpositive and HPV-negative OPSCC should be treated differently, outside of the context of randomised, controlled clinical trials. In view of the excellent prognosis from lower-risk HPV-positive disease, current and future UK studies (De-Escalate HPV, ISRCTN33522080 and PATHOS, UKCRN ID 18645) will investigate whether reduced intensity treatment can maintain favourable outcomes but reduce acute and late toxicity for patients. On the other hand, because HPV-negative and higher risk HPV-positive patients have a poorer prognosis, future trials (CompARE, ISRCTN41478539) will investigate whether escalating treatment will result in better outcomes for these patients.
## Management
Early (T1-T2 N0) oropharyngeal carcinoma General principles of management. Early stage (T1-T2 N0 M0) oropharyngeal carcinoma should ideally be treated with single modality therapy, either primary surgery or RT. There are no high-quality comparative studies of the two treatment modalities within the same population. Retrospective case series demonstrate fiveyear disease-specific survival rates of 81-100 per cent for primary surgery [bib_ref] T1-T2 NO oropharyngeal cancers treated with surgery alone. A GETTEC study, Cosmidis [/bib_ref] (with adjuvant therapy where appropriate) and 77-89 per cent for primary RT, with surgical salvage. [bib_ref] Definitive radiotherapy for tonsillar squamous cell carcinoma, Mendenhall [/bib_ref] Treatment decisions are made based on the size and position of the tumour overall functional deficit.
Surgical management of early (T1-T2 N0) oropharyngeal cancer. Surgery for T1-T2 N0 OPSCC should usually be carried out transorally, either by transoral laser microsurgery (TLM) or transoral robotic surgery (TORS). Oncologic results after transoral resection of the oropharynx appear to be comparable to open surgery and good functional outcomes have been reported after transoral surgery in retrospective series. [bib_ref] Critical review: transoral laser microsurgery and robotic-assisted surgery for oropharynx cancer including..., Moore [/bib_ref] Open approaches are associated with increased severe morbidity and treatment complications and have now fallen out of favour for early stage disease.
During TLM, tumours are removed in several (at least two) planned pieces following trans-tumoural resection. This can cause difficulty in pathological scrutiny of the resected tissue to determine margins, which is compounded by laser artefact and difficulty in orientation. Representative marginal biopsies, taken from the peripheral mucosal resection margins and tumour bed can be carried out and examined pathologically to help rule out the presence of residual microscopic disease after TLM. In contrast to TLM, TORS involves en bloc removal of the tumour in the majority of cases. As a result, surgical margins can be more easily interpreted.
About 10-31 per cent of patients who are clinically T1-T2 N0 will have occult nodal disease. Therefore, patients having surgery to the primary should also undergo ipsilateral selective neck dissection. Surgery to the contralateral neck may also be considered in tumours arising at or very near the midline (in the soft palate, tongue base or posterior pharyngeal wall) in order to obtain pathological staging of the contralateral neck. Evidence suggests dissecting levels II, III and IV and possibly level I if there is anterior extension. [bib_ref] Distributions of cervical lymph node metastases in oropharyngeal carcinoma: therapeutic implications for..., Lim [/bib_ref] Retrospective studies suggest that level IIb does not need to be dissected, as long as there are no findings pre-operatively of level IIa disease. For transoral resections, the neck dissection may be performed at the same time, or as a staged procedure, around two weeks before transoral resection of the primary. A staged approach may help prevent the development of a fistula if there is lateral pharyngeal wall transoral resection. Concomitant transoral resection and neck dissection can also be carried out and good results have been reported. In the latter, local muscle transposition (digastric or sternomastoid) can be performed to augment any defect and decrease risk of fistula. For any transoral resection of the oropharynx, ligation of the individual feeding vessels from the external carotid artery should be performed (ascending pharyngeal, lingual and facial branches) to limit the risk of potentially life-threatening haemorrhage. This should be done in any neck dissection performed as a prior staged procedure.
Although the goal for T1-T2 N0 disease should be single modality treatment, adjuvant RT and/or chemoradiotherapy may be required due to adverse pathological features for recurrence following surgery. Post-operative RT should be planned using the same principles as radical RT; a dose of 60 Gy in 30 fractions is typically recommended. Adjuvant treatment may affect functional outcomes following surgery.
Radical RT for early oropharyngeal cancer. Prior to RT, patients should undergo dietetic, speech and language therapy and dental review. A total dose equivalent of 70 Gy in 35 fractions is used in radical treatment. Hypofractionated schedules (typically 65-66 Gy in 30 fractions) are frequently used. Patients are managed as category 1 patients and RT should be completed on time.
Target volume definition is performed using a contrast-enhanced planning CT scan. Co-registration of the planning CT scan with the diagnostic MRI scan can aid target volume delineation. An anatomical (inclusion of the whole oropharynx) or geometric (inclusion of gross tumour volume with a defined margin) approach may be used for primary target volume delineation. Prophylactic RT should be given to the ipsilateral cervical lymph nodes for lateralised (e.g. tonsillar) tumours and to both sides of the neck for non-lateralised tumours (defined as tumours which involve greater than 1 cm of a midline structure e.g. soft palate and/or tongue base). Radiotherapy to levels II, III and IVa is recommended; level Ib may also be included in cases with anterior extension of tumour and/or involvement of the anterior tonsillar pillar. Planning can be carried out using three-dimensional conformal planning (typically using a 'wedged pair' of RT fields) or intensity modulated radiotherapy (IMRT) and/or Arc therapy. Advanced (T3-T4 N0 and T1-T4 N1-N3) oropharyngeal cancer
## Recommendations
General principles of management. A thorough review of the literature relating to the management of oropharyngeal cancer was published as a Cochrane report in 2009. The only evidence of statistically significant benefit was for the addition of concomitant chemotherapy to post-operative RT. [bib_ref] Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy, Furness [/bib_ref] All other treatment comparisons did not show any statistical differences. In recent years, there has been a tendency to offer primary RT and/or chemoradiotherapy for oropharyngeal carcinoma, as part of an 'organ preservation' strategy. Although there are no good head-to-head comparisons of primary surgery and chemoradiotherapy for stage III/IV OPSCC, outcomes from randomised trials of chemoradiotherapy (e.g. RTOG 0129) are at least comparable to the results of surgical series. One potential concern with an organ preservation approach is that although salvage surgery has been shown to have a high success rate for laryngeal cancer, the success rate of salvage surgery is not the same in other head and neck sites, such as the oropharynx.
The 2013 National Head and Neck Cancer Audit (9th DAHNO Report) concluded that variation in treatment strategies for OPSCC is evident across cancer networks in England and Wales. This is not surprising in view of the fact that current published evidence does not provide a consensus view to define the most appropriate treatment strategy. Treatment decisions for individual patients will depend on the size, position and overall functional deficit, as well as on patient preference and local expertise. Human papilloma virus status has a profound influence on prognosis, and in future, could potentially affect selection of treatment modality. Recruitment into randomised controlled clinical trials addressing these issues is highly recommended.
Surgical management of advanced oropharyngeal carcinoma. Where facilities and expertise exist, transoral resection (by TLM or TORS) of base of tongue, tonsil and pharyngeal wall primary tumours (usually with post-operative (chemo)radiotherapy) has been shown to offer rates of cure which appear to be as good as primary chemoradiotherapy in non-randomised comparisons, with promising functional results. Transoral resection is generally restricted to T1-T2 tumours, although resection of some T3 tumours may be considered if it is anticipated that negative margins can be achieved via a transoral approach. Transoral resection is rarely appropriate for T4 primary tumours. Also, where a larger resection of the soft palate is required, the general consensus is that surgery gives a poor functional outcome. It should be noted that approximately 80 per cent of patients who undergo primary surgery will also receive post-operative RT or chemoradiotherapy.
If transoral resection is not appropriate, e.g. for large primary tumours, then chemoradiotherapy should be considered. Alternatively, open surgical procedures may be considered, which usually require paramedian mandibulotomy for access and reconstruction with a flap. Trans-cervical pharyngotomy alone can be used for tongue base resections. Other approaches, such as glossotomy and lingual release can be used but are not often employed. Reconstruction is generally performed using radial artery free flaps or anterolateral thigh free flaps. Reconstruction using pedicled flaps, such as pectoralis major should be considered sub-optimal.
Functional results following open surgery can be poor, particularly when followed by adjuvant therapy.
There are several published case series that report the likelihood of nodal metastasis for advanced oropharyngeal carcinoma to be over 50 per cent. When managing T3 and T4 oropharyngeal cancers, the N0 neck should be treated electively. When managing the N0 neck surgically, a selective level II, III and IV neck dissection is generally recommended, and in some cases level I may be included. All patients with node positive disease should have a modified neck dissection or at least level I-IV selective neck dissection.
Primary chemoradiotherapy for loco-regionally advanced (stage III-IVb) oropharyngeal carcinoma. Chemoradiotherapy (organ preservation) is an effective treatment choice for advanced head and neck tumours. A RT dose equivalent of 70 Gy in 2 Gy fractions with concurrent cisplatin chemotherapy is considered standard for stage III and/or IV OPSCC. Concurrent weekly cetuximab (a monoclocal antibody targeting the epidermal growth factor receptor) may be given with RT if there is a contraindication to platinum chemotherapy (e.g. renal dysfunction or hearing impairment). Alternatively, radical RT alone can be given for patients with advanced disease who are not fit for concurrent treatment, particularly if they are over 70 years of age when the benefits of concurrent chemotherapy are reduced. Induction chemotherapy may be considered for patients with advanced (T4, N3, N2c) disease to reduce the risk of distant metastases 20 and for selected other patients with bulky primary (T4) and/or nodal disease (N3), but there is currently no high-quality evidence of its efficacy in these indications.
The principles of RT outlining and planning are as described for earlier stage disease. Neck nodes should be included in the treatment fields depending on their probability of involvement and according to the DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines and atlas which were updated in 2013. [bib_ref] Delineation of the neck node levels for head and neck tumors: a..., Gregoire [/bib_ref] Radiotherapy to levels Ib-IVa, V(a,b) and the retropharyngeal nodes (level VIIa) at the level of the oropharynx is generally recommended in a node positive neck. The retrostyloid space (level VIIb) is included when level II is involved and the supraclavicular fossa (levels IVb and Vc) is included when level IVa or V is involved. Radiotherapy should be given to at least the ipsilateral cervical lymph nodes for lateralised tumours and to both sides of the neck for non-lateralised tumours. The issue of whether the contralateral neck should be treated in patients with lateralised oropharyngeal tumours and advanced (N2+) nodal disease remains controversial and will depend on local practice.
Chemoradiotherapy is associated with greater toxicity than RT alone and late toxicity, particularly swallowing dysfunction, can have a significant impact on quality of life. [bib_ref] Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced..., Machtay [/bib_ref] Gastrostomy tube dependence rates of up to 24 per cent at 1 year and 14 per cent at 2 years post-chemoradiotherapy have been reported, although others have reported much lower rates. Improvements in RT techniques (including IMRT) have been shown to reduce late complications following RT. The UK PARSPORT randomised study showed a significant reduction in xerostomia rates with parotid sparing IMRT compared with conventional RT (using parallel opposed fields) in patients with advanced OPSCC. [bib_ref] Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT):..., Nutting [/bib_ref] Ongoing studies are exploring the role of IMRT in improving swallowing function following RT, by reducing radiation dose delivery to the pharyngeal constrictor muscles and other swallowing structures.
Traditionally, patients with advanced nodal disease (N2 or N3) being treated by chemoradiotherapy required a planned neck dissection, with little evidence to support whether neck dissection before or after chemoradiotherapy is more effective. There is now level I evidence from the PET-Neck trial that a PET-CT guided active surveillance policy, with neck dissection only being carried out if residual abnormal or equivocal nodes are present on imaging 10-12 weeks after the end of chemoradiotherapy, results in similar survival rates to a planned neck dissection, with less morbidity, and with higher cost effectiveness. [bib_ref] PETCT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer, Mehanna [/bib_ref] Post-operative radiotherapy and chemoradiotherapy for advanced oropharyngeal carcinoma. The indications for post-operative RT and chemoradiotherapy for OPSCC depend on pathological risk factors for recurrence common to most head and neck squamous carcinomas. Randomised controlled trials and a metaanalysis of results confirm that patients with extra-capsular invasion and/or microscopically involved (<1 mm) surgical resection margins around the primary tumour experience significant benefit in terms of overall and disease free survival from postoperative chemoradiotherapy compared with RT alone. [bib_ref] Defining risk levels in locally advanced head and neck cancers: a comparative..., Bernier [/bib_ref] Post-operative chemoradiotherapy is associated with significant acute and late toxicity and is not generally recommended in patients over 70 years of age and/or patients with poor performance status. Indications for post-operative RT alone include multiple nodal metastasis, T3 or T4 tumours, and tumours with other adverse features, including perineural or lymphovascular invasion. Patients with close (1-5 mm) surgical margins around the primary tumour may be treated with post-operative chemoradiotherapy or RT alone according to the presence or absence of other risk factors for recurrence. Patients should start their adjuvant RT as soon as possible after surgery (ideally within five weeks (35 days) and no later than six weeks (42 days)) to avoid reduced local control and survival due to protracted treatment.
The relevance of traditional risk factors for recurrence (including extra-capsular spread) and the benefit of adjuvant chemotherapy with RT in the context of HPV-positive OPSCC has been questioned by some studies. However, no change in management of patients should occur outside clinical trials. Clinical trials which aim to modify adjuvant treatment based on HPV status are currently ongoing in the UK and USA.
## Ongoing research
Human papilloma virus status appears to have profound influence on prognosis and, in the future, potentially on selection of treatment modality. There are several ongoing or planned clinical trials for HPV-positive and HPV-negative OPSCC and recruitment into clinical trials addressing these issues is highly recommended. Development of biomarker classifiers for treatment selection is also high recommended.
## Recommendations
- Advanced oropharyngeal carcinoma can be treated with primary chemoradiotherapy or transoral surgery and adjuvant (chemo)radiotherapy (R) - The N0 neck should be treated electivelyeither by radiotherapy or selective neck dissection (R) - Patients with advanced nodal (N2 or N3) disease receiving radical chemoradiotherapy should have a PET-CT scan 10-12 weeks after treatment, with a subsequent neck dissection within 4 weeks if residual abnormal or equivocal nodal disease is detected (R)
- Intensity modulated radiotherapy reduces toxicity in patients treated with radical radiotherapy, compared with conventional radiotherapy (R) - Post-operative chemoradiotherapy is currently recommended in patients treated with surgery who have involved primary tumour resection margins and/or extracapsular spread of nodal disease. Otherwise, post-operative radiotherapy alone may be indicated (R)
## Key points
- Oropharyngeal cancer incidence is increasing rapidly in the UK due to the Human papillomavirus (HPV). - HPV association confers better outcomes regardless of treatment modality - Early stage disease should be receive single modality treatment - Advanced disease should receive combined modality treatment - PETCT scanning undertaken at 10-12 weeks post chemo-radiation results in similar survival to planned neck dissection, but with considerably fewer patients requiring neck dissection, less morbidity and is cost-effective - There is insufficient evidence to alter treatment on the basis of HPV status - Patients should be offered the opportunity to participate in the ongoing clinical trials.
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https://www.cambridge.org/core/services/aop-cambridge-core/content/view/3F870614780722B7DB8285503E72CFAC/S0022215116000505a.pdf/div-class-title-oropharyngeal-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf
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Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. There has been significant debate in the management of oropharyngeal cancer in the last decade, especially in light of the increased incidence, clarity on the role of the human papilloma virus in this disease and the treatment responsiveness of the human papilloma virus positive cancers. This paper discusses the evidence base pertaining to the management of oropharyngeal cancer and provides recommendations on management for this group of patients receiving cancer care. Recommendations • Cross-sectional imaging is required in all cases to complete assessment and staging. (R) • Magnetic resonance imaging is recommended for primary site and computed tomography scan for neck and chest. (R) • Positron emission tomography combined with computed tomography scanning is recommended for the assessment of response after chemoradiotherapy, and has a role in assessing recurrence. (R) • Examination under anaesthetic is strongly recommended, but not mandatory. (R) • Histological diagnosis is mandatory in most cases, especially for patients receiving treatment with curative intent. (R) • Oropharyngeal carcinoma histopathology reports should be prepared according to The Royal College of Pathologists Guidelines. (G) • Human papilloma virus (HPV) testing should be carried out for all oropharyngeal squamous cell carcinomas as recommended in The Royal College of Pathologists Guidelines. (R) • Human papilloma virus testing for oropharyngeal cancer should be performed within a diagnostic service where the laboratory procedures and reporting standards are quality assured. (G) • Treatment options for T1–T2 N0 oropharyngeal squamous cell carcinoma include radical radiotherapy or transoral surgery and neck dissection (with post-operative (chemo)radiotherapy if there are adverse pathological features on histological examination). (R) • Transoral surgery is preferable to open techniques and is associated with good functional outcomes in retrospective series. (R) • If treated surgically, neck dissection should include levels II–IV and possibly level I. Level IIb can be omitted if there is no disease in level IIa. (R) • If treated with radiotherapy, levels II–IV should be included, and possibly level Ib in selected cases. (R) • Altering the modalities of treatment according to HPV status is currently controversial and should be undertaken only in clinical trials. (R) • Where possible, patients should be offered the opportunity to enrol in clinical trials in the field. (G)
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Joint Practice Guidelines for Radionuclide Lymphoscintigraphy for Sentinel Node Localization in Oral/Oropharyngeal Squamous Cell Carcinoma
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Joint Practice Guidelines for Radionuclide Lymphoscintigraphy for Sentinel Node Localization in Oral/Oropharyngeal Squamous Cell Carcinoma
Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/ oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the This article
provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.
Keywords Sentinel lymph node biopsy Á Carcinomas, squamous cell Á Head and neck neoplasms Á Technetium Tc-99m human serum albumin colloid Á Radionuclide imaging Oral/oropharyngeal squamous cell cancer (OSCC) is one of the most common cancers worldwide, with more than 274.000 new cases annually. [bib_ref] Global cancer statistics 2002, Parkin [/bib_ref] Three-quarters of cases affect people in the developing world, while in developed countries, OSCC is the eighth most prevalent form of cancer.
Determining the presence or absence of nodal metastasis is of paramount importance for staging, treatment planning, and prognosis. The incidence of occult metastases in patients with clinically node-negative (cN0) OSCC is high, with many series reporting rates greater than 30%. [bib_ref] Effectiveness of selective neck dissection for management of the clinically negative neck, Pitman [/bib_ref] [bib_ref] The patterns of cervical lymph node metastases from squamous carcinoma of the..., Shah [/bib_ref] [bib_ref] Critical assessment of supraomohyoid dissection, Spiro [/bib_ref] [bib_ref] The effect of occult nodal metastases on survival and regional control in..., Gourin [/bib_ref] Cervical lymph node involvement is the most important prognostic factor for patients with OSCC. [bib_ref] The effect of occult nodal metastases on survival and regional control in..., Gourin [/bib_ref] [bib_ref] Evaluation of cervical lymph node metastasis in squamous carcinoma of the head..., Don [/bib_ref] [bib_ref] The efficacy of comprehensive neck dissection with or without postoperative radiotherapy in..., Leemans [/bib_ref] Elective treatment of the clinically negative neck remains a controversial topic. Over the last two decades much work has been undertaken to find reliable predictors of occult metastases, of which tumor depth appears to be the best available. [bib_ref] Micrometastases in carcinoma of the upper aerodigestive tract: detection, risk of metastasizing,..., Ambrosch [/bib_ref] [bib_ref] Depth of invasion is the most significant histological predictor of subclinical cervical..., Kane [/bib_ref] [bib_ref] Predictive factors of occult metastasis and prognosis of clinical stages I and..., Amaral [/bib_ref] [bib_ref] Mode of invasion and lymph node metastasis in squamous cell carcinoma of..., Yamamoto [/bib_ref] However, the predictive capacity of tumor depth and other primary tumor characteristics are still insufficient to negate the need for surgical staging of the cervical node basin. [bib_ref] Does tumor depth affect nodal upstaging in squamous cell carcinoma of the..., Alkureishi [/bib_ref] Elective neck dissection (END) is the current gold-standard staging procedure for the cN0 neck, providing valuable prognostic information regarding nodal status and simultaneously treating those patients found to be node positive (pN?). Previously, ENDs invariably took the form of a modified radical neck dissection, however there is increasing evidence that selective neck dissection is as efficacious as comprehensive neck dissection in treating the negative neck. [bib_ref] Effectiveness of selective neck dissection for management of the clinically negative neck, Pitman [/bib_ref] [bib_ref] Modified neck dissection: a study of 967 cases from 1970 to 1980, Byers [/bib_ref] [bib_ref] Rationale for elective modified neck dissection, Byers [/bib_ref] [bib_ref] Cervical lymph node metastases-diagnostic, therapeutic and prognostic implications, Shah [/bib_ref] [bib_ref] Evolving role of modifications in neck dissection for oral squamous carcinoma, Shah [/bib_ref] [bib_ref] Results of a prospective trial on elective modified radical classical versus supraomohyoid..., Head [/bib_ref] [bib_ref] Rationale for elective neck dissection, Pitman [/bib_ref] [bib_ref] Management of the N0 neck in oral squamous cell carcinoma, Cheng [/bib_ref] The shift toward more conservative surgical procedures has occurred primarily in the last two decades, facilitated by the work undertaken by Lindberg, Byers, and Shah to describe the common patterns of lymphatic drainage. [bib_ref] The patterns of cervical lymph node metastases from squamous carcinoma of the..., Shah [/bib_ref] [bib_ref] Distribution of cervical lymph node metastases from squamous cell carcinoma of the..., Lindberg [/bib_ref] [bib_ref] Selective neck dissections for squamous carcinoma of the upper aerodigestive tract: patterns..., Byers [/bib_ref] Knowledge of these patterns has allowed the extent of neck dissections to be progressively limited to those nodal levels at highest risk, and sentinel node biopsy (SNB) represents an extension of this philosophy.
The aim of this review is to provide an evidence-based guideline for the use of sentinel node biopsy as a staging tool for patients with early OSCC, presenting the best available evidence at the time of writing.
The existing literature was reviewed, utilizing electronic techniques (Medline, Best Evidence, the Cochrane Library, Dare) and hand-searching techniques. Where little or no data existed from randomized controlled prospective trials, emphasis was given to data from large series or reports from recognized experts in the field. It is recognized that higher-level evidence from future studies may modify the recommendations made in this manuscript.
## Definition of a sentinel node
The sentinel node concept states that the spread of a tumor is embolic in nature, via the lymphatics to the firstechelon lymph node(s) encountered in the regional draining basin. These represent the lymph nodes most likely to harbor occult metastases, and are designated the sentinel lymph nodes (SLNs). Excisional biopsy and pathological evaluation of the SLNs therefore allows for prediction of the disease status of the remaining cervical lymph node basin, potentially avoiding the need for a neck dissection. Sentinel lymph nodes need not be those closest to the tumor, and there may be multiple SLNs. [bib_ref] Technical details of intraoperative lymphatic mapping for early stage melanoma, Morton [/bib_ref] With the application of early dynamic lymphoscintigraphy, lymphatic channels are usually visualized, and nodes on a direct drainage pathway may be distinguished. The practical approach may include the combination of available detection techniques.
Lymphatic mapping and sentinel node biopsy (SNB) were first reported in 1977 by Cabanas for penile cancer. [bib_ref] An approach for the treatment of penile carcinoma, Cabanas [/bib_ref] In 1992, Morton and colleagues first described the use of intradermal isosulfan blue dye injection for lymphatic mapping and SLN localization in patients with malignant melanoma. [bib_ref] Technical details of intraoperative lymphatic mapping for early stage melanoma, Morton [/bib_ref] The following year, Alex et al. described a peritumoral intradermal injection of radioactive tracer ( 99 m technetium sulfur colloid), followed by imaging and intraoperative gamma probe radiolocalization of SLNs. [bib_ref] Gamma-probe-guided lymph node localization in malignant melanoma, Alex [/bib_ref] The sentinel node concept has since been extensively studied and validated for patients with cutaneous melanoma and breast cancer. [bib_ref] Management of earlystage melanoma by intraoperative lymphatic mapping and selective lymphadenectomy, Morton [/bib_ref] [bib_ref] Surgical resection and radiolocalization of the SLN in breast cancer using a..., Krag [/bib_ref] Studies to date have also indicated a high level of accuracy in patients with OSCC. [bib_ref] Sentinel node biopsy in head and neck cancer: preliminary results of a..., Ross [/bib_ref] [bib_ref] Sentinel lymph node evaluation in squamous cell carcinoma of the head and..., Stoeckli [/bib_ref]
## Clinical indications
## Inclusion criteria
The most important inclusion criterion for SNB is a clinically negative neck, as defined by physical examination and clinical imaging by computed tomography (CT), contrast-enhanced magnetic resonance imaging (MRI), ultrasound-guided fine-needle aspiration cytology (USg-FNAC), and/or 18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) with or without low-dose CT (PET/CT). [bib_ref] Positron emission tomography in combination with sentinel node biopsy reduces the rate..., Kovács [/bib_ref] There remains considerable debate on the preferred imaging modality, and to date none have the ability to detect small or micrometastatic tumor deposits, but all techniques improve on the sensitivity of palpation alone and are therefore recommended prior to SNB. Recently, the high specificity of PET has been highlighted as an important means of avoiding unnecessary neck dissections. [bib_ref] Positron emission tomography in combination with sentinel node biopsy reduces the rate..., Kovács [/bib_ref] Gross lymphatic involvement can lead to distortion of the normal architecture, leading to aberrant drainage patterns and biopsy of false sentinel nodes. [bib_ref] Predictive factors for failure to identify sentinel nodes in head and neck..., Hornstra [/bib_ref] SNB is therefore contraindicated to stage clinically positive necks.
Following the first report of SNB for OSCC, the technique has undergone extensive validation against the gold-standard END, for tumors located in the oral cavity and accessible subsites of the oropharynx. [bib_ref] Sentinel lymph node evaluation in squamous cell carcinoma of the head and..., Stoeckli [/bib_ref] [bib_ref] The gamma-probe-guided resection of radiolabeled primary lymph nodes, Alex [/bib_ref] [bib_ref] A suggested method for sentinel node biopsy in squamous cell carcinoma of..., Shoaib [/bib_ref] It has been demonstrated to be an accurate means of staging the clinically negative neck, and more recently the potential prognostic value of SNB for these tumor sites has also been highlighted. [bib_ref] Positive sentinel lymph nodes are a negative prognostic factor for survival in..., Kovács [/bib_ref] While SNB has been successfully reported for tumors in other locations such as the hypopharynx and supraglottic larynx, there remain significant technical barriers, and SNB for these sites should therefore still be considered investigational.Poor access to these sites requires general anesthesia and endoscopic guidance for radiotracer injection, precluding the use of preoperative lymphoscintigraphy (LSG), while the close proximity of the primary tumor to the first-echelon lymph nodes can potentially obscure the true location of SLNs. Additionally, advanced stage at presentation is common for these hidden tumors, precluding the use of SNB or indeed any surgical intervention.
There is an existing consensus that SNB for OSCC should be restricted to early tumors staged T1/2. [bib_ref] The ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically..., Ross [/bib_ref] [bib_ref] The first international conference on sentinel node biopsy in mucosal head and..., Ross [/bib_ref] [bib_ref] The second international conference on sentinel node biopsy in mucosal head and..., Stoeckli [/bib_ref] Larger tumors are difficult to completely surround with the tracer injection, tend to drain to multiple lymphatic basins, and in most patients require a neck dissection for access to the primary tumor or defect reconstruction. Inclusion of T3/T4 tumors in study protocols can lead to variability in the accuracy of the technique. [bib_ref] The ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically..., Ross [/bib_ref] The first and most frequent indication for SNB is to stage the ipsilateral cN0 neck in patients with a unilateral primary tumor. A second indication is for assessment of bilateral cN0 necks in primary tumors close to, or crossing, the midline. The third indication is for assessment of the contralateral cN0 neck in primary tumors close to the midline with an ipsilateral cN? neck, in order to decide whether these patients need bilateral neck dissections, or an ipsilateral neck dissection and contralateral SNB only. Patients should also be fit enough preoperatively to withstand a neck dissection.
Patients who have received prior radiation or surgical treatment to the neck are routinely excluded from SNB protocols, since the previous intervention can distort the normal lymphatic pathways and give rise to unexpected patterns of metastasis. It is possible that lymphatic mapping and SNB may yield potentially useful information in these patients. Similarly, patients with small recurrent or second primary tumors may also benefit from lymphatic mapping to guide surgical intervention. However, these applications of the SNB technique, whilst clinically attractive, remain largely unexplored.
## Exclusion criteria
In pregnant women, the urgency and the necessity of staging the neck should be discussed. Lymphoscintigraphy is specifically contraindicated in the pelvis of pregnant women, but no such recommendations are currently available for the head and neck. As discussed in the ''Dosimetry'' section, the risk of fetal damage is negligible during routine SNB procedures. However, SNB protocols should be modified in pregnant patients to minimize risks of radiation exposure and blue-dye injections. For example, the use of a 1-day protocol allows a lower injected radiation dose, and the additional radiation associated with SPECT/CT imaging may not be warranted in the pregnant patient. SNB can be performed in lactating women, but it is advised that breastfeeding be discontinued following the procedure. OSCC is rare in children, though each case should be treated individually. In the UK, Nanocolloid is approved for use in children, though licencing varies between countries. The potential benefits of sentinel node biopsy are not as well delineated in the pediatric population and, in practice, most SNB trial protocols generally exclude these patients from participation. Off-label use of radiopharmaceuticals should be considered with caution and with respect to an individual risk-benefit analysis. Other relative contraindications include known allergy to albumin colloid, and primary tumor treatment by external-beam radiotherapy.
In summary, SNB is currently indicated for cT1/2, cN0 oral, and select oropharyngeal SCC, where it may be considered a valid alternative to elective neck dissection. Other head and neck sites, histologies, and clinical situations remain under investigation.
## Radiopharmaceuticals
# Introduction
A variety of colloidal and soluble tracers have been used over the years for lymph studies. It is believed that radiocolloids are taken up by macrophages in lymph nodes whereas the transit of macromolecules through lymph nodes is delayed simply because of their large molecular size. [bib_ref] Radiopharmaceuticals in sentinel lymph-node detection-an overview, Wilhelm [/bib_ref]
## Choice of radiopharmaceutical
The main radiopharmaceutical used in European studies of sentinel node localization in oral cancers is Tc-99mlabeled human serum albumin colloid (Nanocoll Ò ) (GE Healthcare). Nanocoll Ò has a particle size range of 5-80 nm, with a reported mean size of 8-30 nm. [bib_ref] Radiopharmaceuticals in sentinel lymph-node detection-an overview, Wilhelm [/bib_ref] Although in theory a larger particle such as Albures Ò (GE Healthcare) or Sentiscint Ò (Medi-Radiopharma) may be preferred for tumors in the floor of mouth or anterior tongue where lymphatic densities are high, Nanocoll Ò performs satisfactorily in all tumor types studied. [bib_ref] The ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically..., Ross [/bib_ref] Nanocoll Ò migrates to the sentinel node within minutes, yet prolonged retention allows surgery to take place the following day.
Other radiocolloids which have been used include Tc-99 m rhenium sulfide colloid (Nanocis Ò , IBA), which has been shown to have a mean particle size of 23-25 nm. [bib_ref] Particle sizes of colloids to be used in sentinel lymph node radiolocalization, Jimenez [/bib_ref] Tc-99 m sulfide colloid has also been used. Standard preparations of Tc-99 m sulfide colloid result in a wide range of particle sizes, so the product is often filtered through a 100-or 200-nm membrane filter to obtain a smaller and more uniform size distribution. While there are currently no clinical studies comparing different radiopharmaceuticals, investigators have described satisfactory results with each of the available colloids. [bib_ref] The diagnostic role of radioactivity in sentinel nodes in oral and oropharyngeal..., Kovács [/bib_ref] [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] Preparation and Quality Control Nanocoll Ò is labeled by incubation with Tc-99 m pertechnetate at room temperature for 30 min.Radiochemical purity can be checked by thin-layer chromatography, and labeling efficiency should be [95%. The EANM guidelines on current good radiopharmacy practice (cGRPP, www.eanm.org) recommend that labeling efficiency be checked on each preparation. The stated expiry is 6 h after preparation, although extended stability has been demonstrated. [bib_ref] Validation of an extended shelf-life for Tc-99 m albumin nanocolloid injection, Millar [/bib_ref]
## Drug interactions and adverse effects
No interactions of drugs with radiocolloids are expected following local intradermal or subcutaneous application. Adverse effects are rare and mild following interstitial application of radiocolloids, although allergic reactions have been reported with Nanocoll and the blue dyes used at surgery. [bib_ref] Allergic reaction to nanocolloid during lymphoscintigraphy for sentinel node biopsy, Burton [/bib_ref] [bib_ref] Allergy to technetium-labeled nanocolloidal albumin for sentinel node identification, Chicken [/bib_ref] [bib_ref] Hypersensitivity reaction against patent blue during sentinel lymph node removal in three..., Keller [/bib_ref] The incidence of allergic reactions is too low to quantify, but appropriate emergency medicines should be kept available during the procedure.
## Summary
Tc-99 m-labeled Nanocoll Ò is easy to prepare and supply, and has suitable properties for sentinel node localization in oral cancers, with rapid migration to the sentinel node and prolonged retention.
## Dosimetry: patient
## General remarks
Presently available dosimetric data are derived from the breast cancer SNB literature, where the absorbed doses to patients are determined to be low; therefore, the radiation risk associated with this procedure is low. While no specific OSCC data exist, the radiopharmaceuticals and administered activity are identical, leading to the assumption that OSCC SNB is a safe procedure from the radiation protection point of view.
## Patient exposure
The estimated local radiation dose varies greatly, depending on the administered dose and time to surgery. As mentioned in the ''Injection'' section, there is little consensus on the optimal administered dose and timing of surgery relative to the radiocolloid injection. Most centers perform LSG within 24 h of surgery, but recommendations for administered activity range from 15 MBq (for a sameday procedure) to 120 MBq (for a 2-day procedure) in a total injection volume of 0.4-1.0 ml. The aim is to achieve an activity of at least 10 MBq at the time of surgery. [bib_ref] Sentinel node detection using Tc-99 mrhenium sulphide colloid in breast cancer patients:..., Koizumi [/bib_ref] [bib_ref] EANM-EORTC recommendations for sentinel node diagnostics in melanoma, Chakera [/bib_ref] Current EANM guidelines for SNB in breast cancer report a mean value for the effective dose of 0.048 mSv. [bib_ref] Sentinel node in breast cancer procedural guidelines, Buscombe [/bib_ref] While other authors have reported doses approximately tenfold higher, these remain low compared with other nuclear medicine procedures. [bib_ref] Radiation safety of the sentinel node technique in breast cancer, Waddington [/bib_ref] Extensive calculations performed by the Memorial Sloan-Kettering Cancer Center have confirmed the safety of SNB by reporting an effective dose around 0.2 mSv. [bib_ref] Organ and fetal absorbed dose estimates from Tc-99 m-sulfur colloid lymphoscintigraphy and..., Pandit-Tskar [/bib_ref]
## Fetal exposure
The maximum value for fetal absorbed dose has been calculated to be 0.013 mSv following injection of 18.5 MBq. [bib_ref] Organ and fetal absorbed dose estimates from Tc-99 m-sulfur colloid lymphoscintigraphy and..., Pandit-Tskar [/bib_ref] This dose is equivalent to that received by the mother from 1 day of natural background radiation in the USA, and is orders of magnitude below the 100-200-mSv threshold for deterministic effects (malformation, growth retardation, neurodevelopmental abnormalities). [bib_ref] Radiation safety of the sentinel node technique in breast cancer, Waddington [/bib_ref] Current consensus is that noncancer health effects are not detectable below 50 mSv, while congenital malformations occur above 200 mSv. [bib_ref] Organ and fetal absorbed dose estimates from Tc-99 m-sulfur colloid lymphoscintigraphy and..., Pandit-Tskar [/bib_ref] With respect to childhood cancer induction (stochastic effect), the International Commission on Radiological Protection (ICRP) reports a threshold of 10 mSv for a 40% risk increase.In summary, the advantages of SNB for OSCC outweigh the potential risks of the absorbed radiation dose, and this is also true for pregnant patients. While SNB is not contraindicated in pregnant patients, it is preferable to use a same-day protocol, enabling a lower injected dose. [bib_ref] EANM-EORTC recommendations for sentinel node diagnostics in melanoma, Chakera [/bib_ref]
## Lactating women
The current recommendation is that nursing mothers should suspend breast-feeding for 24 h following radiopharmaceutical injection, during which time the general anesthetic agent and radiocolloid will be excreted in breast milk. 51
## Dosimetry: staff
## Staff in operating room
Studies in breast and melanoma patients have determined the mean whole-body dose received by surgical staff to be \1 lSv per operation, with the maximum dose to the surgeon of \2 lSv. [bib_ref] Radiation safety of the sentinel node technique in breast cancer, Waddington [/bib_ref] [bib_ref] Sentinel node detection in malignant melanoma patients: radiation safety considerations, Sera [/bib_ref] [bib_ref] Radiation safety with breast sentinel node biopsy, Stratmann [/bib_ref] [bib_ref] Radiation doses to staff involved in sentinel node operations for breast cancer, Klausen [/bib_ref] The absorbed doses are further minimized when SNB is performed at 24 h after injection. [bib_ref] Sentinel node biopsy in skin melanoma patients -measurements of absorbed doses of..., Nejc [/bib_ref] Monitoring of operating room personnel for occupational exposure during the procedure is therefore unnecessary, and additional shielding is not required. While the pregnant surgeon or scrub nurse requires specific consideration, participation in fewer than 100 SNB operations during the gestation will remain below the recommended radiation exposure limits for pregnant women. [bib_ref] Radiation doses to staff involved in sentinel node operations for breast cancer, Klausen [/bib_ref]
## Staff in pathology department
Radiation exposure to pathology staff is very low, and should not require badge monitoring. Even personnel performing unusually high numbers of procedures receive radiation doses well below established limits for members of the general public. [bib_ref] Radiation safety considerations for sentinel node techniques, Glass [/bib_ref]
## Radiation safety precautions
Labeling specimens as radioactive for transportation to the laboratory is not required, since the surface dose rate is \5 lGy/h.
## Radioactive clinical waste
Surgical instruments and pathology slides appear to stay at background radiation levels, while measurable contamination of absorptive surgical sponges and other materials used in proximity to the injection site is observed. [bib_ref] Safety guidelines for radiolocalised sentinel node resection, Nugent [/bib_ref] It is advisable to monitor these materials for contamination, and contaminated materials should be held for an appropriate period of decay in storage before disposal. 52,59
## Injection
The lymphatic anatomy within the oral cavity and oropharynx is extremely complicated and varies significantly between subsites, emphasizing the need for precise injection technique. 39,62,63
## Patient preparation
No special preparation is needed. Patients should be fully informed about the procedure, including discussion of potential problems such as bleeding and discomfort, before consent can be obtained.
## Syringe, activity, and volume
Tuberculin syringes with minimal dead space are recommended; otherwise 0.1 mL air may be drawn into the syringe behind the radiocolloid to ensure complete administration. A 25-or 27-gauge needle should be used. The total activity to be injected may vary, depending on the size and location of the primary tumor. As described in the ''Dosimetry'' section, there is currently little consensus on the optimum activity for injection, and this varies considerably from 15 to 120 MBq between studies. [bib_ref] The second international conference on sentinel node biopsy in mucosal head and..., Stoeckli [/bib_ref] [bib_ref] Sentinel node biopsy for oral and oropharyngeal squamous cell carcinoma of the..., Stoeckli [/bib_ref] [bib_ref] Lymphatic mapping to tailor selective lymphadenectomy in cN0 tongue carcinoma: beyond the..., De Cicco [/bib_ref] The total injected activity should be adjusted according to the timing of LSG with respect to surgery. Higher doses are required for a 2-day protocol, in order to ensure that the activity exceeds 10 MBq at the time of surgery. [bib_ref] EANM-EORTC recommendations for sentinel node diagnostics in melanoma, Chakera [/bib_ref] Small volumes of 0.1-0.2 mL per aliquot are recommended to minimize contamination due to the resistance of tongue tissue. Contamination can be avoided by placement of a sheet over the injected region and a gauze swab over the needle puncture site before withdrawal. Following injection, the skin/mucosa should be checked for contamination.
## Injection site and depth, and number of injections
Tracer should be injected at 0.1-0.5 cm from the tumor or scar margin. The number of aliquots to be injected varies (two to four) according to the size and location of the lesion. The tracer should be administered on each side of the tumor/scar, keeping as a reference the orientation of the surgical scar. For lesions in sites with abundant soft tissue (i.e., soft palate or floor of the mouth) four separate submucosal injections must be given around the lesion (at 3, 6, 9, and 12 o'clock). For lesions located in muscle (i.e., tongue), injections should be performed according to the depth of the lesion. Ideally, the operating surgeon should be present for the injections to ensure consistency with injection of blue dye if used. Following injection, bleeding may be controlled with a gauze swab, and the patient should be asked to use a mouth rinse to minimize pooling of the radiotracer in the oral cavity. [bib_ref] A suggested method for sentinel node biopsy in squamous cell carcinoma of..., Shoaib [/bib_ref]
## Imaging
# Introduction
Lymphoscintigraphy uses a gamma camera to assess the drainage of injected radiotracer via the lymphatic capillaries to the larger collector lymphatics until it either passes through, or is retained within, the regional lymph nodes. [bib_ref] Clinical assessment of human lymph flow using removal rate constants of interstitial..., Modi [/bib_ref] Accurate preoperative localization and cutaneous marking of the SLNs correlates well with the precision of the surgical procedure. [bib_ref] Role of lymphoscintigraphy for selective sentinel lymphadenectomy, Uren [/bib_ref] [bib_ref] Kinetics of three lymphoscintigraphic agents in patients with cutaneous melanoma, Glass [/bib_ref] Cameras and Camera Settings (Quality Control)
A large-field-of-view gamma camera equipped with a high-or ultrahigh-resolution low-energy collimator should be used, with a 10-20% window centered on the 140-keV energy peak of Tc-99 m. A two-headed camera allows simultaneous dynamic acquisition in the anterior and a lateral projection, and saves time for the static images and SPECT. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] Quality control for the gamma camera should be routinely performed and should follow published protocols.
## Image acquisition
Dynamic acquisition for 20-30 min (20 s per frame) with a 128 9 128 matrix or 256 9 256 matrix starting immediately after radiotracer injection will show the drainage pattern and help to differentiate between sentinel nodes, which can appear very early following injection, and second-echelon lymph nodes. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] [bib_ref] The impact of superficial injections of radiocolloids and dynamic lymphoscintigraphy on sentinel..., Tartaglione [/bib_ref] Two (or three if a three-headed camera is used) simultaneous images in the anterior and lateral projections are recommended.
Static images in the anterior and lateral projections from one or both sides (and oblique as needed) are acquired (300 s, with a 256 9 256 matrix) to localize the nodes in three dimensions. If hot nodes are not clearly depicted, static images can be repeated at, e.g., 2 h, 4-6 h or even just before surgery. The patient is imaged in the supine position with head up. A small flat pillow under the neck may help to fixate the head and neck area.
SPECT imaging may improve the identification of SLNs, especially close to the injection site. Lesion detectability is increased by attenuation and scatter correction, which is easily accomplished with hybrid SPECT/ CT devices. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] [bib_ref] SPECT-CT for topographic mapping of sentinel lymph nodes prior to gamma probe-guided..., Wagner [/bib_ref] The increased anatomical detail provided with CT improves localization of SLNs to the anatomical neck level. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] SPECT acquisition parameters can be 128 9 128 matrix, 180°in the anterior L-mode rotation, 3°angle step, with 20-25 s per projection or 60 steps per head, 30 s each, with slice thickness of 4.42 mm. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] [bib_ref] Lymphoscintigraphy for sentinel node mapping using a hybrid single photon emission CT..., Khafif [/bib_ref] CT acquisition parameters differ depending on the CT system used. To date, most reports on SPECT/CT for SNB in oral cancer have used a slow, low-end CT scanner (GE Hawkeye) with acquisition performed over 220°using 16 s for each transaxial slice, with a fixed tube current of 2.5 mA, 140 kV, and slice thickness of 10 mm. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] [bib_ref] Lymphoscintigraphy for sentinel node mapping using a hybrid single photon emission CT..., Khafif [/bib_ref] With fast, high-end CT scanners providing higher-quality CT scans, either a low dose or a higher dose of CT can be used. Low-dose parameters can be, e.g., 20 ms per slice, slice thickness/increment 3/3 mm, and 120 kV. If a diagnostic CT scan is required, IV contrast can also be used. If CT images are used for attenuation correction, inspection of both uncorrected and attenuation-corrected SPECT images is recommended, to avoid overlooking contrast-induced artifacts on the latter.
A number of studies have reported advantages of adding SPECT/CT to planar imaging, including identification of missed SLNs, exclusion of ambiguous SLNs, and/or better anatomical localization in 30-47% of patients. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] [bib_ref] Lymphoscintigraphy for sentinel node mapping using a hybrid single photon emission CT..., Khafif [/bib_ref] However, it has been suggested that meticulous oblique planar imaging can visualize the additional SLNs seen with SPECT imaging, and this may represent an adequate alternative. [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] Furthermore, a number of investigators have reported no advantage to SPECT imaging with respect to the number and location of visualized hotspots. [bib_ref] Is there an additional value of SPECT/CT over lymphoscintigraphy for sentinel node..., Haerle [/bib_ref] [bib_ref] Sentinel lymph node mapping using SPECT-CT fusion imaging in patients with oral..., Keski-Santti [/bib_ref] The true role of SPECT imaging for OSCC SNB has yet to be determined. If used, SPECT/CT should not be a substitute for meticulous planar imaging technique.
The location of SLNs harvested during surgery does not always correlate perfectly with the preoperative imaging, though higher-quality CT images can allow visualization of individual SLNs \1 cm, leading to improved preoperative and intraoperative SLN localization. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] [bib_ref] Multimodal image registration for localization of sentinel nodes in head and neck..., Lopez [/bib_ref] Body Contouring
To facilitate topographic localization, a 57Co flood source (or, if available, a 153Gd source) can be used for simultaneous transmission imaging in each projection. Since there is a risk of missing faint nodes when using a transmission source, it has been suggested to repeat the scan without a transmission source. [bib_ref] Lymphoscintigraphy in high-risk melanoma of the trunk: predicting draining node groups, defining..., Uren [/bib_ref] Alternatively, a radioactive point source may be used to outline the patient's contour while recording the scan.
## Image interpretation
On dynamic imaging, SLNs are identified as one or more foci to which lymphatic drainage passes, and may be multiple, in one or several areas of the neck, ipsilateral and/ or contralateral to the primary tumor. [bib_ref] Variability of cutaneous lymphatic flow rates in melanoma patients, Uren [/bib_ref] Imaging should begin immediately, since SLNs can be seen in the first minute after injection. [bib_ref] Lymphoscintigraphic details of sentinel lymph node detection in 82 patients with squamous..., Nieuwenhuis [/bib_ref] Foci appearing only on later images are also labeled as SLNs, and most appear within 1-3 h. [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] [bib_ref] Lymphoscintigraphy for sentinel node mapping using a hybrid SPECT/CT system, Even-Sapir [/bib_ref] According to some reports, SPECT/CT may identify a median of one additional SLN compared with planar imaging. In addition, SLNs located very close to the primary tumor may be detected by SPECT/CT but not with the gamma probe during surgery. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] While the benefits of SPECT/CT have not been universally accepted, both planar and SPECT images demonstrate good or excellent inter-and intraobserver agreement for evaluation of SLNs, with kappa values of 68-89%. [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] [bib_ref] Is there an additional value of SPECT/CT over lymphoscintigraphy for sentinel node..., Haerle [/bib_ref] [bib_ref] Sentinel lymph node mapping using SPECT-CT fusion imaging in patients with oral..., Keski-Santti [/bib_ref] Nonvisualization SLNs are usually detected between 15 and 60 min after radiotracer injection. Failure to detect SLNs may be related to incorrect injection technique or close proximity of SLNs to the injection site (e.g., floor of mouth tumors). In addition, metastatic deposits may block lymphatic drainage, causing nonvisualization of SLNs. [bib_ref] Predictive factors for failure to identify sentinel nodes in head and neck..., Hornstra [/bib_ref] [bib_ref] Need for intensive histopathologic analysis to determine lymph node metastases when using..., Bilde [/bib_ref] Repeat injection and imaging may be considered, however proceeding to neck dissection is preferred in order to avoid a false-negative SLN.
## Aberrant nodes and in-transit sentinel nodes
Individual lymphatic mapping by lymphoscintigraphy is a major advantage of SNB, demonstrating occasional unexpected drainage to, e.g., level IV or contralateral metastases from well-lateralized tumors. [bib_ref] Sentinel node biopsy for oral and oropharyngeal squamous cell carcinoma of the..., Stoeckli [/bib_ref] [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] [bib_ref] Need for intensive histopathologic analysis to determine lymph node metastases when using..., Bilde [/bib_ref] [bib_ref] Functional anatomy of the lymphatic drainage system of the upper aerodigestive tract..., Werner [/bib_ref] [bib_ref] Sentinel lymph node biopsy in squamous cell carcinomas of the lips and..., Frerich [/bib_ref] [bib_ref] The nodal neck level of sentinel lymph nodes in mucosal head and..., Shoaib [/bib_ref] [bib_ref] The number of sentinel nodes identified as prognostic factor in oral epidermoid..., Gallegos-Hernandez [/bib_ref] [bib_ref] Sentinel lymph-node biopsy in head and neck cancer, Hoft [/bib_ref] [bib_ref] Sentinel lymph node biopsy in oral cavity squamous cell carcinoma without clinically..., Kontio [/bib_ref] [bib_ref] Sentinel node biopsy in head and neck cancer, Mozzillo [/bib_ref] In addition, LSG has been reported to detect ''in-transit'' lymph nodes: SLNs lying between the primary tumor and the regional lymph basin. [bib_ref] Interval nodes: the forgotten sentinel nodes in patients with melanoma, Uren [/bib_ref] These have been described in the context of malignant melanoma, but to date there have been no reports of in-transit SLNs in OSCC.
## Report and display
# Introduction
There are two main indications for careful report and display of the results from lymphoscintigraphy:
(1) unambiguous guidance for surgical biopsy, and (2) a comprehensive dataset for ongoing/future studies. [bib_ref] The ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically..., Ross [/bib_ref] [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] Report
The type of radiocolloid, lot number, volume injected, and effective dose should be recorded, along with the initials and title of the nuclear medicine physician or surgeon performing the injection. The type of camera used and imaging technique should be described in detail: [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] 1. Start time for dynamic imaging; 2. Timing and location of the first-echelon node(s) that appear; 3. Timing and number of anterior, posterior, and oblique recordings; 4. Timing and location of any additional (second-echelon) nodes; these should be clearly differentiated from the first-echelon nodes; 5. If CT or hybrid imaging is used, the manufacturer, software, and protocol should be described in detail. The number and location of nodes recorded by these modalities should be described and compared with planar recordings. It should be clearly stated if the results of the tomographic images differ from the planar recordings.
Shine-through from the primary tumor or opposite side should be described and marked clearly on the images. Increased absorption in the thyroid gland can be seen due to unstable colloid solution as a result of a colloid production error, and this may lead to difficulties in interpreting the lymphoscintigraphic images. [bib_ref] Lymphoscintigraphy in tumors of the head and neck using double tracer technique, Klutmann [/bib_ref] Artifacts may also occur due to cutaneous contamination at the time of injection. [bib_ref] Contamination problem with sentinel node localization procedure: a case study, Warner [/bib_ref] Rarely, a widened lymphatic capillary may form a ''colloid lake;'' however, the associated hotspot will invariably disappear during subsequent imaging, in contrast with true SLNs.
## Display
Lymphoscintigraphic findings should be summarized by the nuclear medicine physician, providing a clear, unambiguous report for preoperative consultation. In addition, hardcopy or digital copies of the LSG images should be available to the surgeon, both prior to and during surgery. [bib_ref] The ability of lymphoscintigraphy to direct sentinel node biopsy in the clinically..., Ross [/bib_ref] [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] Skin Marking
First-echelon nodes should be marked on the skin using one color of indelible marker, guided by gamma camera and handheld gamma probe. [bib_ref] Localization of sentinel nodes in breast cancer: a novel method and device..., Laasanen [/bib_ref] Second-echelon nodes should be marked with a different color, and clearly differentiated.
## Use of dye
# Introduction
The use of blue dye in head and neck mucosal cancer sentinel node surgery is optional. However, when used it is a useful adjunct to aid SLN localization and harvest. Blue dye cannot be used alone to perform OSCC SNB, but can be used in addition to radiolocalization with preoperative LSG and intraoperative gamma probe use. [bib_ref] A suggested method for sentinel node biopsy in squamous cell carcinoma of..., Shoaib [/bib_ref] Following injection, blue dye drains to the SLNs via the same lymphatic pathways as radiocolloid, staining the channels, which can then be followed to the first-echelon nodes. Direct visualization and dissection of these channels is a natural process for the head and neck surgeon.
Rarely, nonradioactive blue nodes may contain metastases in the absence of a tumor-positive radioactive node; two such SLNs were reported in a series of 40 patients undergoing SNB with both radiocolloid and blue dye injection. [bib_ref] The accuracy of head and neck carcinoma sentinel lymph node biopsy in..., Shoaib [/bib_ref] The handheld gamma probe is more sensitive for the detection of sentinel nodes, and not all radioactive nodes will also appear blue. [bib_ref] Sentinel node biopsy in head and neck cancer: preliminary results of a..., Ross [/bib_ref] However, blue dye may aid the surgeon perform SNB, both for technical success of the procedure and for identification of subclinical nodal metastasis.
## Contraindications and special precautions
Blue dye is contraindicated in children, pregnant women, lactating women, and those who have a history of allergy to the blue dye or any of its ingredients. It can, however, be used in all mucosal sentinel node procedures, for any malignant process for which the procedure has been deemed suitable, including OSCC.
## Blue dyes
In the UK and Europe, the blue dye used is Patent Blue V (Laboratoire Guerbet, Aulnay-Sous-Bois, France; which comes in 2-ml vials at 2.5% concentration. Outside of Europe, the use of other agents such as Isosulfan Blue (Lymphazurin TM) is more common. Gloves should be worn to avoid staining, and a gauze swab used to prevent dye spillage where possible. The dye will rarely mask the edge of the tumor and, if this is a concern, the tumor edge can be marked prior to injection with staples or diathermy marks.
## Fig. 1 patent blue v dye
## Timing of injection
Patent Blue V dye is injected at the time of surgery, under general anesthetic. It takes approximately 10-15 min for a significant amount of dye to travel from the injection site to the sentinel node and this is the approximate time it takes to scrub, prepare the patient, make the initial excision, and begin to explore the neck. The patient and anesthetist should be informed that the dye will be excreted in the urine, and the urine will remain discolored for approximately 2 days.
## Injection technique
One vial of dye is injected slowly into the tissues surrounding and deep to the tumor, to minimize leakage from ulcerated tumors. Gauze swabs may be used to protect normal tissue and mop up excess dye. The number of injections is usually between two and four, but is as many as is necessary to completely surround the tumor on its deep and lateral surfaces. Occasionally it may be necessary to grab the tongue with forceps or a retracting suture during the injection. The injection site should not be massaged, in order to maintain oncologic safety of the procedure.
## Adverse effects
Anaphylaxis and allergic reactions, while rare, are a possibility, and clinicians should be mindful of this during the injection. [bib_ref] Anaphylaxis to isosulfan blue and cross-reactivity to patent blue V: case report..., Scherer [/bib_ref] In the event of a reaction, the injection should be discontinued and appropriate resuscitation performed. A decision should be made as to whether to continue or abandon the procedure based on clinical findings and discussion between the surgeon and anesthetist. The mucosa is stained after injection, however the dye tends not to diffuse more than the margins of excision of the tumor and it has not been the authors' (T.S.) experience that dye interferes with pulse oximetry or pathologic interpretation of the excised tumor specimen. [bib_ref] A suggested method for sentinel node biopsy in squamous cell carcinoma of..., Shoaib [/bib_ref] In summary, injection of blue dye is a useful adjunct to gamma probe localization of the sentinel node. It is an optional procedure, but one that offers significant advantages for OSCC SNB.
## Gamma probe
# Introduction
There are a wide variety of gamma probes available with individual feature sets, each requiring specific training and information. In many countries, effective competency training is required as part of the regulations governing the use of radioactivity.
## Probe components
The gamma probe is a radiation detector, providing a count rate from gamma rays. The handheld probe contains the radiation detector, either a crystal or a solid-state device, with surrounding metal shielding and collimation to give a restricted field of view . It is connected to a power supply and an analyzer unit which receives electrical signals from the radiation detector. The analyzer and handheld probe together form the probe system, which may be powered by mains connection or battery. The analyzer provides a response related to the detected count rate, usually by audible pitch or volume variation and by a visual display as a dial or digital count rate (counts per second, cps). The probe technology is described in a number of reference books.Probe Size and Shape
Probes typically have outer dimensions of 12-15 mm, with smaller probes producing problems related to the smaller-less sensitive-detector, and less adequate shielding of the probe housing from gamma rays. Probe tips may be angled relative to the handle. This may be viewed as an advantage for minimal-access surgery, or a disadvantage due to surgeon preference.
## Probe performance
Probe performance is described in terms of its spatial resolution and its count sensitivity. [bib_ref] Specification and performance of intraoperative gamma probes for sentinel node detection, Perkins [/bib_ref] [bib_ref] Evaluation of surgical gamma probes for radioguided sentinel node localisation, Tiourina [/bib_ref] [bib_ref] A method to evaluate intra-operative gamma probes for sentinel lymph node localisation, Britten [/bib_ref] Spatial resolution indicates how spread out the signal is from a point source;
FIG. 2 Components of the gamma probe sensitivity is the number of cps for a given strength of source. At a typical node depth of 30 mm, a point-source node will appear to be about 25 mm wide due to the imperfect spatial resolution of the probe, and resolution worsens with increasing distance. Many nodes contain well below 1% of the injected activity, and with a 6 h half-life of Tc-99 m the activity in a given node can be low, particularly if the surgery is delayed after injection of the radiopharmaceutical. A probe should be able to achieve sensitivity in the range 650-900 cps/MBq of Tc-99 m for a 3-cm-deep node. For a 3-cm-deep node with 1% uptake from a 40 MBq injection of radiocolloid, with surgery at 2 h after injection, the surgeon will see a count rate of about 220 cps. The detected count rate falls rapidly with deeper nodes, and if this arises with lower percentage uptake and longer delay from surgery there may be a much lower count rate and more difficult localization. With experience, localization at low count rates is possible, but with greater variability, longer search time, and less confidence than at higher count rates.
The probe also picks up counts from sources that are not directly in front of the probe; gamma rays can penetrate through the side of the probe, and scattered gamma rays can enter the detector. Adequate shielding of the probe is therefore important, especially for OSCC due to close proximity of the injection site. The rejection of scatter is achieved by having a probe with a good ''energy resolution,'' and with a narrow window.
## Probe controls
The probe analyzer has a number of settings affecting practical performance of the probe, and therefore ease of SLN localization. These include:
Energy Window Setting For Tc-99 m, the probe should be set to a fixed energy level of 140 keV, but the ''width'' setting is variable. The wider the window, the higher the sensitivity, but the greater the scatter detected. This is especially problematic close to the injection site, and the ''high-sensitivity'' (wider window) setting is therefore most useful for low-uptake nodes remote from the injection site.
Collimation Collimators may be removable, allowing great gain in sensitivity while sacrificing spatial resolution. Removal of the collimation can aid localization of lowuptake nodes remote from the injection site.
Additional Shielding Direct penetration of gamma rays through the side of the probe may be reduced by the use of lead plates to shield the injection site.
Integration Time Some systems allow averaging of the signal over time, reducing signal variability. Integration times [1 s must be used with caution, since the user may be misled by the delay between the probe position and the corresponding sound signal.
## Count range
The probe produces an audible change in pitch between a minimum and maximum cps range, e.g., 100-1000 cps. Counts outside the set range will all produce the same (low or high) pitch, necessitating adjustment. Inappropriate range setting can lead to failure of localization. Some probe systems can automatically adjust the pitch range for the detected counts, though this can be confusing when trying to get a sense of the absolute count at any point.
## Care of the probe and quality assurance
All radiation detectors must be checked and managed within a quality assurance (QA) program. Surgeons are advised to work closely with their nuclear medicine colleagues and medical physicists in setting up quality control (QC) procedures. Recommendations for testing are:
- On purchase, tests of performance are advised to give a reference value for sensitivity, energy resolution, and spatial resolution, and to form a baseline for day-to-day checks; - Before each use, a basic check of function and performance with determination of count rate sensitivity to a long-lived radioactive source and its energy spectrum; - Visual inspection for damage, particularly cables and connectors. All users must be advised that the probe detector is easily damaged by dropping; - In the operating room, aiming the probe at the injection site can demonstrate that the probe is functioning; however, this is not a substitute for QC checks since even a 50% loss in sensitivity would not have any effect on the general response to the injection site.
## Sterility
The probe is placed into a sterile sheath, though this makes the probe tip larger. The skin surface may be scanned before sheathing, in which case the probe must be decontaminated by wiping with 70% alcohol or other supplier-recommended agent. When removing a sheath, care must be taken not to accidentally take off any removable collimator, since these are costly to replace.
## Surgical technique and gamma probe detection
The following remarks are valid provided that (a) preoperative lymphoscintigraphy is carried out and (b) no cervical cutaneous flap will be raised.
## Procedure
At the time of lymphoscintigraphy, SLNs are marked on the skin surface under scintigraphic guidance of a Co57labeled marker pen (held 90°to the skin surface) and controlled transcutaneously by the nuclear medicine physician with a collimated, handheld gamma probe. Marking the skin with the head and neck in a position as similar as possible to the positioning during surgery may facilitate harvesting of the sentinel node.
Following radiotracer injection and LSG, patients undergo general anesthesia and preparation for operation. Optionally, blue dye may be injected at this time. Transoral excision of the primary tumor is performed either before or after sentinel node biopsy. Prior excision reduces the problem of shine-through from the injection site, but potentially limits the usefulness of blue dye due to rapid transit times through the lymphatics from the injection sites.
In the operating room, the gamma probe is covered with sterile latex and applied transcutaneously to confirm the accuracy of the skin markings, which may have changed due to changes in patient positioning between LSG and surgery. [bib_ref] The application of sentinel node radiolocalization to solid tumors of the head..., Alex [/bib_ref] The theoretically optimal search pattern is to start closest to the injection site, with the probe perpendicular to the skin, using a raster pattern of 2-cm-spaced parallel lines at right angles to the direction of the injection site. A rise in activity is then confirmed by scanning in the other direction. Scanning should be no faster than a few cm/s. However, excessively slow scanning can lead to loss of information from the change in pitch as the probe passes over a hot node. The drop in counts as the probe is angulated whilst over a hot spot can confirm location.
## Location
The lymphoscintigraphy images and skin markings guide the site of incision, which is placed along the relaxed skin tension lines and positioned to facilitate excision of the scar should subsequent neck dissection be required. Sentinel nodes are reached using one or more small incisions, and removed from levels I-V according to the Robbins classification. [bib_ref] Standardizing neck dissection terminology. Official Report of the Academy's Committee for Head..., Robbins [/bib_ref] Subplatysma skin flaps are not routinely raised for biopsy-only procedures. The gamma probe is introduced into the space along the plane of dissection and angled in various directions to guide the surgeon to the sentinel node, which is then excised. Sentinel nodes in the jugular chain are found close to the internal jugular vein and those in level I will usually be found in the submandibular triangle. If blue dye is used, blue-stained lymphatics may be followed to the sentinel nodes, which may be hot, blue or both. The anatomical location of the sentinel nodes should be noted, as should its color and radioactivity ex vivo in the operating theatre because both blue dye and radioactivity will dissipate before the pathological examination. In order to avoid potential confusion, surgeons and histopathologists should agree beforehand on the exact nomenclature used for labeling sentinel nodes and drainage basins. Following excision of SLNs, repeated readings are taken of the excision bed to ensure that there are no adjacent hot nodes that also need to be removed.
## Selection of nodes
In OSCC, multiple SLNs are usually present, with reported mean numbers of 1.3 to 4 (range 1-11).Preoperative LSG may underestimate the number of SLNs, especially when multiple SLNs are in close proximity. [bib_ref] Sentinel lymph-node biopsy in head and neck cancer, Hoft [/bib_ref] [bib_ref] Staging N0 oral cancer: lymphoscintigraphy and conventional imaging, Thomsen [/bib_ref] However, the numerous other advantages of preoperative LSG counter the suggestion that it may safely be omitted from the procedure. [bib_ref] Sentinel lymph-node biopsy in head and neck cancer, Hoft [/bib_ref] Careful consideration of inactive lymph nodes in the immediate vicinity of SLNs is imperative. Although nonsentinel nodes should not be excised, there may be a scenario where closely adjacent nodes are almost completely excised while dissecting out a sentinel node. Although this is uncommon, the nonsentinel node thus labeled may be sent for pathological examination. [bib_ref] Sentinel lymph node excision. Treatment method of the N0 neck in patients..., Kovacs [/bib_ref] While preoperative imaging should detect the majority of grossly involved nodes, clinical staging remains imperfect. [bib_ref] Sentinel node in head and neck cancer: use of size criterion to..., Alkureishi [/bib_ref] Any suspicious lymph nodes observed during SNB must be excised, even in the absence of radioactivity, since gross lymphatic involvement may block the flow of radiotracer to these nodes. See also the section on ''Measured Radioactivity.'' SLNs are ranked according to their respective tracer uptake ex vivo, with the SLN with the highest activity named SLN1, that with the second highest activity SLN2, and so forth. This does not mean that SLN2 is dependent on SLN1, as metastases may be found in any of the multiple SLNs independently. [bib_ref] The accuracy of head and neck carcinoma sentinel lymph node biopsy in..., Shoaib [/bib_ref] [bib_ref] The definition of a sentinel node, Nieweg [/bib_ref] [bib_ref] Number and location of radiolabeled, intraoperatively identified sentinel nodes in 48 head..., Werner [/bib_ref] [bib_ref] A new approach to pretreatment assessment of the N0 neck in oral..., Hyde [/bib_ref] Close Spatial Relation
The problems of shine-through, whereby the high radioactivity levels from the injection site are detected from behind the tissue of interest, and scatter, in which the direction of radioactivity from the injection site is changed by the tissues and detected by the probe, are most prevalent in the submandibular and submental areas of the neck.For floor-ofmouth tumors, where the distance between primary site and SLN is smallest, this creates technical difficulty and results in lower SLN identification rates (86%, versus 96% for other OSCC subsites). [bib_ref] Sentinel node biopsy in head and neck cancer: preliminary results of a..., Ross [/bib_ref] [bib_ref] Sentinel node biopsy in oral/oropharyngeal squamous cell cancer: five year follow-up, Alkureishi [/bib_ref] [bib_ref] Sentinel node biopsy in oral squamous cell carcinoma, Civantos [/bib_ref] Careful positioning of the gamma probe, judicious use of malleable lead shields, and excision of the primary tumor before SLN localization may all help to minimize these effects. [bib_ref] A suggested method for sentinel node biopsy in squamous cell carcinoma of..., Shoaib [/bib_ref] Another option to improve identification in level I is to perform some initial dissection below the level of the marginal mandibular nerve, transecting the tissues down to the level of the mylohyoid muscle. In this manner, the lymph nodes are mobilized away from the oral cavity, and the gamma probe placed into the newly created tunnel and directed inferiorly away from the injection site. [bib_ref] Sentinel node biopsy in cancer of the oral cavity. Operative technique, Civantos [/bib_ref]
## Activity counting
Following excision, SLN radioactivity is confirmed ex vivo using the gamma probe, and must be above background activity to be classified as hot. [bib_ref] Sentinel lymph node biopsy in oral cancer: validation of technique and clinical..., Thomsen [/bib_ref] The SLN should be placed on a surface away from the patient, or on the upturned probe tip (facing the ceiling). Anatomic location and radioactivity levels (cps) are recorded for all excised nodes. All radioactive nodes should be considered SLNs because, while there exists some confusion over the exact definition of a SLN, it is best to err on the side of patient safety. [bib_ref] The definition of a sentinel node, Nieweg [/bib_ref] The lymphatic basin should be rechecked for reduced radioactivity after SLN excision. [bib_ref] A preliminary study on sentinel lymph node biopsy: feasibility and predictive ability..., Chikamatsu [/bib_ref] Bed counts in the neck after removal of SLN almost never exceed 8-10 cps (with the head of the probe slightly turned away from the injection site).
## Risk
Sentinel node biopsy is not without risks, and injuries to the facial and spinal accessory nerves are possible through minimal exposure. Although complications rates of less than 1% are reported, the risk of injury to these nerves via minimal-access incisions is theoretically higher during SNB as compared with neck dissection. Similarly, neck dissection following positive SNB represents re-exploration in a recently operated field, and carries with it the higher risks of nerve or vessel damage. This reinforces the need for minimal tissue injury during the initial SNB procedure. [bib_ref] Sentinel node biopsy in cancer of the oral cavity. Operative technique, Civantos [/bib_ref] Experience It is clear that experience is needed before a surgeon starts performing sentinel node biopsy, as it carries a steep learning curve. This has led to the recommendation of completion of at least ten SNB-assisted elective neck dissections before the procedure is performed alone. [bib_ref] The first international conference on sentinel node biopsy in mucosal head and..., Ross [/bib_ref] In addition, it is necessary for practitioners of SNB to understand the theoretical aspects, including handling of radioactivity and optimal use of gamma probes.
## Measured radioactivity (cps)
The role of measured cps during gamma probe detection is unclear. Because of the narrow anatomic relationships, defining a lower cutoff point for SLNs is practically impossible. It has been suggested that the number of harvested SLNs may be limited to the three nodes with the highest absolute cps, or the highest ratio of ex vivo nodeto-background activity (as for early studies in melanoma), in order to reduce surgical morbidity. [bib_ref] Gamma-probe-guided lymph node localization in malignant melanoma, Alex [/bib_ref] [bib_ref] Sentinel lymph-node biopsy in head and neck cancer, Hoft [/bib_ref] [bib_ref] Sentinel node detection in N0 cancer of the pharynx and larynx, Werner [/bib_ref] [bib_ref] Intraoperative radiolympho-scintigraphy improves sentinel lymph node identification for patients with melanoma, Albertini [/bib_ref] [bib_ref] Intraoperative lymphatic mapping for early-stage melanoma of the head and neck, Bostick [/bib_ref] [bib_ref] The clinical relevance of sentinel lymph nodes identified with radiolymphoscintigraphy, Brobeil [/bib_ref] [bib_ref] The use of intraoperative radiolymphoscintigraphy for sentinel lymph node biopsy in patients..., Glass [/bib_ref] For correct staging, at least the three nodes with the highest activity should be excised as SLNs, and all positive sentinels are detected within the first five nodes of highest activity in each patient. [bib_ref] Sentinel lymph-node biopsy in head and neck cancer, Hoft [/bib_ref] [bib_ref] Sentinel lymph node excision. Treatment method of the N0 neck in patients..., Kovacs [/bib_ref] [bib_ref] Sentinel node detection in N0 cancer of the pharynx and larynx, Werner [/bib_ref] More than five SLNs are very rare, with three-quarters of patients having B3 SLNs. For safety's sake, all radioactive nodes should be excised. [bib_ref] The role of SPECT-CT in the lymphoscintigraphic identification of sentinel nodes in..., Bilde [/bib_ref] [bib_ref] Sentinel lymph node excision. Treatment method of the N0 neck in patients..., Kovacs [/bib_ref] In a study investigating the role of radioactivity in SNB, Kovacs et al. found no significant difference in absolute cps between positive and negative SLNs (medians of 157 and 235 cps, respectively), and the positive SLN need not have the highest tracer accumulation (range 13-4,716 cps). [bib_ref] Sentinel lymph node excision. Treatment method of the N0 neck in patients..., Kovacs [/bib_ref] Activity in SLNs was not found to correlate with administered dose (in MBq), and the highest activity was found in level II. The authors reported that in each patient there was one SLN with a significantly higher cps rate than the remaining active nodes, and this node could be found in all levels.
Following SLN excision, the remaining lymphatic basin is searched for residual radioactive nodes by means of an in situ survey measurement. A count rate less than one-tenth of the excised node with the lowest radioactivity is considered indicative that all SLNs have been identified and removed. In some centers, lymph nodes with count rates of less than one-tenth of the ''hottest'' excised node are not removed. This practice is based on the results of the large Sunbelt Melanoma trial, demonstrating a low failure rate of 2%. [bib_ref] Sunbelt Melanoma Trial. Lessons learned from the Sunbelt Melanoma Trial, Mcmasters [/bib_ref] However, no similar data have yet been reported for SCC.
The time from injection has also been found not to affect the relative counts between SLNs, or if it does, it affects the results only in case of very large time spans of [14 h, depending on the half-life of the tracer used. [bib_ref] The definition of the sentinel lymph node in melanoma based on radioactive..., Carlson [/bib_ref] [bib_ref] Standardized probedirected sentinel node dissection in melanoma, Essner [/bib_ref] It is important, however, that the time span between injection and surgery is consistent for a given study population.
As a result, the absolute radioactivity counts are less important than relative levels between the excised nodes in the context of SNB. Similarly, absolute radioactivity counts cannot be compared between centers due to differences in protocol.
## Pathology evaluation of sentinel node
In OSCC, SNB has been examined only in the context of relatively small observational cohort studies, and the pathology protocols have typically been designed to detect micrometastases (MMs) and isolated tumor cells (ITCs) with high sensitivity. At present, the significance of finding MMs and ITCs is unknown in OSCC. The grade of evidence is currently at level III, as described in the SIGN methodology for clinical guidelines. 122 Several large-scale validation studies (ACOSOG and the University of Miami, SENT, the Danish national group, and the Brazilian head and neck group) are currently underway. [bib_ref] Sentinel node biopsy in cancer of the oral cavity. Operative technique, Civantos [/bib_ref] [bib_ref] Sentinel node biopsy in cancer of the oral cavity, Civantos [/bib_ref] [bib_ref] Sentinel node biopsy for squamous cell carcinoma of the oral cavity: preliminary..., Ross [/bib_ref] [bib_ref] Need for intensive histopathologic analysis to determine lymph node metastases when using..., Bilde [/bib_ref] [bib_ref] Predictive value of sentinel node biopsy in head and neck cancer, Chone [/bib_ref]
## Histological definitions
The present International Union against Cancer (UICC) definitions are shown in [fig_ref] TABLE 1 UICC: No contact with vessel wall before a further six numbered serial sections... [/fig_ref].Whilst these definitions have been largely accepted, little information is available regarding the evidence on which they were based. The relationship of these definitions to tumor-node-metastasis (TNM) coding is demonstrated in [fig_ref] TABLE 2: Comparison of UICC and TNM classifications Generic TNM coding for sentinel nodes... [/fig_ref].
One element which is clearly subjective in nature is the assessment of cell viability, as the significance of individual cytokeratin-positive ''nonviable cells'' is difficult to establish. Various terms have been employed for these cells, including ''mummified cells'' or thanatosomes. [bib_ref] Thanatosomes'': a unifying morphogenetic concept for tumor hyaline globules related to apoptosis, Papadimitriou [/bib_ref] The present authors' practice (K.H., P.S.) is to include such elements in the morphological description, with careful correlation to the adjacent hematoxylin and eosin (H&E)stained section. Features which may be useful include the lack of a nucleus, but the biological potential of these cells is as yet unknown.
In addition, the presence of cells in the lymphatic plexus should always be recorded. Whilst their significance is unknown, it appears that they do not represent extracapsular extension of tumor.
## Protocol
A well-defined, written, standard operating procedure should be established between the surgical team and the reporting pathology laboratory. This should include how the specimen should be delivered to the laboratory, and outline the supporting documentation which accompanies it and appropriate elements of radiological protection practice. Other important elements may include agreed turnaround times and the manner in which the results are to be reported. An overview of the proposed pathologic evaluation protocol is presented in [fig_ref] FIG. 3: Pathology evaluation of sentinel lymph nodes FIG [/fig_ref].
## Gross sectioning
The node or nodal basin should be fixed in 10% neutral buffered formalin (or equivalent) for 24 h, as per standard laboratory practice. The nodes are described macroscopically, including dimensions, and excess fat is carefully trimmed away. Nodes less than 2 mm (longest dimension) should be processed whole, while nodes 2-5 mm should be cut through the hilum or longest pole-to-pole diameter, and both halves processed en face. Nodes greater than 5 mm should be cut into 2-mm slices, longest pole to pole, with processing of all slices en face.
Step Sectioning A routine H&E section is prepared, and metastatic disease reported if present. If negative, six exact serial sections are mounted, and separately numbered 1-6. Next, 150 lm material is discarded, or retained for research, Much of the published literature has utilized AE1/AE3 pancytokeratin antibody. However, concern has been expressed regarding the specificity of this anticytokeratin cocktail. Cross-reactivity is a problem seen with a number of pan-cytokeratin antibodies, and may mandate the use of more than one antibody in SNB protocols to clearly delineate MMs and ITCs from other elements in the node, such as dendritic cells and macrophages. However, presently it is reasonable to assume that any reputable commercially available pancytokeratin antibody (such as AE1/AE3 or MNF116) may be used. It is important to recognize artifacts, and any cytokeratin-positive components should always be compared with adjacent sections stained by hematoxylin and eosin [bib_ref] The effect of occult nodal metastases on survival and regional control in..., Gourin [/bib_ref] [bib_ref] Evaluation of cervical lymph node metastasis in squamous carcinoma of the head..., Don [/bib_ref] [bib_ref] The efficacy of comprehensive neck dissection with or without postoperative radiotherapy in..., Leemans [/bib_ref] [bib_ref] Micrometastases in carcinoma of the upper aerodigestive tract: detection, risk of metastasizing,..., Ambrosch [/bib_ref] [bib_ref] Depth of invasion is the most significant histological predictor of subclinical cervical..., Kane [/bib_ref].
## Microscopy
Sections should be examined using a good-quality bright-field microscope and equivocal findings discussed with an experienced colleague. Where pancytokeratinpositive cells are present it is essential that adjacent sections are stained to allow morphological comparison.
## Report
The side, number, and level of each node basin in the neck must be recorded. A diagram provided by the surgical team should be incorporated into the pathology record where possible.
The report must include details of the numbers of nodes found in each individual basin and which nodes were hot, blue, both or unlabeled. The dimensions of each node must be included and the macroscopic appearance of the gross and cut surfaces stated.
## - macrometastasis
- Note the largest dimension of the metastatic deposit in each node, and whether extracapsular spread is present or not.
- Micrometastasis
- Should be recorded, even in the presence of macrometastasis - The largest dimension should be recorded - Anatomical location within the node: capsular, subcapsular, parenchymal - Unifocal or multifocal: it is often not possible to be confident of the exact numbers - Presence of extracapsular spread. This is permitted if the deposit is peripherally located and is associated with a reactive stromal response
## - isolated tumor cells (itc)
- If evident, should be recorded, even in the presence of macro-or micrometastasis - If cohesive: the size of the largest deposit should be stated - If dispersed: note the anatomical distribution - Benign inclusions including nevus cells, salivary inclusions, and false-positive cytokeratin artifacts (e.g., dendritic cells or scattered nonviable anucleate cells) should be recorded. The histopathological features of ITCs need careful description, as the UICC size cutoff by necessity encompasses small metastases which vary greatly in size and presumably in biological potential. Positive findings using nonmorphological methods in the absence of histologically proven metastasis are generally considered as ITCs.
# Other methodologies
Frozen Sections The use of frozen-section evaluation for SLNs has been described in a number of recent reports, and the results appear promising, with negative predictive values ranging from 83% to 99%. [bib_ref] Sentinel node biopsy for oral and oropharyngeal squamous cell carcinoma of the..., Stoeckli [/bib_ref] [bib_ref] Intraoperative diagnosis of cancer metastasis in sentinel lymph node of oral cancer..., Terada [/bib_ref] [bib_ref] The value of frozen section analysis of the sentinel lymph node in..., Tschopp [/bib_ref] These results are in contrast to an earlier report by Civantos et al., who described poor sensitivity of frozen section compared with step-serial sectioning in a series of 43 oral cancer patients. [bib_ref] Lymphatic mapping and sentinel lymphadenectomy for 106 head and neck lesions: contrasts..., Civantos [/bib_ref] The main advantage of the technique is that it may allow a majority of patients to undergo a single-stage procedure. While the use of frozen section is advocated by some authors, it has not yet gained universal acceptance.
## Imprint cytology
The use of imprint cytology in conjunction with frozen sections in the assessment of SLNs has been described in other tumors such as breast adenocarcinoma. One study in OSCC based on 30 cases demonstrated high sensitivity and specificity, though a recent study showed frozen section to FIG. 5 A micrometastasis found in the seventh level of a sentinel node that was clear on initial sectioning. Viable nucleated squamous cells are present in a cohesive group. Section quality is suboptimal and recutting is not possible be a more accurate method of intraoperative diagnosis. [bib_ref] Intraoperative diagnosis of cancer metastasis in sentinel lymph node of oral cancer..., Terada [/bib_ref] [bib_ref] Intraoperative neck staging using sentinel node biopsy and imprint cytology in oral..., Asthana [/bib_ref] Imprint cytology has an advantage over frozen section in that no tissue is lost in the generation of the sample, however much larger studies are required before considering adoption into the protocol.
Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) Methods with increased sensitivity, such as cytokeratin RT-PCR, have been suggested. The small number of studies published demonstrate expression of cytokeratins in nodes which were metastasis negative on initial assessment. However, only a proportion of the nodes demonstrated metastases on serial sectioning. [bib_ref] The diagnostic accuracy of reverse transcription-PCR quantification of cytokeratin mRNA in the..., Garrel [/bib_ref] [bib_ref] Clinical evaluation of a new molecular method for detection of micrometastases in..., Shores [/bib_ref] The clinical role of these methods in the future remains uncertain given the ongoing concerns regarding their specificity together with the associated medicolegal problems, given that significant tissue must be used which has not been assessed histopathologically.
## Burden of work
The authors recognize that, on average, 2.5 sentinel node basins are yielded per neck side. The protocol above may produce up to 12 levels per node. If three nodes are present in each basin there could be 180 slides to examine. On the other hand, the majority of sentinel nodes are small and the nodes from a single basin can often be grouped into one cassette (using ink to identify ''hot'' and ''blue'' nodes), saving laboratory time and effort. In addition, the described protocol has the ability to detect all MMs. According to Cochran's principle, metastatic deposits tend to cluster in the plane of the hilum, and some authors argue the case for examination of bisected sentinel nodes at three or six levels only. [bib_ref] Pathobiology of the sentinel node, Cochran [/bib_ref] Although such a protocol can theoretically miss a MM, it may turn out that no useful information is added by leveling through the block beyond six levels. [bib_ref] Sentinel lymph nodes in cancer of the oral cavity: is central stepsectioning..., Thomsen [/bib_ref] However, several studies report that additional sentinel nodes are upstaged by step-serial sectioning with cytokeratin immunohistochemistry, compared with H&E only. [bib_ref] Need for intensive histopathologic analysis to determine lymph node metastases when using..., Bilde [/bib_ref]
# Outcome analysis
The success of this multidisciplinary staging technique depends on good communication between all of the individual components; imaging, surgery, and histopathology. The multidisciplinary team (MDT) setting should be utilized for the discussion of every patient, and regular audit of patient outcomes against published data should be carried out. SLNs should be successfully located and harvested in [90% patients. [bib_ref] Sentinel node biopsy in head and neck cancer: preliminary results of a..., Ross [/bib_ref] The accuracy of the technique can be assessed by the proportions of patients whose SLN contain metastases, which should match that of END (20-30%, depending on patient population and tumor size). [bib_ref] Micrometastasis in oral/oropharyngeal squamous cell carcinoma: Incidence, histopathological features and clinical implications, Woolgar [/bib_ref] Lastly, the rate of false negatives (SLN-negative patients who develop early recurrent disease) should be \5%. [bib_ref] Sentinel node biopsy: the technique and the feasibility in head and neck..., Von Buchwald [/bib_ref] Further studies are required to determine the full clinical significance of micrometastasis and individual tumor cells in OSCC. The biological potential of the tumor cells may vary with differing types of tumors, and clinical decisions currently have to be made on the basis of grade, stage, and margin status of the primary lesion as well as on microscopic findings in the sentinel node. [bib_ref] Sentinel node biopsy: interpretation and management of patients with immunohistochemistry-positive sentinel nodes..., Rutgers [/bib_ref] [bib_ref] Correlation of histopathologic findings with clinical and radiologic assessments of cervical lymph-node..., Woolgar [/bib_ref] The optimum protocol will hopefully emerge from the large-scale trials and studies currently in progress. [bib_ref] Sentinel node biopsy in oral/oropharyngeal squamous cell cancer: five year follow-up, Alkureishi [/bib_ref] [bib_ref] Sentinel node biopsy in cancer of the oral cavity, Civantos [/bib_ref] [bib_ref] Sentinel node biopsy for squamous cell carcinoma of the oral cavity: preliminary..., Ross [/bib_ref] [bib_ref] Need for intensive histopathologic analysis to determine lymph node metastases when using..., Bilde [/bib_ref] [bib_ref] Predictive value of sentinel node biopsy in head and neck cancer, Chone [/bib_ref] One of the major aims of SNB in OSCC is to achieve better staging, and thorough pathological examination of SLNs remains the standard.
## Summary
Successful application of the SNB technique is dependent on good communication between all members of the multidisciplinary team, and this joint guideline represents an extension of that approach. Sentinel node biopsy provides an additional tool for staging patients with early OSCC. However, it is not without limitations, and all practitioners of SNB must be aware of these. It is hoped that this document will serve as a reference outlining the optimal practice for the provision of SNB in patients with OSCC, based on the best currently available evidence. As such, the use of the above protocol is recommended until further data, in the form of results from currently underway large prospective studies, become available.
ACKNOWLEDGEMENT The authors would like to thank the European Association of Nuclear Medicine's Physics, Dosimetry, and Radiopharmacy Committees for their assistance in production of this manuscript.
OPEN ACCESS This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
[fig] FIG. 3: Pathology evaluation of sentinel lymph nodes FIG. 4 Isolated tumor cells stained by AE1/AE3 in a sentinel lymph node [/fig]
[fig] FIG. 6: Cytokeratin-positive cells in a sentinel node stained by CKC pan cytokeratin. The white arrow shows a contaminant squame (this can be ascertained by the geometric outline, lack of nucleus, and by focusing at high power). The black arrows show nonnucleated individual tumor cells, and dendritic cells can be seen in the background FIG. 7 A group of nucleated isolated tumor cells stained by AE1/ AE3 in a sentinel node FIG. 8 Multinucleated and mononuclear macrophages revealed by the detailed protocol in a sentinel node that was clear in the first sections. These were suspicious for ITCs within the island FIG. 9 Adjacent field to Fig. 5 stained by AE1/AE3, showing absence of tumor cells [/fig]
[table] TABLE 2: Comparison of UICC and TNM classifications Generic TNM coding for sentinel nodes pNX (sn) Sentinel lymph node could not be assessed pN0 (sn) No sentinel node metastasis pN1 (sn) Sentinel node metastasis Sentinel nodes with micrometastasis only are identified by (mi) pN1 (sn) (mi) single ipsilateral node with micrometastasis pN2 (sn) (mi) multiple ipsilateral nodes with micrometastasis Sentinel nodes with isolated tumor cells are coded separately for morphological and nonmorphological techniques such as PCR or flow cytometry pN0 (i-)(sn) No sentinel lymph node metastasis histologically, negative morphological findings for isolated tumor cells (ITC) pN0 (i?)(sn) No sentinel lymph node metastasis histologically, positive morphological findings for isolated tumor cells (ITC) pN0 (mol-)(sn) No sentinel lymph node metastasis histologically, negative nonmorphological findings for isolated tumor cells (ITC) pN0 (mol?)(sn) No sentinel lymph node metastasis histologically, positive nonmorphological findings for isolated tumor cells (ITC) [/table]
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US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis
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US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis
## Background epidemiology of non-tuberculous mycobacteria in individuals with cystic fibrosis
Non-tuberculous mycobacteria (NTM) are increasingly being isolated from the sputum of adults and children with cystic fibrosis (CF), both in North America and in Europe. [bib_ref] Mycobacterial isolations in young adults with cystic fibrosis, Smith [/bib_ref] [bib_ref] Prospective study of mycobacterial infections in patients with cystic fibrosis, Hjelte [/bib_ref] [bib_ref] Nontuberculous mycobacteria in adult patients with cystic fibrosis, Kilby [/bib_ref] [bib_ref] Nontuberculous mycobacterial disease in adult cystic fibrosis patients, Aitken [/bib_ref] [bib_ref] The role of mycobacteria other than tuberculosis (Mott) in patients with cystic-fibrosis, Hjelt [/bib_ref] [bib_ref] Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis, Olivier [/bib_ref] [bib_ref] Mycobacterium abscessus and children with cystic fibrosis, Sermet-Gaudelus [/bib_ref] [bib_ref] Prospective study on nontuberculous mycobacteria in patients with and without cystic fibrosis, Leitritz [/bib_ref] [bib_ref] Late diagnosis defines a unique population of long-term survivors of cystic fibrosis, Rodman [/bib_ref] [bib_ref] Prevalence and antimicrobial susceptibility of microorganisms isolated from sputa of patients with..., Valenza [/bib_ref] [bib_ref] Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Levy [/bib_ref] [bib_ref] Nontuberculous mycobacterial infection in patients with cystic fibrosis: a multicenter prevalence study, Girón [/bib_ref] [bib_ref] Non-tuberculous mycobacteria in children with cystic fibrosis: isolation, prevalence, and predictors, Radhakrishnan [/bib_ref] [bib_ref] Nontuberculous mycobacteria in cystic fibrosis, Razvi [/bib_ref] [bib_ref] Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis, Esther [/bib_ref] [bib_ref] Nontuberculous mycobacterial infection in cystic fibrosis patients at the Colorado Cf Center, Martiniano [/bib_ref] [bib_ref] Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis..., Roux [/bib_ref] Estimates of the prevalence of NTM in the CF population have ranged from 1.3% in the earliest study reported in 1984 1 to 32.7% in a review of individuals with CF over the age of 40 years in Colorado. [bib_ref] Late diagnosis defines a unique population of long-term survivors of cystic fibrosis, Rodman [/bib_ref] To date, the largest studies published examined 986, [bib_ref] Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis, Olivier [/bib_ref] 1216 [bib_ref] Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis, Esther [/bib_ref] and 1582 [bib_ref] Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis..., Roux [/bib_ref] individuals with CF and reported rates of NTM-positive cultures of 13.0%, 13.7% and 6.6%, respectively. Recently, analysis of US Cystic Fibrosis Foundation (CFF) registry data has shown prevalence rates for NTM-positive culture in the USA of 12% 18 but with considerable variation between individual states (0-28%). [bib_ref] Nontuberculous mycobacteria among patients with cystic fibrosis in the United States: screening..., Adjemian [/bib_ref] The NTM species most commonly identified in individuals with CF from North America and Europe are the slow-growing Mycobacterium avium complex (MAC) (including M. avium, M. intracellulare and M. chimaera), which can be found in up to 72% of NTM-positive sputum cultures, [bib_ref] Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis, Olivier [/bib_ref] and the rapidgrowing M. abscessus complex (MABSC) (comprising the subspecies M. abscessus subsp abscessus (M. a. abscessus), M. a. bolletii [bib_ref] rpoB gene sequence-based characterization of emerging non-tuberculous mycobacteria with descriptions of Mycobacterium..., Adékambi [/bib_ref] and M. a. massiliense (the latter currently classified as part of M. a. bolletii)), which in many centres has now become the most common NTM isolated from individuals with CF. [bib_ref] Mycobacterium abscessus and children with cystic fibrosis, Sermet-Gaudelus [/bib_ref] Other less commonly isolated species include M. simiae, 11 M. kansasii and M. fortuitum. [bib_ref] An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Griffith [/bib_ref] There are geographical differences in both the prevalence of NTM-positive cultures and also the relative frequency of different species seen between but also within countries. [bib_ref] Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis, Olivier [/bib_ref] [bib_ref] Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis..., Roux [/bib_ref] [bib_ref] Nontuberculous mycobacteria among patients with cystic fibrosis in the United States: screening..., Adjemian [/bib_ref] [bib_ref] Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia, Qvist [/bib_ref] NTM acquisition is strongly associated with age in individuals with CF, with prevalence increasing from 10% in children aged 10 years, to over 30% in adults over the age of 40 years. [bib_ref] Late diagnosis defines a unique population of long-term survivors of cystic fibrosis, Rodman [/bib_ref] In individuals with an adult diagnosis of CF, over 50% (mostly females) have NTM-positive airway cultures. [bib_ref] Late diagnosis defines a unique population of long-term survivors of cystic fibrosis, Rodman [/bib_ref] There appear to be species-specific differences in age-related prevalence within CF cohorts, with MAC more commonly isolated from adults over 25 years of age, while MABSC is isolated from all age groups, but peaks between those 11 and 15 years of age in some studies. There may also be species-specific differences in virulence: individuals with MABSC-positive cultures are more likely to meet American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) criteria for diagnosing NTM pulmonary disease (NTM-PD, see Diagnosis of NTM-PD in CF section), and have worse morbidity and mortality associated with a more rapid decline in lung function. [bib_ref] Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis, Esther [/bib_ref] [bib_ref] Mycobacterium avium and Mycobacterium abscessus complex target distinct cystic fibrosis patient subpopulations, Catherinot [/bib_ref] There has been a rise over the last four decades in the reported prevalence of NTM-positive cultures in respiratory samples from individuals with CF, [bib_ref] Mycobacterial isolations in young adults with cystic fibrosis, Smith [/bib_ref] an increase in part mirroring temporal changes seen in the non-CF cohort. [bib_ref] A spatial epidemiological analysis of nontuberculous mycobacterial infections in Queensland, Chou [/bib_ref] [bib_ref] Increasing recovery of nontuberculous mycobacteria from respiratory specimens over a 10-year period..., Koh [/bib_ref] [bib_ref] Nontuberculous pulmonary mycobacteriosis in Denmark: incidence and prognostic factors, Andréjak [/bib_ref] [bib_ref] Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems, Prevots [/bib_ref] [bib_ref] Changing epidemiology of pulmonary nontuberculous mycobacteria infections, Thomson [/bib_ref] [bib_ref] Nontuberculous mycobacteria in respiratory tract infections, Simons [/bib_ref] [bib_ref] Spatial clusters of nontuberculous mycobacterial lung disease in the United States, Adjemian [/bib_ref] [bib_ref] Pulmonary nontuberculous mycobacterial disease, Marras [/bib_ref] While increasing detection rates may reflect enhanced surveillance and/or improved microbiological detection, there are a number of lines of evidence suggesting a true rise in the frequency of NTM infection. A number of CF studies [bib_ref] Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection, Renna [/bib_ref] show year on year increases in NTM-positive cultures with no change in surveillance intensity or culture methodology. There has been an increase over time in rates of skin test reactivity to NTM antigens in US population-based testing studies, [bib_ref] Nontuberculous mycobacterial sensitization in the United States: national trends over three decades, Khan [/bib_ref] potentially indicating increasing exposure to NTM (see below). Furthermore, the relative frequency of M. abscessus detection in NTM-positive samples from individuals with CF has increased remarkably over time both in the USA and in Europe, [bib_ref] Prospective study of mycobacterial infections in patients with cystic fibrosis, Hjelte [/bib_ref] 6 15 17 23 27 suggesting real changes in NTM acquisition rates (rather than increased sampling).
Possible reasons for the potential increased frequency of NTM-positive cultures in individuals with CF include: increases in environmental exposure to NTM through more permissive temperature settings of home water heaters [bib_ref] Nontuberculous mycobacteria from household plumbing of patients with nontuberculous mycobacteria disease, Falkinham [/bib_ref] and more contact with shower aerosols, increased antibiotic usage creating more NTM favourable lung niches, [bib_ref] Mycobacterium avium and Mycobacterium abscessus complex target distinct cystic fibrosis patient subpopulations, Catherinot [/bib_ref] greater chronic use of medications that might impair host immunity to NTM, [bib_ref] Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection, Renna [/bib_ref] and/or spread of NTM through person-to-person transmission. NTM-PD in individuals with CF NTM can cause progressive inflammatory lung damage, a condition termed 'NTM pulmonary disease' (NTM-PD), which is defined by the presence of specific microbiological, clinical and radiological features described in Diagnosis of NTM-PD in CF section. However, it has become clear that NTM can also transiently, intermittently or permanently reside within the lungs of individuals with CF without causing NTM-PD, thus representing asymptomatic infection and creating considerable difficulties in deciding how best to screen for and diagnose NTM. [bib_ref] Clinical significance of a first positive nontuberculous mycobacteria culture in cystic fibrosis, Martiniano [/bib_ref] Further challenges exist in knowing how best to identify NTM in respiratory samples, when and how to initiate treatment for NTM-PD (as highlighted by a recent Cochrane review [bib_ref] Antibiotic treatment for nontuberculous mycobacteria lung infection in people with cystic fibrosis, Waters [/bib_ref] and how NTM may impact individuals under consideration for lung transplantation. As a consequence, the CFF and European Cystic Fibrosis Society (ECFS) sought to generate a consensus recommendations document to support and standardise the management of NTM infection in individuals with CF, permitting prospective evaluation of current best practice and forming a foundation for future research programmes.
These consensus statements have been developed to assist in the management both of adults and children with CF who are infected with NTM. Given the virtual absence of published evidence to guide paediatric care, [bib_ref] Standard versus biofilm antimicrobial susceptibility testing to guide antibiotic therapy in cystic..., Waters [/bib_ref] recommendations for children with CF infected with NTM are based on extrapolated adult data, the practical experience of experts and appropriate adjustment of drug regimens, and are, except where stated, the same as for adults.
# Methods
## Expert committee structure
The CFF and the ECFS invited experts to participate in the statement development process. The 19-member committee consisted of professionals (10 US and 9 European) with expertise in CF and NTM, and included adult and paediatric CF physicians, lung transplant physicians, microbiologists, infectious disease specialists and a parent of an individual with CF. The committee convened in May 2012 and was divided into five subgroups, each responsible for a specific topic: Epidemiology and Risk Factors, Screening, Microbiology, Treatment and Transplantation. Each subgroup developed topic-specific questions using the PICO format (Population, Intervention, Comparison, Outcome. [bib_ref] Development of a framework to identify research gaps from systematic reviews, Robinson [/bib_ref] Questions were reviewed and approved by the entire committee before systematic literature searches were conducted.
## Review process and consensus vote
The members of each subgroup used the PICO questions to guide literature searches in PubMed. Searches were limited to the English language and the period 1984 to 2013. Subgroup members also searched for topic-relevant guidelines through searches of the ATS website, the IDSA website, the Clinical Laboratory Standards Institute (CLSI) website and the UK CF Trust website.
After reviewing the relevant literature and existing guidelines, subgroup members drafted recommendation statements. In October 2012, a second meeting was convened and subgroups finalised draft recommendation statements. The committee also voted to set 80% agreement of all 19 members as the threshold for acceptance of a recommendation statement and not to use the GRADE system of evaluating published evidence, given the paucity of clinical trial data.
Each subgroup submitted final draft questions for entry into an electronic survey tool (Survey Monkey) for the purposes of anonymous voting and comment by all members. A project coordinator administered the survey and committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or between 7 and 9 being considered 'good' agreement. Space for entering free text was also provided after each statement to allow members to cite literature in support of their opinions or suggested revisions. All committee members were required to vote on each statement regardless of their role or expertise. Multiple rounds of voting and revisions to the statements were conducted, and for each round committee members were requested to complete their voting within 3 weeks. The committee chairs reviewed the results from each round and updated the statements based on comments entered by respondents for subsequent rounds.
## External review
A draft of the recommendations was presented at the 2013 North American Cystic Fibrosis Conference and the European Cystic Fibrosis Society Meeting. Additionally, the committee solicited feedback from the CF communities in the USA and in Europe, which included physicians, nurses, physical and respiratory therapists, parents and individuals with CF. All comments collected from this process were reviewed and addressed by the committee in the development of the final recommendation statements.
# Results
## Final recommendations and results of the consensus vote
Three rounds of voting were conducted to achieve 80% consensus for each statement. Fifty-three statements were included in the first round of voting and 50 statements in the second and third rounds. Final statements and the consensus are reported in table 1. Recommendation 24: The CF Foundation and the ECFS recommend that treatment of M. abscessus complex pulmonary disease should involve an intensive phase followed by a continuation phase 100 Recommendation 25: The CF Foundation and the ECFS recommend that the intensive phase should include a daily oral macrolide (preferably azithromycin) in conjunction with 3-12 weeks of intravenous amikacin and one or more of the following: intravenous tigecycline, imipenem or cefoxitin, guided but not dictated by drug susceptibility testing. The duration of intensive phase therapy should be determined by the severity of infection, the response to treatment and the tolerability of the regimen 83 Recommendation 26: The CF Foundation and the ECFS recommend that the continuation phase should include a daily oral macrolide (preferably azithromycin) and inhaled amikacin, in conjunction with 2-3 of the following additional oral antibiotics: minocycline, clofazimine, moxifloxacin and linezolid, guided but not dictated by drug susceptibility testing 89 Recommendation 27: The CF Foundation and the ECFS recommend that individuals with M. abscessus complex pulmonary disease should be managed in collaboration with experts in the treatment of NTM and CF, as drug intolerance and drug-related toxicity occur frequently, and changes in antibiotic therapy are often required Recommendation 1: The CF Foundation and the ECFS recommend that the potential for cross-infection of NTM (particularly MABSC) between individuals with CF should be minimised by following national infection control guidelines. CF-related lung disease is a clear risk factor for the development of NTM-PD and is presumed to relate to the presence of structural lung damage, impaired mucociliary clearance and inflamed airways; all of which are thought to favour the development of chronic NTM infection. [bib_ref] Susceptibility to nontuberculous mycobacterial lung disease, Sexton [/bib_ref] Cystic Fibrosis Transmembrane conductance Regulator (CFTR) dysfunction may, of itself, predispose to NTM infection (although the pathophysiology is unknown), since rates of heterozygosity for CFTR mutations within the non-CF population with pulmonary NTM disease are high (30-50%). However, other risk factors that predispose specific individuals with CF to acquire NTM or to develop NTM-PD are, for the most part, poorly understood, with many studies presenting conflicting results. Potential risk factors for NTM acquisition are listed below.
## Lung function
There have been conflicting reports on whether an individual's spirometry results are related to the likelihood of finding NTM-positive samples, with some studies suggesting no association with lung function, 13 a positive association of NTM acquisition with higher FEV 1 % predicted 6 or, conversely, with worse lung function. [bib_ref] Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Levy [/bib_ref] Support for the possibility that NTM acquisition is more likely in CF individuals with severe lung disease comes from observations that the prevalence of NTM-positive sputum samples in patients referred for lung transplantation has been reported to be as high as 19.7%. [bib_ref] Non-tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation, Chalermskulrat [/bib_ref]
## Lung infection with specific pathogens
In some studies, individuals with CF with NTM-positive samples are more likely to have Staphylococcus aureus infection Recommendation 36: The CF Foundation and the ECFS recommend that a schedule for detecting drug toxicity (including hearing loss, visual loss, renal impairment and liver function test abnormalities) should be set in place at the time of NTM treatment initiation and implemented throughout treatment based on the specific drugs prescribed 100 Recommendation 37: The CF Foundation and the ECFS recommend that an HRCT scan of the lungs should be performed shortly before starting NTM treatment and at the end of NTM treatment to assess the radiological response and less likely to have Pseudomonas aeruginosa chronic pulmonary infection. Other studies, however, have reported NTM positivity associated with higher rates of P. aeruginosa infection, [bib_ref] Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Levy [/bib_ref] and variably associated with S. maltophilia infection. In contrast, Aspergillus fumigatus has consistently been associated with the presence of NTM-positive cultures, [bib_ref] Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Levy [/bib_ref] with some reports indicating an association with allergic bronchopulmonary aspergillosis. [bib_ref] Mycobacterium abscessus and children with cystic fibrosis, Sermet-Gaudelus [/bib_ref] Medications Corticosteroids
The impact of systemic steroids on NTM acquisition is controversial. There have been suggestions that steroids may protect against 58 or predispose towards NTM infection, [bib_ref] Nontuberculous mycobacteria in cystic fibrosis associated with allergic bronchopulmonary aspergillosis and steroid..., Mussaffi [/bib_ref] or may not influence the risk of NTM acquisition. Recent data from non-CF populations, however, have suggested that oral as well as some types of inhaled corticosteroids are associated with increased risk of NTM acquisition. [bib_ref] Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis, Andréjak [/bib_ref] [bib_ref] Increased risk of nontuberculous mycobacterial infection in asthmatic patients using long-term inhaled..., Hojo [/bib_ref] [bib_ref] Environment or host? A case-control study of risk factors for Mycobacterium avium..., Dirac [/bib_ref] Proton pump inhibitors
The impact of proton pump inhibitor (PPI) is unclear. PPI use has been reported to be associated with the development of MAC pulmonary disease in non-CF cohorts, [bib_ref] Gastroesophageal reflux disease, acid suppression, and Mycobacterium avium complex pulmonary disease, Thomson [/bib_ref] and may promote gastrointestinal survival of NTM and subsequent lung infection through gastric aspiration.
Azithromycin Particular attention has recently been paid to the role of longterm azithromycin use as a risk factor for the acquisition of NTM. In a single centre study of CF adults, Renna et al [bib_ref] Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection, Renna [/bib_ref] reported increases in annual rates of NTM infection associated with chronic azithromycin use, postulating, through in vitro studies and mouse infection models, that azithromycin blocked autophagic killing of NTM within macrophages. While supporting findings from a previous case-control study reporting increased azithromycin use in individuals with NTM, [bib_ref] Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Levy [/bib_ref] other large retrospective studies have shown no such association. [bib_ref] Nontuberculous mycobacterial infection in patients with cystic fibrosis: a multicenter prevalence study, Girón [/bib_ref] This includes a recent nested case-control analysis within the CF registry, which suggested long-term azithromycin use may protect against infection with NTM. [bib_ref] Epidemiology of nontuberculous mycobacterial infections and associated chronic macrolide use among persons..., Binder [/bib_ref]
## Acquisition of ntm through cross-infection
Person-to-person transmission of NTM has traditionally been considered unlikely. Two separate studies have shown that patients, even siblings living in the same household for more than 10 years, have unique strains, suggesting a lack of person-to-person transmission. However, a case report from the University of Washington described a possible outbreak of M. a. massiliense in five patients 48 with potential transmission occurring during synchronous clinic visits. Recently, whole genome sequencing and antimicrobial susceptibility testing performed on 168 consecutive isolates of M. abscessus from 31 patients attending an adult CF centre in the UK revealed frequent, probably indirect, transmission of M. a. massiliense between individuals with CF despite conventional crossinfection measures. [bib_ref] Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic..., Bryant [/bib_ref] The results of these studies indicate that cross-infection may be an important mechanism for the acquisition of M. abscessus (at least within the CF population). To date, there has been no published evidence suggesting person-to-person transmission of other NTM species.
Other factors extrapolated from data in non-CF populations or studies on M. tuberculosis that might contribute to NTM acquisition in individuals with CF include: low vitamin D, the presence of gastro-oesophageal reflux disease, low body mass index or malnutrition. [bib_ref] The relationship between malnutrition and tuberculosis: evidence from studies in humans and..., Cegielski [/bib_ref]
## Screening how often should individuals with cf be screened for ntm?
Recommendation 2: The CF Foundation and the ECFS recommend that cultures for NTM be performed annually in spontaneously expectorating individuals with a stable clinical course.
Recommendation 3: The CF Foundation and the ECFS recommend that, in the absence of clinical features suggestive of NTM-PD, individuals who are not capable of spontaneously producing sputum do not require screening cultures for NTM.
Over the past two decades, a number of expert opinions and reviews have urged routine screening for NTM in the general CF population. However, the optimal frequency and methodology for NTM surveillance in individuals with CF are not known. NTM are common in the environment, and are likely to be transiently introduced on a regular basis into the airways of individuals with CF. More frequent screening will, therefore, result in detection of more positive cultures, 11 many of which will not be associated with the presence of NTM-PD, [bib_ref] Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis, Olivier [/bib_ref] 30 58 generating anxiety in patients and caregivers and initiating further (potentially invasive) investigations. However, signs and symptoms of NTM disease are often subtle and non-specific, and the diagnosis can be delayed for years or missed altogether in the absence of effective surveillance. [bib_ref] Nontuberculous mycobacterial disease in adult cystic fibrosis patients, Aitken [/bib_ref] Furthermore, systematic screening may help researchers more accurately identify factors influencing poorly understood host susceptibility, acquisition, transmission and virulence of NTM. It is important to emphasise that screening refers to obtaining samples from individuals with no clinical, microbiological or radiological suspicion of NTM infection, and should be distinguished from strategies to investigate and diagnose NTM disease (covered in Diagnosis of NTM-PD in CF section).
While our understanding of those factors predisposing individuals with CF to NTM infection is incomplete, there is, nevertheless, agreement that certain patient populations are at greater risk and therefore probably require more frequent surveillance. These populations include: those with advanced lung disease and previous NTM-positive cultures, and those living in areas with high NTM prevalence. Conversely, in individuals with no recognised risk factors, the prevalence of NTM infection is likely to be low; thus less frequent, perhaps annual, surveillance is warranted. In addition, NTM screening is important before starting long-term azithromycin treatment to avoid inadvertent macrolide monotherapy in individuals with undiagnosed NTM infection (in keeping with published guidelines. [bib_ref] Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health, Mogayzel [/bib_ref]
## )
How should screening for NTM be performed?
## Recommendation 4:
The CF Foundation and the ECFS recommend that culture and smears for acid-fast bacilli (AFB) from sputum should be used for NTM screening.
Recommendation 5: The CF Foundation and the ECFS recommend against the use of oropharyngeal swabs for NTM screening.
The majority of published reports describing the prevalence of NTM in the CF population utilised AFB smear and culture from sputum as the standard screening method. To date, there has been no direct comparison between the sensitivity of samples from spontaneously expectorated sputum samples, and sputum induced by use of hypertonic saline. Analysis of induced sputum provides equal or better detection of 'standard' CF pathogens [bib_ref] Sputum induction in routine clinical care of children with cystic fibrosis, Al-Saleh [/bib_ref] and the procedure is in widespread use to collect samples for mycobacterial culture among CF Centres worldwide.
However, the Consensus Committee felt that, due to its inconvenience, induced sputum collection should not be used as a screening tool in individuals with no features suggestive of NTM-PD who are incapable of spontaneously producing sputum. As discussed in Microbiology section, there are currently no other validated screening methods to detect NTM in individuals with CF. Although positive cultures have been detected through laryngeal suction, oropharyngeal swabs, or gastric aspirate, there are insufficient data to support their use. Skin testing for delayed-type hypersensitivity against NTM antigens does not appear sufficiently sensitive or specific to use for surveillance in the CF population. Serological assays, such as IgG against Mycobacterium antigen A60 for NTM surveillance, appear promising, [bib_ref] Measurement of immunoglobulin G against mycobacterial antigen A60 in patients with cystic..., Ferroni [/bib_ref] but have not been validated in the CF population.
MICROBIOLOGY What respiratory tract samples should be used to evaluate individuals with CF for suspected NTM-PD?
Recommendation 6: The CF Foundation and the ECFS recommend that culture and smears for AFB from sputum, induced sputum, bronchial washings or bronchoalveolar lavage samples can be used to evaluate individuals with CF suspected to have NTM-PD.
Recommendation 7: The CF Foundation and the ECFS recommend against the routine use of transbronchial biopsies to detect NTM in individuals with CF suspected to have NTM-PD.
Recommendation 8: The CF Foundation and the ECFS recommend against the use of oropharyngeal swabs to perform diagnostic smears and cultures in individuals with CF suspected to have NTM-PD.
Currently, sputum, induced sputum, bronchial washings and bronchoalveolar lavage samples are routinely used to evaluate individuals for suspected NTM-PD. [bib_ref] European Manual of Clinical Microbiology, Delogu [/bib_ref] Samples for NTM should be processed for smear microscopy, preferably by fluorescence, and for culture. Microscopy allows for direct evaluation of the bacterial burden, and may indicate false-negative culture results through excessive sample decontamination or overgrowth of conventional bacteria. Oropharyngeal swabs should not be used for the detection of NTM, since they do not consistently provide sufficient material for culture. [bib_ref] European Manual of Clinical Microbiology, Delogu [/bib_ref] A staged approach should be adopted for obtaining diagnostic samples; testing spontaneously expectorated or induced sputum (if available) before resorting to bronchoscopy. Although there are no published studies comparing the relative performance of these different methods for detection of NTM, the presence of negative sputum samples in individuals with radiological and clinical suspicion of NTM disease should prompt CT-guided bronchoscopic sampling, as, for example, in nodular bronchiectatic disease. [bib_ref] Yield of computed tomography and bronchoscopy for the diagnosis of Mycobacterium avium..., Tanaka [/bib_ref] [bib_ref] Usefulness of bronchial lavage for the diagnosis of pulmonary disease caused by..., Sugihara [/bib_ref] [bib_ref] Diagnosis of nontuberculous mycobacterial infections, Van Ingen [/bib_ref] While trans-bronchial biopsies can reveal NTM (on microscopy or culture) and may demonstrate granulomatous inflammation (supporting NTM disease rather than transient colonisation), they should not be obtained routinely in individuals with CF given the significant risks of bleeding and pneumothorax. [bib_ref] Population-based estimates of transbronchial lung biopsy utilization and complications, Tukey [/bib_ref] How should respiratory tract samples from individuals with CF be cultured for NTM?
Recommendation 9: The CF Foundation and the ECFS recommend that respiratory tract samples should be cultured using both solid and liquid media.
Recommendation 10: The CF Foundation and the ECFS recommend that the incubation duration for NTM cultures should be for a minimum of 6 weeks.
## Recommendation 11:
The CF Foundation and the ECFS recommend that an NTM culture should be processed within 24 h of collection to optimise the detection of NTM in respiratory samples. If a delay in processing is anticipated, refrigeration of samples is advised.
The most sensitive and rapid way to detect viable mycobacteria is to culture samples (following decontamination to remove conventional bacteria and fungi) in liquid media using an automated growth detection system (such as Mycobacteria Growth Indicator Tube (MGIT) ; a process widely used around the world. However, concomitant culture on solid media may increase the diagnostic yield since NTM can be detected despite incomplete sample decontamination. [bib_ref] Detection of rapidly growing mycobacteria in routine cultures of samples from patients..., Esther [/bib_ref] Since decontamination procedures substantially reduce the viability of mycobacteria in samples, attempts have been made to use highly selective agar for solid culture of unprocessed sputum. A recent study, using agar designed for Burkholderia cepacia complex culture, [bib_ref] Detection of rapidly growing mycobacteria in routine cultures of samples from patients..., Esther [/bib_ref] demonstrated an improvement in detection of rapidly growing mycobacteria from 0.7% with conventional liquid culture to 2.8%. The duration, both of liquid and solid culture methods, has not been rigorously tested but the vast majority of pathogenic NTM will grow by 6 weeks-the current recommended duration in US and European laboratories. [bib_ref] European Manual of Clinical Microbiology, Delogu [/bib_ref] Laboratory processing of samples should ideally be performed within 24 h of collection to avoid overgrowth by conventional bacteria, which can reduce NTM viability [bib_ref] Survival of mycobacteria in sputum at different temperatures, Traore [/bib_ref] and prevent successful decontamination. [bib_ref] Survival of mycobacteria in sputum at different temperatures, Traore [/bib_ref] Studies have shown that refrigeration of samples may improve NTM detection from sputum samples [bib_ref] Rate of recovery of Mycobacterium tuberculosis from frozen acid-fast-bacillus smear-positive sputum samples..., Tessema [/bib_ref] and should be considered if delays longer than 24 h in processing are anticipated.
How should respiratory tract samples from individuals with CF be decontaminated to optimise the detection of NTM?
Recommendation 12: The CF Foundation and the ECFS recommend that respiratory tract samples should be decontaminated using the standard N-acetyl L-cysteine, NALC, (0.5%)-NaOH (2%) method.
Recommendation 13: The CF Foundation and the ECFS recommend that, if a sample remains contaminated with Gram-negative bacteria after standard NALC-NaOH decontamination, it should be further treated with either 5% oxalic acid or 1% chlorhexidine.
Adequate sample decontamination to remove conventional bacteria and fungi is essential to permit culture-based detection of mycobacteria, [bib_ref] European Manual of Clinical Microbiology, Delogu [/bib_ref] but often fails in CF samples given high densities of P. aeruginosa and other microbes. 39-41 Since enhanced decontamination protocols adversely impact on NTM viability in samples, 90 a two-step approach to sample processing should be adopted. [bib_ref] Improved decontamination method for recovering mycobacteria from patients with cystic fibrosis, Bange [/bib_ref] Virtually all US and European clinical microbiology laboratories currently use an NALC-NaOH decontamination step prior to mycobacterial culture. [bib_ref] Improved decontamination method for recovering mycobacteria from patients with cystic fibrosis, Bange [/bib_ref] The addition of a second decontamination step using oxalic acid has been shown to permit the recovery of NTM from persistently contaminated samples albeit with reduced sensitivity. [bib_ref] Proficiency testing of clinical microbiology laboratories using modified decontamination procedures for detection..., Whittier [/bib_ref] Alternatively, use of 1% chlorhexidine as a first step may improve the recovery of mycobacteria, but at the expense of higher rates of residual sample contamination. [bib_ref] Value of the chlorhexidine decontamination method for recovery of nontuberculous mycobacteria from..., Ferroni [/bib_ref] Chlorhexidine negatively affects the performance of the MGIT automated liquid culture system, because it needs to be neutralised with lecithin; lecithin generates random fluorescence reactions from the MGIT system sensor, limiting its use. [bib_ref] Value of the chlorhexidine decontamination method for recovery of nontuberculous mycobacteria from..., Ferroni [/bib_ref] Should non-culture-based methods be used to detect NTM in respiratory tract samples from individuals with CF?
## Recommendation 14:
The CF Foundation and the ECFS recommend against the use of non-culture-based methods for detecting NTM in respiratory tract samples.
A number of studies have been published on the use of PCR-based detection methods for NTM from respiratory samples. [bib_ref] Development and evaluation of a molecular assay for detection of nontuberculous mycobacteria..., Peter-Getzlaff [/bib_ref] [bib_ref] Evaluation of the GenoType Mycobacteria Direct assay for detection of Mycobacterium tuberculosis..., Franco-Alvarez De Luna [/bib_ref] [bib_ref] Evaluation of the GenoType Mycobacteria Direct assay for the simultaneous detection of..., Seagar [/bib_ref] [bib_ref] Multicenter evaluation of a pathogenic mycobacterium screening probe, Emler [/bib_ref] [bib_ref] Detection of mycobacterial DNA from sputum of patients with cystic fibrosis, Devine [/bib_ref] To date, however, none have been robustly evaluated for CF sputum samples, nor have they demonstrated sufficiently high sensitivity and specificity on smear-negative samples [bib_ref] Development and evaluation of a molecular assay for detection of nontuberculous mycobacteria..., Peter-Getzlaff [/bib_ref] to recommend their routine diagnostic use. Furthermore, the clinical significance of PCR-positive respiratory samples is currently unknown.
How should NTM isolates from individuals with CF be identified?
Recommendation 15: The CF Foundation and the ECFS recommend that all NTM isolates from individuals with CF should undergo molecular identification.
Recommendation 16: The CF Foundation and the ECFS recommend that all NTM isolates from individuals with CF should be identified to the species level, except for M. intracellulare, M. avium and M. chimaera, where identification can be limited to MAC and MABSC, which should be subspeciated.
As individual NTM species differ in their potential to cause clinical disease in humans [bib_ref] Clinical and taxonomic status of pathogenic nonpigmented or late-pigmenting rapidly growing mycobacteria, Brown-Elliott [/bib_ref] and in their response to specific antibiotics, correct species identification of NTM isolates is clinically important. Moreover, in the case of M. abscessus, the ability to identify isolates to the subspecies level (M. a. abscessus, M. a. bolletii, M. a. massiliense) may predict treatment response [bib_ref] Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus, Koh [/bib_ref] and potentially permit targeted therapy. [bib_ref] Macrolide treatment for Mycobacterium abscessus and Mycobacterium massillense infection and inducible resistance, Choi [/bib_ref] M. a. massiliense harbours a partial erm41 gene deletion, preventing inducible macrolide resistance, and leads to more successful outcomes with macrolide-based antibiotic regimens than in infections with M. a. abscessus (which has a full length, functional erm41 gene). [bib_ref] Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus, Koh [/bib_ref] There is no gold standard for NTM species identification. Molecular methods have now surpassed biochemical tests for NTM identification in many laboratories. [bib_ref] Identification of nontuberculous mycobacteria in clinical samples using molecular methods: a 3-year..., Couto [/bib_ref] [bib_ref] Comparative evaluation of the new version of the INNO-LiPA Mycobacteria and genotype..., Padilla [/bib_ref] [bib_ref] Performance assessment of new multiplex probe assay for identification of mycobacteria, Tortoli [/bib_ref] [bib_ref] Evaluation of INNO-LiPA MYCOBACTERIA v2: improved reverse hybridization multiple DNA probe assay..., Tortoli [/bib_ref] [bib_ref] Use of the INNO-LiPA-MYCOBACTERIA assay (version 2) for identification of Mycobacterium avium-Mycobacterium..., Lebrun [/bib_ref] [bib_ref] Rapid identification of Mycobacteria to the species level using INNO-LiPA Mycobacteria, a..., Suffys [/bib_ref] [bib_ref] Rapid identification of mycobacteria to species level by PCR-restriction fragment length polymorphism..., Devallois [/bib_ref] [bib_ref] hsp65 sequencing for identification of rapidly growing mycobacteria, Ringuet [/bib_ref] Although matrix-assisted laser desorption ionisation-time of flight mass spectrometry has shown promise in providing rapid speciation of NTM, 108-112 the optimal method for protein extraction from mycobacteria and the exact discriminatory power of this method have yet to be established.
Among molecular methods, three techniques are in current clinical use. The first includes line probe assays, which are easy to perform but costly, and permits accurate identification of the most frequently encountered NTM species but not subspeciation of M. abscessus. The second technique is PCR product restriction analysis in which amplified gene fragments are restriction digested to yield different sized fragments, which are then resolved by gel electrophoresis and correlated with specific species. [bib_ref] Rapid identification of mycobacteria to the species level by polymerase chain reaction..., Telenti [/bib_ref] This technique is mostly used in low-resource settings and is at least comparable to the line probe assays. [bib_ref] Rapid identification of mycobacteria to species level by PCR-restriction fragment length polymorphism..., Devallois [/bib_ref] The third technique is ( partial) gene sequencing, which permits a higher level of discrimination, often to subspecies level, but is only available in laboratories with access to sequencing facilities. The choice of the optimal sequencing strategy is not straightforward. Although partial 16S ribosomal RNA (rRNA) gene sequencing provides insufficient discrimination, particularly between M. abscessus and M. chelonae, 115 a number of other gene sequences (such as partial hsp65 and rpoB gene sequences) have been successfully used. [bib_ref] hsp65 sequencing for identification of rapidly growing mycobacteria, Ringuet [/bib_ref] [bib_ref] Inaccuracy of single-target sequencing for discriminating species of the Mycobacterium abscessus group, Macheras [/bib_ref] For subspeciation of M. abscessus, a multilocus sequence typing approach has recently been validated. [bib_ref] Inaccuracy of single-target sequencing for discriminating species of the Mycobacterium abscessus group, Macheras [/bib_ref] [bib_ref] Multilocus sequence analysis and rpoB sequencing of Mycobacterium abscessus (sensu lato) strains, Macheras [/bib_ref] [bib_ref] Multilocus sequence typing scheme for the Mycobacterium abscessus complex, Macheras [/bib_ref] An alternative strategy close to subspeciation is to measure erm gene associated inducible macrolide resistance by phenotypic drug susceptibility testing (DST). This does not distinguish accurately between M. abscessus subspecies but does offer the data for which the subspeciation is generally performed-whether or not there is inducible macrolide resistance.
Should DST be performed on NTM isolates from individuals with CF?
Recommendation 17: The CF Foundation and the ECFS recommend that for MAC, clarithromycin susceptibility testing should be performed on an isolate recovered prior to initiation of treatment. Clarithromycin susceptibility testing should also be performed on subsequent isolates if the patient (a) fails to culture convert after 6 months of NTM treatment; (b) recultures MAC after initial culture conversion while on NTM treatment or (c) recultures MAC after completion of NTM treatment.
Recommendation 18: The CF Foundation and the ECFS recommend that for MABSC, susceptibility testing should include at least clarithromycin, cefoxitin and amikacin (and preferably also tigecycline, imipenem, minocycline, moxifloxacin and linezolid).
Recommendation 19: The CF Foundation and the ECFS recommend that DST should be performed in accordance with CLSI guidelines.
Based on current published data, the exact role of DST and its potential to guide regimen selection and predict outcomes in NTM lung disease in patients with CF, remains unknown. [bib_ref] Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria, Van Ingen [/bib_ref] The CLSI has published guidelines on DST of NTM. [bib_ref] Multicenter study of prevalence of nontuberculous mycobacteria in patients with cystic fibrosis..., Roux [/bib_ref] Its European counterpart, the European Committee on Antimicrobial Susceptibility Testing (EUCAST), presently has no guidelines for DST of NTM. [bib_ref] European Manual of Clinical Microbiology, Delogu [/bib_ref] It is important to appreciate that, although CLSI guidelines provide breakpoint concentrations to interpret minimum inhibitory concentrations (MICs) as 'susceptible' or 'resistant', these cut-offs have had very limited clinical validation, and no clinical validation has been performed in patients with CF. Moreover, limited pharmacokinetic (PK) data are now available for MAC lung disease to support breakpoint concentrations, [bib_ref] The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment, Van Ingen [/bib_ref] there are no representative PK or pharmacodynamic data to guide treatment of patients with CF.
Breakpoints for clarithromycin susceptibility of MAC have been validated in HIV-related disseminated MAC disease and in retrospective series of MAC lung disease. [bib_ref] Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria, Van Ingen [/bib_ref] Since the presence of macrolide resistance predicts worse clinical outcomes and requires augmented treatment, [bib_ref] Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung..., Griffith [/bib_ref] susceptibility to macrolides should be tested on isolates prior to treatment initiation and during treatment in refractory cases defined as those individuals who (1) fail to culture convert after 6 months of NTM treatment; (2) reculture MAC after initial culture conversion while on NTM treatment or (3) reculture MAC after completion of NTM treatment.
A very recent study has shown that amikacin MICs >64 mg/L are measured only in MAC isolates that have mutations associated with amikacin resistance, that is, in the 16S rRNA gene. These strains are cultured from patients with significant aminoglycoside exposure, such as individuals with CF, and for disease caused by these strains, amikacin is unlikely to have any beneficial effect. [bib_ref] In vitro activity of amikacin against isolates of Mycobacterium avium complex with..., Brown-Elliott [/bib_ref] For rapidly growing mycobacteria including M. abscessus, clinical validation has only been performed in series of extrapulmonary disease, [bib_ref] Treatment of nonpulmonary infections due to mycobacterium-fortuitum and mycobacterium-chelonei on the basis..., Wallace [/bib_ref] and only for cefoxitin, aminoglycosides and co-trimoxazole. In series of M. abscessus lung disease, the outcomes of macrolide-based treatment are generally poor and do not correlate well with in vitro susceptibilities potentially due to erm 41 -dependent inducible macrolide resistance and relative short duration of adequate regimens, which were often interrupted because of toxicity. Indeed, in the absence of a functional erm 41 gene, response to macrolide-containing treatments has been good. [bib_ref] Multicenter evaluation of a pathogenic mycobacterium screening probe, Emler [/bib_ref] The CLSI has recommended routine testing for inducible macrolide resistance by performing extended incubation of isolates in the presence of clarithromycin, as inducible resistance may predict treatment failure.For M. simiae, the role of DST is unknown, although the generally poor outcomes of treatment have been correlated with a lack of synergistic activity between rifampicin and ethambutol, an in vitro observation that still awaits clinical validation. [bib_ref] Drug susceptibility testing and pharmacokinetics question current treatment regimens in Mycobacterium simiae..., Van Ingen [/bib_ref] Some molecular methods to assess drug susceptibility exist, but are not yet routinely available. For example, sequencing of the 16S rRNA and 23S rRNA genes can reveal mutations associated with high-level resistance to aminoglycosides and macrolides, respectively. [bib_ref] Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria, Van Ingen [/bib_ref] Recommendation 21: The CF Foundation and the ECFS recommend that other CF pathogens and comorbidities should be considered as potential contributors to a patient's symptoms and radiological features when determining the clinical significance of NTM-positive cultures.
Recommendation 22: The CF Foundation and the ECFS recommend that NTM treatment should be considered for individuals with CF who have ATS/IDSA defined NTM-PD.
Recommendation 23: The CF Foundation and the ECFS recommend that individuals receiving azithromycin as part of their CF medical regimen who have a positive NTM culture should not continue azithromycin treatment while evaluation for NTM disease is underway, as azithromycin monotherapy may lead to resistance. A macrolide agent may be included in a multidrug treatment regimen if criteria are met for NTM disease.
In contrast to M. tuberculosis, a single positive culture of NTM does not necessarily indicate that an individual has NTM-PD. To address the difficulty of making a diagnosis of NTM-PD, the ATS/IDSA proposed a set of clinical, radiological and microbiological criteria required to define an individual as having NTM-PD (ref 22; box 1). Although these criteria have not been validated for individuals with CF, they have been widely adopted by NTM specialists around the world and provide an operational definition for NTM-PD, which supports clinical decision-making and facilitates research. The Statements Committee therefore concluded that, in the absence of an alternate, CF-validated definition, the ATS/IDSA criteria should be used for the definition of NTM-PD in individuals with CF.
## Microbiological criteria for ntm-pd
Individuals should have two or more positive sputum cultures of the same NTM species or one positive culture from bronchoscopic lavage or wash. The threshold for the number of positive sputum samples is derived from an observational study of individuals without CF with MAC in which 98% individuals with at least two positive sputum cultures developed progressive radiographic change compared to only 2% with one positive culture. [bib_ref] Diagnosis of disease caused by mycobacterium-avium complex, Tsukamura [/bib_ref] The type of NTM species isolated is also important. Thus, isolation of M. abscessus is more likely to reflect NTM-PD than culturing usually non-pathogenic species such as M. gordonae and M. terrae complex.
## Radiological criteria for ntm-pd
In the context of CF-related lung disease, a chest radiograph is unlikely to be of use for the investigation of NTM-PD. High-resolution CT (HRCT) scan changes supporting a diagnosis of NTM-PD would include: inflammatory nodules, new tree-in-bud opacities ( particularly in areas of mild underlying bronchiectasis) and cavitation. [bib_ref] Nontuberculous mycobacterial infection: CT scan findings, genotype, and treatment responsiveness, Kim [/bib_ref] However, these changes are non-specific, particularly in individuals with severe CF-related lung disease, and may reflect infection with more common CF pathogens, inadequate airway clearance or the development of allergic bronchopulmonary aspergillosis (ABPA).
## Clinical criteria for ntm-pd
NTM-PD should be suspected in individuals with worsening respiratory symptoms (breathlessness, increased cough and sputum production) and/or declining pulmonary function tests that do not respond to antibiotic therapy targeting conventional CF-associated bacteria and optimised airway clearance. Night sweats, fevers, chest pains and weight loss (although uncommon) may also suggest possible NTM-PD.
NTM treatment should be considered in individuals with CF who fulfil ATS/IDSA criteria for NTM-PD. However, the decision to start treatment is a clinical one based on an do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded. C. Making the diagnosis of NTM-PD does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients.
amalgamation of patient factors, the NTM species involved, the risks of treatment side effects, adherence concerns and the expected outcomes of treatment.
## Recommended clinical practice for diagnosis
A suggested algorithm for the investigation of individuals with CF suspected of having NTM-PD is shown in [fig_ref] Figure 1: A suggested algorithm for the investigation of individuals with clinical suspicion of... [/fig_ref]. When being investigated for potential NTM-PD, individuals should discontinue drugs liable to compromise NTM culture (such as macrolides, fluoroquinolones, aminoglycosides, co-trimoxazole, linezolid and doxycycline) prior to sputum sample collection. In the case of azithromycin, intracellular accumulation within phagocytes may require a washout period of 2 weeks or more to allow for drug clearance. If sputum samples are persistently culture negative, but clinical or radiological suspicion of NTM-PD remains, bronchoscopy with targeted sampling of areas with suggestive HRCT changes may be indicated. Individuals receiving azithromycin as part of their CF medical regimen, who have a positive surveillance NTM culture, should not continue azithromycin treatment while evaluation for NTM disease is underway, as azithromycin monotherapy may lead to the development of macrolide resistance.
Other CF pathogens and comorbidities should be considered as potential contributors to a patient's symptoms and radiological features when determining the clinical significance of NTM-positive cultures. All aspects of CF care should be reviewed and optimised in order to determine the clinical significance of NTM in the sputum. Specifically, consider a trial of NTM-sparing intravenous antibiotics (ie, avoid carbapenems, cefoxitin, tigecycline, fluoroquinolones, linezolid and amikacin) that target conventional bacteria; and assess for CF-related diabetes, uncontrolled gastrointestinal reflux disease, and clinical and immunological features of ABPA. Likewise, adequate treatment of sinus disease, nutritional support and effective airway clearance strategies should be implemented.
Before starting NTM treatment, side effects, the importance of adherence to therapy and complications of treatment should be discussed with patients, and these discussions documented in the medical notes. Discussion of the risk of treatment failure should be clearly documented.
TREATMENT Which antibiotic regimen should be used in individuals with CF who have ATS/IDSA-defined MABSC pulmonary disease?
Recommendation 24: The CF Foundation and the ECFS recommend that treatment of MABSC pulmonary disease should involve an intensive phase followed by a continuation phase.
Recommendation 25: The CF Foundation and the ECFS recommend that the intensive phase should include a daily oral macrolide (preferably azithromycin) in conjunction with 3-12 weeks of intravenous amikacin and one or more of the following: intravenous tigecycline, imipenem or cefoxitin, guided but not dictated by DST. The duration of intensive phase therapy should be determined by the severity of infection, the response to treatment and the tolerability of the regimen.
Recommendation 26: The CF Foundation and the ECFS recommend that the continuation phase should include a daily oral macrolide ( preferably azithromycin) and inhaled amikacin, in conjunction with 2-3 of the following additional oral antibiotics: minocycline, clofazimine, moxifloxacin and linezolid, guided but not dictated by DST.
Recommendation 27: The CF Foundation and the ECFS recommend that individuals with MABSC pulmonary disease should be managed in collaboration with experts in the treatment of NTM and CF, as drug intolerance and drug-related toxicity occur frequently, and changes in antibiotic therapy are often required.
Recommendation 28: The CF Foundation and the ECFS recommend that monotherapy with a macrolide or other antimicrobial should never be used in the treatment of MABSC pulmonary disease.
There are no published randomised controlled trials evaluating treatment outcomes in individuals with M. abscessus pulmonary infections. Current treatment recommendations from the ATS and IDSA recommend consideration of a multidrug treatment regimen, but note that long-term sputum conversion is difficult to achieve and thus, alternative goals such as symptomatic improvement, radiographic regression of opacities or microbiological improvement, may be more realistic. [bib_ref] An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Griffith [/bib_ref] The ATS/IDSA recommendations were based primarily on a single large study of 154 patients with lung disease caused by rapidly growing mycobacteria, in which more than 80% of patients were infected by M. abscessus. 135 Treatment outcomes were extremely poor; however, the patients did not receive the currently recommended combination of antibiotics.
Since the publication of the last ATS/IDSA guidelines, [bib_ref] An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Griffith [/bib_ref] there have been several studies that reported treatment outcomes in individuals without CF with pulmonary disease due to M. abscessus. Jeon et al 136 described treatment outcomes in 65 non-CF adults, in South Korea, with M. abscessus lung disease, who received a standardised treatment regimen. The regimen included 4 weeks of amikacin (15 mg/kg/day in two divided doses) and cefoxitin (200 mg/kg/day in three divided doses) along with clarithromycin (1000 mg/day in two divided doses), ciprofloxacin (1000 mg/day in two divided doses) and doxycycline (200 mg/day in two divided doses). The total duration of therapy was 24 months and at least 12 months after sputum culture conversion. Fifty-four (83%) patients responded with improved symptoms and 48 (74%) with improved HRCT findings. Sputum conversion and maintenance of negative sputum cultures for more than 12 months was achieved in 38 (58%) patients. This rate was significantly lower (17%) in patients whose isolates were resistant to clarithromycin. In contrast, in the 14 (22%) patients who underwent resectional surgery, negative sputum cultures were achieved and maintained in 7 (88%) of 8 with preoperatively positive cultures. The authors concluded that a standardised regimen was moderately effective, but adverse reactions were frequent. Among 107 patients with M. abscessus pulmonary infection at National Jewish Health in Denver, CO, 69 non-CF individuals were treated and followed for a mean duration of 34 months. [bib_ref] Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary..., Jarand [/bib_ref] Patients were treated with individualised treatment regimens following ATS/IDSA recommendations. Twenty (29%) patients remained culture positive, 16 (23%) converted but experienced relapse, 33 (48%) converted to negative and did not relapse, while 17 (16%) died during the study period. There were significantly more surgical patients than medical patients whose culture converted and remained negative for at least 1 year (57% vs 28%, p=0.022). As in the previous study from South Korea, surgery may have been beneficial. However, surgical management is less likely to be applicable in individuals with CF in whom focal pulmonary disease is uncommon.
In a follow-up study, Koh et al 97 reported significant differences in outcomes based on which subspecies of M. abscessus was causing the infection. Treatment response rates to a standardised multidrug regimen were much higher in patients with M. a. massiliense than in those with M. a. abscessus: sputum culture conversion occurred in 88% of patients with M. a. massiliense compared with 25% with M. a. abscessus (p<0.001). All of the M. a. abscessus isolates contained a full length, functional erm 41 that was shown to result in inducible macrolide resistance when the isolates were incubated with clarithromycin. In contrast, the MIC of M. a. massiliense strains did not increase after incubation with the macrolide agent because the erm 41 gene contained a deletion, making it non-functional. Recent data from this same group of investigators have indicated that clarithromycin is a much stronger inducer of erm 41 than azithromycin, suggesting that the latter macrolide may be a better choice when treating M. a. abscessus infections. [bib_ref] Macrolide treatment for Mycobacterium abscessus and Mycobacterium massillense infection and inducible resistance, Choi [/bib_ref] Despite the clinical significance of M. abscessus lung infection in patients with CF, data on treatment outcomes are extremely limited. There is one anecdotal report that describes eradication of M. abscessus in an individual with CF who received a prolonged course of therapy with alternating month inhaled amikacin plus oral clarithromycin. [bib_ref] Aerosolized amikacin and oral clarithromycin to eradicate Mycobacterium abscessus in a patient..., Colin [/bib_ref] However, this appears to be an uncommon outcome in practice. A recent case series of 52 individuals, including 15 with CF, with M. abscessus and/or M. chelonae infection, suggests that tigecycline-based regimens may be of benefit, with 10/15 individuals with CF showing some improvement. [bib_ref] Clinical experience in 52 patients with tigecycline-containing regimens for salvage treatment of..., Wallace [/bib_ref] Recommended clinical practice for antibiotic treatment for M. abscessus pulmonary disease in CF A typical treatment schedule for individuals with CF with M. abscessus infection is shown in [fig_ref] Figure 2: Typical treatment schedules for individuals with CF with Mycobacterium abscessus or MAC... [/fig_ref]. Antibiotic dosing regimens are listed in table 2 with important side effects/toxicities described in table 3.
Given the lack of clinical trial data to inform treatment decisions there is a lot of variation in how patients are treated. An initial intensive phase is typically used to rapidly decrease the bacterial load. A combination of two intravenous drugs with demonstrated in vitro activity is administered for several weeks to months in combination with one or more oral drugs. Intravenous drug regimens of amikacin with cefoxitin and/or imipenem and/or tigecycline are the most commonly used combinations. Oral drugs with demonstrated in vitro activity include the macrolides (clarithromycin and azithromycin), linezolid, clofazimine and, occasionally, ciprofloxacin and/or moxifloxacin. After the intensive phase of therapy, patients are usually treated with at least two oral drugs in addition to a macrolide with or without inhaled antibiotics.
However, there is growing concern that treatment of M. abscessus isolates that have either a functional erm 41 gene (resulting phenotypically in inducible macrolide resistance) or a 23S rRNA mutation (leading to high level constitutive macrolide resistance) may be compromised by switching from intravenous to oral therapy (given the relatively poor efficacy of oral antibiotics) and, therefore, continuous/very extended intravenous therapy with two or more effective antibiotics may be indicated in these cases.
The choice of intravenous agents is based on in vitro activity and the toxicity profile of the drug. In addition to amikacin, imipenem is perhaps the best choice as companion intravenous therapy; the drug shows in vitro activity and the side effect profile is better than that of cefoxitin and tigecycline. In the study reported by Jeon et al, [bib_ref] Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65..., Jeon [/bib_ref] 60% of the patients started on cefoxitin had to have the drug discontinued due to drug-related toxicity, after a median of 22 days of treatment. Neutropaenia occurred in 51% and thrombocytopaenia in 6% of patients on cefoxitin. Tigecycline has a low MIC against M. abscessus and showed efficacy against M. abscessus in combination. [bib_ref] Clinical experience in 52 patients with tigecycline-containing regimens for salvage treatment of..., Wallace [/bib_ref] However, it is associated with significant nausea and vomiting, which has made it difficult to administer for a prolonged period. [bib_ref] Clinical experience in 52 patients with tigecycline-containing regimens for salvage treatment of..., Wallace [/bib_ref] There are few oral drugs with significant in vitro activity against M. abscessus; the macrolides are the only oral drugs with consistent activity although their use may be potentially limited by inducible resistance (as described above) or acquired point mutations in the 23S rRNA. There are no clinical trials comparing azithromycin to clarithromycin in M. abscessus infection, so the choice of which macrolide to use is typically based on the in vitro activity, side effects profile and consideration of drug interactions. Clarithromycin has slightly better in vitro activity than azithromycin but there are conflicting reports regarding the impact of erm 41 gene expression with each of these drugs. [bib_ref] Macrolide treatment for Mycobacterium abscessus and Mycobacterium massillense infection and inducible resistance, Choi [/bib_ref] Clarithromycin is a stronger inhibitor of the P450 enzyme system than is azithromycin, so drug interactions are more common.
Linezolid shows in vitro activity in approximately 50% of M. abscessus isolates (although there is considerable geographical variation); however, haematological (anaemia, thrombocytopaenia) and neurological ( peripheral neuropathy, optic neuritis) toxicities are common, particularly when linezolid is dosed 600 mg two times a day for prolonged courses. For this reason, many practitioners give 600 mg once daily to reduce the risk of adverse effects. However, care should be exercised in individuals chronically co-infected with methicillin-resistant Staphylococcus aureus (MRSA) since long-term linezolid therapy may encourage MRSA resistance. The fluoroquinolones and minocycline/doxycycline rarely show in vitro activity although they were included in the standardised treatment regimen used in the report by Jeon et al. [bib_ref] Macrolide treatment for Mycobacterium abscessus and Mycobacterium massillense infection and inducible resistance, Choi [/bib_ref] Finally, clofazimine has significant in vitro activity against M. abscessus. [bib_ref] In vitro synergy between clofazimine and amikacin in treatment of nontuberculous mycobacterial..., Van Ingen [/bib_ref] However, this drug, used to treat leprosy, is not readily available in the USA at this time, although it can be obtained with an IRB-approved protocol through submission of an individual patient use IND to the Food and Drug Administration. Instructions for this process can be found on the NTM Info and Research, Inc, website (http://www.ntminfo. org/clofazimine).
The lack of oral antibiotics with activity against M. abscessus has led clinicians to use inhaled amikacin, usually during the continuation phase of therapy. There are no studies correlating treatment outcomes in patients with M. abscessus infection with the dose of inhaled amikacin and, therefore, there is a great deal of variation in the dose used (250-500 mg), and frequency of administration (daily to twice daily). A recent study, targeting treatment refractory NTM patients, most of whom were without CF with M. abscessus, evaluated the effect of adding inhaled amikacin to their oral and/or intravenous drug regimens. [bib_ref] Inhaled amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease, Olivier [/bib_ref] Among the 20 patients with persistently positive cultures, 8 (40%) had at least one negative culture and 5 (25%) had persistently negative cultures after addition of inhaled amikacin. Inhaled amikacin was stopped in 7 (35%) due to toxicity. There is currently significant interest in the potential use of a liposomal formulation of amikacin (which may improve drug delivery within the lung and into infected macrophages) as part of a multidrug regimen for both M. abscessus and MAC. Large multicentre studies are ongoing.
The optimum duration of therapy is not known. Based on studies in individuals without CF, even prolonged treatment regimens were associated with high rates of failure and recurrence. Many patients who do not convert their cultures to negative on therapy may still benefit from continuing or repeating courses of treatment. abscessus treatment is divided into an initial intensive phase with an oral macrolide ( preferably azithromycin) and intravenous amikacin with one or more additional intravenous antibiotics (tigecycline, imipenem, cefoxitin) for 3-12 weeks (depending on severity of infection, response to treatment, and the tolerability of the regimen), followed by a continuation phase of oral macrolide ( preferably azithromycin) and inhaled amikacin with 2-3 additional antibiotics (minocycline, clofazimine, moxifloxacin, linezolid). Antibiotic choices should be guided but not dictated by drug susceptibility testing. Baseline and interval testing for drug toxicity is essential (B). MAC treatment (for clarithromycin-sensitive disease) should be with a daily oral macrolide ( preferably azithromycin), rifampin and ethambutol. An initial course of injectable amikacin or streptomycin should be considered in the presence of (i) AFB smear positive respiratory tract samples, (ii) radiological evidence of lung cavitation or severe infection and (iii) systemic signs of illness. Baseline and interval testing for drug toxicity is essential (AFB, acid-fast bacilli; CF, cystic fibrosis; HRCT, high-resolution CT; MAC, Mycobacterium avium complex).
## Treatment for mac
Which antibiotic regimen should be used in individuals with CF who have ATS/IDSA-defined MAC pulmonary disease?
Recommendation 29: The CF Foundation and the ECFS recommend the same antibiotic regimen for treatment of all species within the MAC.
Recommendation 30: The CF Foundation and the ECFS recommend that clarithromycin-sensitive MAC pulmonary disease should be treated with a daily oral antibiotic regimen containing a macrolide ( preferably azithromycin), rifampin and ethambutol.
Recommendation 31: The CF Foundation and the ECFS recommend against the use of intermittent (three times per week) oral antibiotic therapy to treat MAC pulmonary disease.
## Recommendation 32:
The CF Foundation and the ECFS recommend that monotherapy with a macrolide or other antimicrobial agent should never be used in the treatment of MAC pulmonary disease.
Recommendation 33: The CF Foundation and the ECFS recommend that an initial course of intravenous amikacin should be considered for the treatment of MAC pulmonary disease in the presence of one or more of the following: (i) AFB smear positive respiratory tract samples, (ii) radiological evidence of lung cavitation or severe infection and (iii) systemic signs of illness.
Recommendation 34: The CF Foundation and the ECFS recommend that clarithromycin-resistant MAC pulmonary disease should be managed in collaboration with experts in the treatment of NTM and CF. There are very few published randomised controlled trials evaluating treatment for MAC pulmonary disease (MAC-PD) in non-HIV-positive patients and none in individuals with CF. In the pre-macrolide era, a UK trial of individuals without CF and with largely cavitary disease reported that those randomised to receive rifampin and ethambutol had a combined failure/relapse rate of 41% compared to 16% of patients randomised to receive rifampin, ethambutol and isoniazid ( p=0.033).In a subsequent study on a similar cohort, patients randomised to receive rifampin, ethambutol and clarithromycin had an allcause mortality of 48% compared to 30% of patients randomised to receive rifampin, ethambutol and ciprofloxacin. 144 However, only 13% of patients in the clarithromycin group failed treatment or relapsed compared to 23% in the ciprofloxacin group.
In addition, there have been several non-comparator studies evaluating outcomes in HIV-negative patients with MAC-PD. The majority utilised a three oral drug regimen including a macrolide (clarithromycin or azithromycin), a rifamycin (rifampin or rifabutin) and ethambutol, in combination with an initial course of an aminoglycoside (streptomycin, amikacin or kanamycin). [bib_ref] Clarithromycin regimens for pulmonary Mycobacterium avium complex-the first 50 patients, Wallace [/bib_ref] The culture conversion rate varied considerably between studies (13-82%), but on the whole, in 55-65% of patients, the culture converted after 6-12 months treatment and, when reported, the mean time from starting treatment to culture conversion was 3-5 months. Treatment failure was associated with previous MAC-PD treatment, cavitary disease, smear positivity, clarithromycin resistance at initiation of treatment, intolerance of NTM therapy and acquired clarithromycin resistance. [bib_ref] Clarithromycin regimens for pulmonary Mycobacterium avium complex-the first 50 patients, Wallace [/bib_ref] An alternative regimen using clofazimine with a macrolide and ethambutol in a study of 30 patients resulted in a culture conversion rate of 87% and a treatment success rate of 67%. [bib_ref] Treatment of Mycobacterium avium-intracellulare complex lung disease with a macrolide, ethambutol, and..., Field [/bib_ref] Although 5 (19%) patients relapsed an average of 17 months after completing treatment, all MAC isolates remained clarithromycin sensitive, raising the possibility of reinfection rather than treatment failure. [bib_ref] Macrolide/azalide therapy for nodular/bronchiectatic Mycobacterium avium complex lung disease, Wallace [/bib_ref] In another case series utilising clofazimine in combination with clarithromycin and minocycline, the culture conversion rate was 64% in patients completing the study (47% overall), which may indicate the importance of ethambutol as part of the multidrug regimen in the treatment of MAC-PD. [bib_ref] Clarithromycin with minocycline and clofazimine for Mycobacterium avium intracellulare complex lung disease..., Roussel [/bib_ref] Clarithromycin resistance developed in up to 15% of patients receiving treatment for MAC-PD and this was generally associated with clarithromycin monotherapy or the prescription of inadequate companion medications. When taken in combination with ethambutol and a rifamycin, acquired clarithromycin resistance developed in only 12/303 (4%) of patients. In the context of clarithromycin resistance, the best treatment responses were seen in patients who underwent surgical resection and received >6 months of an injectable aminoglycoside (amikacin or streptomycin), 124-126 as 11/14 (79%) so treated achieved culture conversion compared to 1/27 (4%) of those not surgically resected and not receiving injectables. [bib_ref] Clarithromycin therapy for bacteremic mycobacterium-avium complex disease-a randomized, double-blind, dose-ranging study in..., Chaisson [/bib_ref] While intermittent and daily dosing regimens appear equally effective in several case series of individuals without CF, intermittent regimens may be associated with less toxicity, better tolerability and adherence, and lower cost. However, a large multicentre study utilising an intermittent dosing regimen in individuals with moderate or severe MAC-PD (including many with cavitary disease and with prior treatment failure), reported a culture conversion rate of only 13% after 12 months of treatment. There have, to date, been no studies in individuals with CF to determine an optimal dosing regimen for MAC therapy, but concerns about drug absorption and lung penetration in CF have meant that many centres have adopted daily dosing protocols.
It is unclear if use of an aminoglycoside during the initial phase of MAC antibiotic therapy is beneficial. In a multicentre study involving 146 HIV-negative patients with MAC-PD, participants were randomised to receive intramuscular streptomycin (15 mg/kg) or placebo thrice weekly for the first 3 months of therapy, in addition to clarithromycin, rifampin and ethambutol. Streptomycin-treated patients had a significantly higher culture conversion rate after approximately 2 years of treatment than did placebo patients (71% vs 51%, p<0.05), but a third of patients in each group experienced sputum relapse and there were no significant differences in symptoms or radiological response between groups. [bib_ref] A double-blind randomized study of aminoglycoside infusion with combined therapy for pulmonary..., Kobashi [/bib_ref] Furthermore, there was no statistically significant difference in culture conversion rates between individuals who received an initial course of intramuscular kanamycin (78%) compared to those who did not (58%) in a nonrandomised study involving patients with MAC-PD. [bib_ref] Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease, Tanaka [/bib_ref] Recently, the use of aerosolised amikacin in addition to standard multidrug macrolide-based regimens was reported in six HIV-negative individuals with MAC-PD who had failed standard therapy. [bib_ref] Aerosolized amikacin for treatment of pulmonary Mycobacterium avium infections: an observational case..., Davis [/bib_ref] While four patients were culture negative after 6 months of therapy, one later cultured M. chelonae (resistant to amikacin), two re-cultured MAC and one patient was unable to tolerate prolonged therapy with aerosolised amikacin. A recent case series of the impact of nebulised amikacin (250 mg once or twice daily) 142 in 20 individuals without CF with treatment refractory NTM-PD (of whom 5 had MAC) reported adverse events in 35% of cases. Two patients discontinued therapy due to hearing loss. Studies examining the use of liposomal amikacin (which may have a better side effects profile) for the treatment of NTM in individuals with CF are ongoing.
## Recommended clinical practice antibiotic treatment for mac-pd in cf
A typical treatment schedule for individuals with CF with MAC infection is shown in [fig_ref] Figure 2: Typical treatment schedules for individuals with CF with Mycobacterium abscessus or MAC... [/fig_ref]. Antibiotic dosing regimens are listed in table 2 with important side effects/toxicities described in table 3.
Individuals with clarithromycin sensitive MAC-PD should be treated with a daily oral antibiotic regimen that includes a macrolide, rifampin and ethambutol (15 mg/kg), consistent with the ATS/IDSA recommendations for individuals with severe nodular bronchiectatic disease. [bib_ref] An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Griffith [/bib_ref] Intermittent oral antibiotic therapy is not recommended due to the nature of the underlying lung disease and concerns regarding antibiotic absorption in CF. While there are no head to head trials showing a difference in outcome between individuals with MAC-PD treated with clarithromycin or azithromycin, the latter may be the macrolide of choice in CF, as it can be taken once daily, its serum levels may be less affected by rifamycins [bib_ref] The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment, Van Ingen [/bib_ref] and it has well established benefits in individuals with CF in addition to its effects on NTM.
Individuals with a high bacterial load (suggested by smear positivity, radiological evidence of lung cavitation and/or significant inflammatory change or the presence of systemic symptoms) may benefit from an initial (1-3 month) course of injectable amikacin or streptomycin, in addition to the standard three-drug regimen for MAC-PD. While the available data do not show a difference in toxicity between amikacin regimens dosed at 15 mg/kg once daily or 25 mg/kg thrice weekly, ototoxicity was found in 37% of all participants (associated with older age and larger cumulative dose), vestibular toxicity in 8% (usually reversible) and nephrotoxicity in 15% (usually mild and reversible). [bib_ref] Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases, Peloquin [/bib_ref] Streptomycin, although less widely used for MAC-PD than amikacin, may have less ototoxicity than amikacin. [bib_ref] Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases, Peloquin [/bib_ref] The use of aerosolised amikacin in place of an intravenous aminoglycoside may be preferable in terms of reduced burden of care and toxicity, but outcome data are limited and it is unlikely to be helpful for patients with cavitary disease in whom drug levels at the site of infection may be subtherapeutic.
The major risk factors for the development of clarithromycinresistant MAC-PD are macrolide monotherapy and prior macrolide treatment with inadequate companion medications. Thus, macrolides (often prescribed for their anti-inflammatory effects in CF) should be discontinued immediately following isolation of a mycobacterial species, and macrolides should never be prescribed in the treatment of MAC-PD without two appropriate companion antibiotics. Macrolide therapy is not generally recommended in the context of clarithromycin-resistant MAC-PD, [bib_ref] An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Griffith [/bib_ref] but macrolides may still be beneficial in this context in CF due to their nonantibiotic properties. Individuals with clarithromycin-resistant MAC-PD may respond to a regimen including a parenteral aminoglycoside, a rifamycin (usually rifabutin) and ethambutol, in addition to one or more companion medications (accepting that there are limited data to guide practice) [bib_ref] An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Griffith [/bib_ref] such as a quinolone or clofazimine. Rifabutin may be useful in the treatment of clarithromycin-resistant MAC-PD, but adverse events (particularly blood dyscrasias, gastrointestinal upset and polyarthralgia) are more common and often necessitate dose reduction or complete cessation of treatment. [bib_ref] Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment..., Griffith [/bib_ref] [bib_ref] Azithromycin activity against Mycobacterium avium complex lung disease in patients who were..., Griffith [/bib_ref] [bib_ref] Varying dosages of rifabutin affect white blood cell and platelet counts in..., Griffith [/bib_ref] Surgical resection might also be helpful in selected individuals with localised severe bronchiectatic disease, but this management is less likely to be useful in CF as MAC-PD is more likely to be diffuse.
Ethambutol ocular toxicity (optic or retrobulbar neuritis) may present with blurred vision, decreased acuity, central scotomas, impaired red-green colour discrimination and peripheral visual field defects. Ocular toxicity was identified in 6% of individuals without CF with MAC-PD receiving ethambutol at a dose of 25 mg/kg/day for the first 2 months followed by 15 mg/kg/day for the remainder of treatment. [bib_ref] Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease, Griffith [/bib_ref] Ocular toxicity is more likely to occur in the context of MAC-PD than in patients receiving tuberculosis (TB) treatment due to the longer duration of therapy. While individuals prescribed ethambutol should have regular visual acuity and colour vision testing, visual symptoms often occur before measurable changes can be identified. Thus, patients should be educated about the potential side effects of ethambutol and encouraged to self-report changes in vision, following which ethambutol therapy should be discontinued until an ophthalmological assessment has taken place.
It is not uncommon for more than one NTM species to be isolated from an individual with CF. In these circumstances, continued microbiological surveillance is advisable to determine which species is/are persistently positive and which is/are likely to be causing disease. NTM-PD is also commonly associated with ABPA and/or the identification of Aspergillus spp in sputum or lavage specimens. As rifamycins increase the hepatic metabolism of azole antifungal agents, the treatment of Aspergillus in the context of MAC-PD is more difficult. One approach is to use rifabutin in place of rifampin (as it is the rifamycin with the least cytochrome P450 enzyme induction) in conjunction with the usual companion medications for MAC and voriconazole, or posaconazole, which may be less affected by rifabutin co-medication than voriconazole is, with adjustment of drug doses according to levels. If therapeutic drug monitoring (TDM) is not available, other approaches include using nebulised amikacin or clofazimine in place of rifampin. 150
## Treatment: generic recommendations
What outcome monitoring should be performed in individuals with CF receiving treatment for NTM-PD?
Recommendation 35: The CF Foundation and the ECFS recommend that individuals with CF receiving NTM treatment should have expectorated or induced sputum samples sent for NTM culture every 4-8 weeks throughout the entire course of treatment to assess the microbiological response.
Recommendation 36: The CF Foundation and the ECFS recommend that a schedule for detecting drug toxicity (including hearing loss, visual loss, renal impairment and liver function test abnormalities) should be set in place at the time of NTM treatment initiation and implemented throughout treatment based on the specific drugs prescribed.
Recommendation 37: The CF Foundation and the ECFS recommend that an HRCT scan of the lungs should be performed shortly before starting NTM treatment and at the end of NTM treatment, to assess the radiological response.
What duration of antibiotic therapy is recommended for individuals with CF receiving treatment for NTM-PD?
Recommendation 38: The CF Foundation and the ECFS recommend that NTM antibiotic therapy should be prescribed for 12 months beyond culture conversion (defined as three consecutive negative cultures, with the time of conversion being the date of the first of the three negative cultures) as long as no positive cultures are obtained during those 12 months.
Recommendation 39: The CF Foundation and the ECFS recommend that individuals who fail to culture convert despite optimal NTM therapy may benefit from long-term suppressive antibiotic treatment.
Treatment: TDM Should TDM be performed in individuals with CF receiving treatment for NTM-PD?
Recommendation 40: The CF Foundation and the ECFS recommend that, when amikacin is given intravenously or when streptomycin is given intravenously or intramuscularly, serum levels should be monitored and dosing adjusted to minimise ototoxicity and nephrotoxicity.
Recommendation 41: The CF Foundation and the ECFS recommend against routinely obtaining serum levels of other antimycobacterial drugs. However, absorption of oral medications is often reduced in CF. Therefore use of TDM should be considered for individuals failing to improve despite taking recommended drug regimens or for those on concomitant medications with significant interactions with NTM drugs.
TDM seeks to quantify the relationship between drug dose, serum (plasma) concentration and clinical response, [bib_ref] Therapeutic drug monitoring in antituberculosis chemotherapy, Yew [/bib_ref] and to thereby maximise therapeutic response while avoiding toxicity. The potential benefits of TDM during NTM treatment in individuals with CF include adjusting drug dosing to: A. Correct for drug-drug interactions that could adversely affect serum antibiotic levels: Drug-drug interactions frequently occur among agents used to treat NTM. Rifampin (more than rifabutin) may increase the metabolism of several drugs including clarithromycin, azithromycin and moxifloxacin, while rifabutin increases azithromycin levels and decreases moxifloxacin levels. . Maximise the PK and pharmacodynamic (PD) parameters of antibiotics to optimise efficacy: The PK/PD indices that correlate with clinical efficacy vary by antimicrobial agent. [bib_ref] The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment, Van Ingen [/bib_ref] To exert maximal activity, drugs such as aminoglycosides and ethambutol require high peak concentrations relative to the pathogen's minimal inhibitory concentration (C max /MIC). Ciprofloxacin and rifampin require a high concentration time or area under the plasma concentration curve measured over 24 h to MIC ratio (AUC 0-24 / MIC) and β-lactam agents require as much time as possible whereby the concentration persists above the infecting organism's MIC (%T> MIC). Macrolide agents such as azithromycin have weak concentration-dependent effects and time effects, but these agents exert their activity through intracellular activity, tissue penetration and prolonged, persistent effects, due to their long half-life. [bib_ref] Macrolides: pharmacokinetics and pharmacodynamics, Van Bambeke [/bib_ref] C. Overcome CF-related differences in absorption, distribution and clearance of drugs: Individuals with CF have different renal and non-renal clearance of several drugs when compared to individuals without CF, due to reduced bioavailability, increased volume of distribution and more rapid clearance. In addition, hepatic disease and diabetes may further influence drug metabolism and absorption. Several recent reviews have addressed evidence-based dosing for various agents used for treatment of pulmonary exacerbations in CF. [bib_ref] Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: I. aztreonam and..., Zobell [/bib_ref] [bib_ref] Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. cephalosporins and..., Zobell [/bib_ref] [bib_ref] Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: III. fluoroquinolones, Stockmann [/bib_ref] [bib_ref] Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: IV. colistimethate sodium, Young [/bib_ref] While the relevance of the recommended dosing schedules is unknown for treatment of NTM, it is possible that individuals with CF would need higher dosages of mycobacterial drugs. With the exception of aminoglycosides, the clinical utility of TDM during treatment for NTM is unknown for individuals with and without CF due to a lack of rigorous studies, although some experts have recommended TDM for mycobacterial agents on a case-by-case basis. [bib_ref] Therapeutic drug monitoring in the treatment of tuberculosis, Peloquin [/bib_ref] A recent retrospective study assessed the PK and pharmacodynamic parameters for 481 patients with disease caused by MAC. [bib_ref] The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment, Van Ingen [/bib_ref] Peak serum concentrations within reference/normal ranges were only achieved for ethambutol, clarithromycin and azithromycin, in 52%, 44% and 65% of patients, respectively. In addition, pharmacodynamic targets for C max /MIC or AUC 0-24 /MIC were rarely achieved. However, these observations were not linked with clinical outcomes.
Another recent evaluation of the potential utility for TDM in 130 individuals without CF treated for MAC found no association between peak plasma/MIC ratios for clarithromycin, rifampin or ethambutol, and clinical outcomes. [bib_ref] Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease, Koh [/bib_ref] As previously observed, rifampin had a substantial impact on clarithromycin levels; those treated with both drugs had a median peak plasma clarithromycin concentration of 0.3 mg/mL, while those treated with rifabutin had a median peak plasma concentration of 1.8 mg/mL, and those with M. abscessus (n=60) treated without rifampin had a median peak plasma concentration of 3.8 mg/ mL. In all, 97% of patients with MAC treated with daily therapy and 100% of patients on intermittent therapy reached the target of 2 mg/mL for clarithromycin. These experts concluded that TDM for treatment of MAC lung disease may not be beneficial (although the effects of dose optimisation on clinical outcomes were not evaluated).
To the best of our knowledge, there is only one case series, published over a decade ago, examining the potential role of TDM in CF. Ten patients with CF with mycobacterial disease (6 with MAC, 3 with M. abscessus and 1 with M. tuberculosis) had serum drug concentration measurements performed 2 and 4 h after ingestion. [bib_ref] Therapeutic drug monitoring in patients with cystic fibrosis and mycobacterial disease, Gilljam [/bib_ref] Monitoring serum levels at two time points helped distinguish between poor absorption and delayed absorption. Half of the patients had inadequate serum levels for one or more drugs, and one patient clinically improved following dose adjustments that achieved target serum levels. However, target concentrations were not achieved for several patients. Notably, this study did not compare outcomes in patients with and without TDM.
## Treatment: adjuvant therapy and surgery
In the context of infectious disease, adjuvants have been defined as 'therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering the organism less virulent or killing it by other means'. [bib_ref] Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis, Hurley [/bib_ref] A number of approaches have been proposed as candidates for adjuvant therapy in NTM infection in CF, including interferon γ (IFNγ; or agents that promote IFNγ release) and vitamin D. Drug delivery vehicles, such as liposomes, may be considered adjuvants. Liposomes have been studied as a mode of delivering amikacin for infection with P. aeruginosa in CF, [bib_ref] Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa..., Clancy [/bib_ref] and this approach is also being evaluated (clinicaltrials.gov/show/ NCT01315236) for NTM.
## Does ifnγ therapy improve treatment outcomes in individuals with cf who have ntm-pd?
Recommendation 42: The CF Foundation and the ECFS recommend against the use of IFNγ as adjuvant therapy for NTM-PD in individuals with CF.
IFNγ plays a critical role in the host defence against NTM infection: (1) deficiencies in IFNγ signalling (caused by deleterious mutations [bib_ref] Human host genetic factors in nontuberculous mycobacterial infection: lessons from single gene..., Haverkamp [/bib_ref] or neutralising autoantibodies 175 ) lead to (usually disseminated) NTM infection in individuals without CF; (2) inoculation of mice deficient in IFNγ or IFNγ receptors results in disseminated NTM infection; [bib_ref] Host immune response to rapidly growing mycobacteria, an emerging cause of chronic..., Chan [/bib_ref] (3) addition of IFNγ to NTM-infected human macrophages in vitro enhances intracellular killing probably through autophagy stimulation. [bib_ref] Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection, Renna [/bib_ref] In non-CF individuals, adjuvant IFNγ therapy in NTM infection has been examined in several studies. An uncontrolled trial of IFNγ was conducted in seven patients with presumed primary immunodeficiency (three with familial susceptibility to MAC and four with idiopathic CD4 lymphopaenia) who had disseminated NTM disease refractory to conventional antibiotic therapy. [bib_ref] Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. A preliminary..., Holland [/bib_ref] All the patients improved with the introduction of subcutaneous IFNγ two or three times per week.
In a randomised, placebo controlled trial, 32 patients with pulmonary NTM disease (30 with MAC) were randomised to receive either intramuscular IFNγ (1×10 6 IU) or placebo once daily for 4 weeks and then three times weekly for 20 weeks 178 in addition to daily oral azithromycin, ciprofloxacin, ethambutol and rifampin. The primary outcome (a composite end point of improvements in symptoms, radiology and microbiology) was achieved at 6 months by 72% (13/18) of patients in the IFNγ arm compared to 36% (5/14) receiving placebo ( p=0.037). The greater response rate with IFNγ was sustained at 12 months after completion of treatment. However, the small study size, the use of composite end points and the lack of microbiological response after 6 months treatment mean that these data need to be interpreted with caution.
Furthermore three large trials (ClinicalTrials.gov Identifiers NCT00001318, NCT00111397 and NCT00043355) examining IFNγ therapy for pulmonary NTM disease remain unpublished or have been terminated (potentially due to lack of efficacy), again questioning the role of IFNγ adjuvant therapy.
## Does vitamin d supplementation improve treatment outcomes in individuals with cf who have ntm-pd?
Recommendation 43: The CF Foundation and the ECFS recommend that vitamin D should be supplemented according to national CF care guidelines.
Vitamin D is thought to play a critical role in host defence against mycobacteria. In vitro and ex vivo treatment with vitamin D of human macrophages infected with M. tuberculosis enhances intracellular killing (through stimulating antimicrobial peptide production [bib_ref] IFN-gamma-and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin..., Martineau [/bib_ref] and autophagy. [bib_ref] Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin, Yuk [/bib_ref] Furthermore, several epidemiological studies have shown an association of vitamin D deficiency with reactivation of TB and, recently, the presence of NTM-PD. [bib_ref] Severe vitamin D deficiency is associated with non-tuberculous mycobacterial lung disease: a..., Jeon [/bib_ref] However, interventional trials of vitamin D supplementation in patients with active pulmonary TB have had mixed results, [bib_ref] Old wine in new bottles: vitamin D in the treatment and prevention..., Martineau [/bib_ref] and there are no trials of vitamin D as an adjuvant treatment for NTM disease. Should surgery be considered in individuals with CF who have NTM-PD?
Recommendation 44: The CF Foundation and the ECFS recommend that lung resection should only be considered under extraordinary circumstances and in consultation with experts on the treatment of NTM and CF. Surgical resection has been used extensively in the management of pulmonary mycobacterial infection in order to excise localised infection, debulk severe disease, or excise cavities or damaged lung into which antibiotic penetration may be impaired. In no cases has surgery been used as a substitute for antibiotic therapy. There are no randomised trials of surgery for the treatment of pulmonary NTM disease in any patient group. While many publications report the use of lung resection (pneumonectomy, lobectomy or segmentectomy) with combination antibiotic therapy in NTM infection, most are case reports with no comparator group receiving only medical therapy thereby preventing objective assessment of the efficacy of surgery.
Nonetheless, three series of individuals without CF do contain some comparison data although the potential for selection bias of patients considered suitable for surgery makes interpretation difficult. The first series 136 comprised of 65 patients, from South Korea, with pulmonary M. abscessus infection. Surgery was performed in 14 patients who failed to achieve sputum culture conversion, became culture positive again after a period of culture negativity or experienced disease-related complications such as haemoptysis. Of the eight patients who were sputum culture positive before surgery, seven became culture negative postoperatively (compared to culture conversion rates of 38/65 for the group as a whole). A second study, from the USA, [bib_ref] Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary..., Jarand [/bib_ref] reported outcomes for 69 patients with pulmonary M. abscessus infection all treated with combination antibiotics, 23 of whom underwent additional surgical resection. Indications for surgery included the presence of localised bronchiectasis, cavitary disease and haemoptysis. In the surgical group, significantly more patients (13/23) became persistently sputum culture negative compared to those in the medical treatment only group . A third study, also from the USA, described outcomes in 51 patients with macrolide-resistant MAC-PD. [bib_ref] Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung..., Griffith [/bib_ref] Individuals receiving both surgical resection and injectable aminoglycoside therapy had greater sputum conversion rates (11/14 patients) than those receiving neither treatment modality (2/37 patients).
A recent review of case series published over the last 40 years 184 suggests that localised resection (lobectomy or segmentectomy) should be considered for severe, localised, unilateral NTM disease that has failed to respond to conventional antibiotic therapy. In the context of CF, however, localised NTM disease is extremely rare (or at least very difficult to identify), and the risks of thoracic surgery are high and therefore the potential benefits of surgical resection limited.
## Transplantation
Should individuals with CF with current or previous NTM-positive cultures be referred for lung transplantation?
Recommendation 45: The CF Foundation and the ECFS recommend that all individuals with CF being considered for lung transplantation should be evaluated for NTM-PD.
Recommendation 46: The CF Foundation and the ECFS recommend that the presence of current or previous respiratory tract samples positive for NTM should not preclude individuals being considered for lung transplantation.
Recommendation 47: The CF Foundation and the ECFS recommend that individuals with CF who have NTM-PD and are being evaluated for transplantation should start treatment prior to transplant listing.
Recommendation 48: The CF Foundation and the ECFS recommend that individuals with CF receiving NTM treatment with sequential negative cultures may be eligible for transplant listing.
Recommendation 49: The CF Foundation and the ECFS recommend that individuals with CF who have completed treatment for NTM-PD with apparent eradication of the organism may be eligible for transplant listing.
Recommendation 50: The CF Foundation and the ECFS recommend that the presence of persistent MABSC or MAC infection despite optimal therapy is not an absolute contraindication to lung transplant referral.
The International Society for Heart and Lung Transplantation (ISHLT) International Guidelines lists 'colonisation with highly resistant or virulent mycobacteria' as a relative contra-indication for selection as a lung transplant candidate. [bib_ref] International guidelines for the selection of lung transplant candidates: 2006 update-a consensus..., Orens [/bib_ref] There is, however, limited published information on transplant outcomes for individuals with previous or concurrent NTM infection, with very few reports (usually from single centres) specifically examining CF cohorts. The risk of NTM infection post-transplantation is not well defined. A study of 201 CF and non-CF transplant recipients [bib_ref] Non-tuberculous mycobacterium infection after lung transplantation is associated with increased mortality, Huang [/bib_ref] suggested that postoperative NTM acquisition was associated with increased mortality (HR 2.61), independent of bronchiolitis obliterans syndrome. However, these data should be interpreted keeping the following in mind: very little data were available on the presence of pulmonary NTM pretransplant; the vast majority of patients did not have CF or even bronchiectasis; and non-NTM-related causes were major contributors to death in fatal cases. In contrast, a recent study of CF and non-CF transplant recipients [bib_ref] Non-tuberculous mycobacterial infection among lung transplant recipients: a 15-year cohort study, Knoll [/bib_ref] The largest CF-specific case series comes from the University of North Carolina Chapel Hill experience between 1990 and 2003. [bib_ref] Non-tuberculous mycobacteria in end stage cystic fibrosis: implications for lung transplantation, Chalermskulrat [/bib_ref] One hundred and forty-six patients with CF underwent lung transplantation and 31 listed for transplantation. Of those individuals referred, 19.7% were NTM culture positive pretransplant. Rates of NTM following lung transplantation were 3.4%. Pretransplant infection with M. abscessus was recognised as a significant risk factor for recurrence of NTM posttransplantation. Although there was no effect on mortality, posttransplant NTM infection caused significant morbidity as patients developed M. abscessus-associated skin and soft tissue infection or pulmonary disease caused by MAC and other NTM species. There are several published case series of successful outcomes for individuals with CF who have culture positive M. abscessus infection at the time of transplantation. [bib_ref] Lung transplantation in patients with cystic fibrosis and Mycobacterium abscessus infection, Gilljam [/bib_ref] However, NTM-related complications in this group may be more frequent, and include persistent soft tissue or wound infections, 186 empyema and disseminated NTM infection. Although a small series, the University of North Carolina (UNC) report suggests no effect of the presence of pretransplant M. abscessus positive cultures on post-transplant mortality. [bib_ref] Lung transplant outcomes in cystic fibrosis patients with pre-operative Mycobacterium abscessus respiratory..., Lobo [/bib_ref] The Consensus statements Committee concluded that all individuals with CF should be evaluated for NTM disease prior to referral for lung transplantation, given the very high reported rates of NTM culture positivity for this group, and the fact that untreated NTM infection may represent an increased (and potentially modifiable) postoperative risk. Consequently, if NTM-PD is diagnosed, treatment should be started prior to transplant listing.
# Conclusion
The management of individuals with CF infected with NTM is extremely challenging. The limited amounts of published research and clinical trial data provide inadequate evidence to base management decisions on how best to screen, diagnose, detect and treat NTM-PD. As a response to this urgent clinical need, the CF Foundation and the ECFS formed a committee of clinicians, scientists and infectious disease experts to develop recommendations to guide and assist clinicians in the management of NTM-PD in individuals with CF. The committee believes these recommendations should serve as a benchmark for current medical care while providing a framework to inform the development of clinical, translation and basic research studies to generate robust evidence on which to base future iterations of these management guidelines, leading to better outcomes for individuals with CF infected with NTM.
[fig] 89 Recommendation 28: The CF Foundation and the ECFS recommend that monotherapy with a macrolide or other antimicrobial should never be used in the treatment of M. abscessus complex pulmonary disease RISK FACTORS Are there modifiable risk factors for the development of NTM-PD in individuals with CF? [/fig]
[fig] 94 Recommendation 38: The CF Foundation and the ECFS recommend that NTM antibiotic therapy should be prescribed for 12 months beyond culture conversion (defined as three consecutive negative cultures, with the time of conversion being the date of the first of the three negative cultures) as long as no positive cultures are obtained during those 12 months 94 Recommendation 39: The CF Foundation and the ECFS recommend that individuals who fail to culture convert despite optimal NTM therapy may benefit from long-term suppressive antibiotic treatment 94 Recommendation 40: The CF Foundation and the ECFS recommend that, when amikacin is given intravenously or when streptomycin is given intravenously or intramuscularly, serum levels should be monitored and dosing adjusted to minimise ototoxicity and nephrotoxicity100 Recommendation 41: The CF Foundation and the ECFS recommend against routinely obtaining serum levels of other anti-mycobacterial drugs. However, absorption of oral medications is often reduced in CF. Therefore use of therapeutic drug monitoring should be considered for individuals failing to improve despite taking recommended drug regimens or for those on concomitant medications with significant interactions with NTM drugs 100 Recommendation 42: The CF Foundation and the ECFS recommend against the use of interferon γ as adjuvant therapy for NTM pulmonary disease in individuals with CF 89 Recommendation 43: The CF Foundation and the ECFS recommend that vitamin D should be supplemented according to national CF care guidelines 94 Recommendation 44: The CF Foundation and the ECFS recommend that lung resection should only be considered under extraordinary circumstances and in consultation with experts on the treatment of NTM and CF 83 Recommendation 45: The CF Foundation and the ECFS recommend that all individuals with CF being considered for lung transplantation should be evaluated for NTM pulmonary disease 100 Recommendation 46: The CF Foundation and the ECFS recommend that the presence of current or previous respiratory tract samples positive for NTM should not preclude individuals being considered for lung transplantation 94 Recommendation 47: The CF Foundation and the ECFS recommend that individuals with CF who have NTM pulmonary disease and are being evaluated for transplantation should start treatment prior to transplant listing 100 Recommendation 48: The CF Foundation and the ECFS recommend that individuals with CF receiving NTM treatment with sequential negative cultures may be eligible for transplant listing 100 Recommendation 49: The CF Foundation and the ECFS recommend that individuals with CF who have completed treatment for NTM pulmonary disease with apparent eradication of the organism may be eligible for transplant listing 100 Recommendation 50: The CF Foundation and the ECFS recommend that the presence of persistent M. abscessus complex or MAC infection despite optimal therapy is not an absolute contraindication to lung transplant referral 94 AFB, acid-fast bacilli; CF, cystic fibrosis; CLSI, Clinical Laboratory Standards Institute; ECFS, European Cystic Fibrosis Society; HRCT, High-resolution CT; MAC, M. avium complex; NTM, non-tuberculous mycobacteria. [/fig]
[fig] 127: DIAGNOSIS OF NTM-PD IN CF Should the ATS/IDSA criteria for the diagnosis of NTM-PD be used in individuals with CF? Recommendation 20: The CF Foundation and the ECFS recommend that ATS/IDSA criteria for the diagnosis of NTM-PD should be used in individuals with CF (ATS/IDSA 2007 Statement). [/fig]
[fig] Figure 1: A suggested algorithm for the investigation of individuals with clinical suspicion of NTM-PD (AFB, acid-fast bacilli; CF, cystic fibrosis; FEV 1 , forced expiratory volume in 1 s; HRCT, high-resolution CT; NTM-PD, non-tuberculous mycobacteria pulmonary disease). [/fig]
[fig] Figure 2: Typical treatment schedules for individuals with CF with Mycobacterium abscessus or MAC pulmonary disease. (A) M. [/fig]
[table] Table 1: NTM recommendation statementsRecommendation 1: The CF Foundation and the ECFS recommend that the potential for cross-infection of NTM (particularly Mycobacterium abscessus complex) between individuals with CF should be minimised by following national infection control guidelines Recommendation 2: The CF Foundation and the ECFS recommend that cultures for NTM be performed annually in spontaneously expectorating individuals with a stable clinical course Recommendation 3: The CF Foundation and the ECFS recommend that, in the absence of clinical features suggestive of NTM pulmonary disease, individuals who are not capable of spontaneously producing sputum do not require screening cultures for NTM Recommendation 4: The CF Foundation and the ECFS recommend that culture and smears for AFB from sputum should be used for NTM screening 100 Recommendation 5: The CF Foundation and the ECFS recommend against the use of oropharyngeal swabs for NTM screening 100 Recommendation 6: The CF Foundation and the ECFS recommend that culture and smears for AFB from sputum, induced sputum, bronchial washings or bronchoalveolar lavage samples can be used to evaluate individuals with CF suspected to have NTM pulmonary disease.Recommendation 7:The CF Foundation and the ECFS recommend against the routine use of transbronchial biopsies to detect NTM in individuals with CF suspected to have NTM pulmonary diseaseRecommendation 8: The CF Foundation and the ECFS recommend against the use of oropharyngeal swabs to perform diagnostic smears and cultures in individuals with CF suspected to have NTM pulmonary disease 100 Recommendation 9: The CF Foundation and the ECFS recommend that respiratory tract samples should be cultured using both solid and liquid media 100 Recommendation 10: The CF Foundation and the ECFS recommend that the incubation duration for NTM cultures should be for a minimum of 6 weeks 100 Recommendation 11: The CF Foundation and the ECFS recommend that an NTM culture should be processed within 24 h of collection to optimise the detection of NTM in respiratory samples. If a delay in processing is anticipated, refrigeration of samples is advised Recommendation 12: The CF Foundation and the ECFS recommend that respiratory tract samples should be decontaminated using the standard N-acetyl L-cysteine, NALC, (0.5%)-NaOH (2%) method 100 Recommendation 13: The CF Foundation and the ECFS recommend that, if a sample remains contaminated with Gram-negative bacteria after standard NALC-NaOH decontamination, it should be further treated with either 5% oxalic acid or 1% chlorhexidine 100 Recommendation 14: The CF Foundation and the ECFS recommend against the use of non-culture-based methods for detecting NTM in respiratory tract samples 100 Recommendation 15: The CF Foundation and the ECFS recommend that all NTM isolates from individuals with CF should undergo molecular identification 100 Recommendation 16: The CF Foundation and the ECFS recommend that all NTM isolates from individuals with CF should be identified to the species level, except for M. intracellulare, M. avium and M. chimaera, where identification can be limited to MAC, and M. abscessus complex, which should be subspeciated Recommendation 17: The CF Foundation and the ECFS recommend that for MAC, clarithromycin susceptibility testing should be performed on an isolate recovered prior to initiation of treatment. Clarithromycin susceptibility testing should also be performed on subsequent isolates if the patient (a) fails to culture convert after 6 months of NTM treatment; (b) recultures MAC after initial culture conversion while on NTM treatment or (c) recultures MAC after completion of NTM treatment Recommendation 18: The CF Foundation and the ECFS recommend that for M. abscessus complex, susceptibility testing should include at least clarithromycin, cefoxitin and amikacin (and preferably also tigecycline, imipenem, minocycline, moxifloxacin and linezolid) Recommendation 19: The CF Foundation and the ECFS recommend that drug susceptibility testing should be performed in accordance with CLSI guidelines 100 Recommendation 20: The CF Foundation and the ECFS recommend that ATS/IDSA criteria for the diagnosis of NTM pulmonary disease should be used in individuals with CF (ATS/IDSA 2007 Statement) Recommendation 21: The CF Foundation and the ECFS recommend that other CF pathogens and comorbidities should be considered as potential contributors to a patient's symptoms and radiological features when determining the clinical significance of NTM-positive cultures 100 Recommendation 22: The CF Foundation and the ECFS recommend that NTM treatment should be considered for individuals with CF who have ATS/IDSA defined NTM pulmonary disease 100Recommendation 23: The CF Foundation and the ECFS recommend that individuals receiving azithromycin as part of their CF medical regimen who have a positive NTM culture should not continue azithromycin treatment while evaluation for NTM disease is underway as azithromycin monotherapy may lead to resistance. A macrolide agent may be included in a multidrug treatment regimen if criteria are met for NTM disease89 [/table]
[table] Table 2: Antibiotic-dosing regimens used to treat Mycobacterium avium complex and Mycobacterium abscessus complex pulmonary disease in cystic fibrosis [/table]
[table] Table 3: Important side effects/toxicities of antibiotics and advisable monitoring procedures for MAC and MABSC in CF [/table]
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https://thorax.bmj.com/content/thoraxjnl/71/Suppl_1/i1.full.pdf
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Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease such as cystic fibrosis (CF). Pulmonary disease caused by NTM has emerged as a major threat to the health of individuals with CF but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened an expert panel of specialists to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM pulmonary disease in individuals with CF. Nineteen experts were invited to participate in the recommendation development process. Population, Intervention, Comparison, Outcome (PICO) methodology and systematic literature reviews were employed to inform draft recommendations. An anonymous voting process was used by the committee to reach consensus. All committee members were asked to rate each statement on a scale of: 0, completely disagree, to 9, completely agree; with 80% or more of scores between 7 and 9 being considered ‘good’ agreement. Additionally, the committee solicited feedback from the CF communities in the USA and Europe and considered the feedback in the development of the final recommendation statements. Three rounds of voting were conducted to achieve 80% consensus for each recommendation statement. Through this process, we have generated a series of pragmatic, evidence-based recommendations for the screening, investigation, diagnosis and treatment of NTM infection in individuals with CF as an initial step in optimising management for this challenging condition.
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The Egyptian clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease
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The Egyptian clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease
# Introduction
The landscape of chronic liver disease in Egypt has drastically changed over the past few decades, with the decreasing prevalence of viral hepatitis and increasing prevalence of metabolic-associated fatty liver disease (MAFLD) (formerly known as nonalcoholic fatty liver disease . MAFLD has risen in prevalence to alarming levels, placing an enormous burden on individuals and healthcare systems. Despite the magnitude of the problem, no regional guidelines have been developed to tackle this disease.
This document provides the clinical practice guidelines of the key Egyptian opinion leaders on MAFLD screening, diagnosis, and management. The participants performed a detailed systematic review of the literature retrieved after an extensive PubMed search up to March 2021 on particular domains of interest, and deciphered the current scientific evidence into simple practice guidelines with recommendations to improve the routine clinical practice on patients with MAFLD.
These guidelines cover various aspects in the management of MAFLD, including epidemiology, screening, diagnosis, evaluation, and treatment. The statements in this guideline are according to the Grading of Recommendation Assessment, Development, and Evaluation approach. [bib_ref] A new system for grading recommendations in evidence based guidelines, Harbour [/bib_ref] In case of disagreement, the final grading of evidence and recommendations was determined by a majority vote.
The document considers our local situations and the burden of clinical management for the healthcare sector and is proposed for daily clinical practical use and to orchestrate it with the advancing knowledge and research of MAFLD. Particular reference to special groups was done whenever necessary. The ultimate goal is to improve awareness of MAFLD and patient care, encourage dialogue between various stakeholders for the development of health policies, and assist in the decision-making process by providing evidence-based data. In addition, we identified some areas of gap in our knowledge and set an agenda for calling for research studies in our Egyptian population. As it is expected that new evidence will emerge from Egyptian cohorts, updates to these guidelines might be required in the future.
## Epidemiology
Over the past five decades, the nutrition pattern of the Egyptian population has witnessed an overall increase in energy intake. Nutrition moved to a type of diet with increases in the intake of fast food, red meat, vegetable oils, processed foods, and soft drinks, and decrease in the intake of fresh fruits and vegetables. [bib_ref] Dietary trends in the Middle East and North Africa: An ecological study, Golzarand [/bib_ref] It is estimated that up to 40% of the fat consumed by women in Egypt is saturated fat, [bib_ref] Nutritional status and anthropometric measurements among women in Egypt, National Survey, Mahmood [/bib_ref] and the rates of the low intake (below five servings per day) of fresh fruit and vegetables in Egypt is up 80%.In contrast, Egypt is on track to meet the World Health Organization (WHO) recommendations for the elimination of hepatitis C, with a dramatic decline in the number of hepatitis C virus (HCV) cases. [bib_ref] National Committee for the Control of Viral Hepatitis. One step closer to..., Esmat [/bib_ref] [bib_ref] The nutrition transition in Egypt: Obesity, undernutrition and the food consumption context, Galal [/bib_ref] Therefore, the profile of liver disease in Egypt is witnessing a trajectory shift from one of communicable to noncommunicable diseases. [bib_ref] Cardiovascular disease in the Eastern Mediterranean region: Epidemiology and risk factor burden, Turk-Adawi [/bib_ref] [bib_ref] Metabolic health in the Middle East and north Africa, Azizi [/bib_ref] [bib_ref] Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, Younossi [/bib_ref] Parallel to these changes, although the prevalence of overweight and obesity (a body-mass index (BMI) of 25 kg/ m²or greater) has risen globally between 1980 and 2013 in both men (from 28.8% to 36.9%) and women (from 29.8% to 38.0%); the largest increases in the rate of obesity worldwide were seen in Egypt. [bib_ref] Worldwide trends in insufficient physical activity from 2001 to 2016: A pooled..., Guthold [/bib_ref] Indeed, Egypt is among the top 10 countries with the highest levels of obesity worldwide; >71.2% of adult men were overweight and 26.4% were obese, and 79.4% of adult women were overweight and 48.4% were obese. [bib_ref] Worldwide trends in insufficient physical activity from 2001 to 2016: A pooled..., Guthold [/bib_ref] Worryingly, the prevalence rates of overweight and obesity among school children and adolescents were 31.5% and 12.7%, respectively, among boys less than 20 years, and 39.5% and 14.4%, respectively, among girls of the same age group. [bib_ref] Global, regional, and national prevalence of overweight and obesity in children and..., Ng [/bib_ref] Similarly, the average prevalence of insufficient physical activity in Egypt is 31.0%, which is higher than the global prevalence of 27.5%. This number was even higher in females (38.8%) than in males (23.2%). [bib_ref] Worldwide trends in insufficient physical activity from 2001 to 2016: A pooled..., Guthold [/bib_ref] The prevalence of MAFLD has risen in parallel with the aforementioned changes, with direct clinical and economic burden. Although there is scant data on the magnitude of MAFLD in Egypt, available data suggest that Egypt has one of the highest prevalence of MAFLD, affecting more than one-third of the population, compared to a global prevalence of about 25%. [bib_ref] Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, Younossi [/bib_ref] [bib_ref] Genetic contributions to NAFLD: Leveraging shared genetics to uncover systems biology, Eslam [/bib_ref] [bib_ref] Genetics and epigenetics of NAFLD and NASH: Clinical impact, Eslam [/bib_ref] Specific studies suggest that the prevalence range of MAFLD in Egypt is approximately 47.5%, with 56.7% having fibrosis, [bib_ref] 214-LB: Vibration-controlled transient elastography reveals alarming prevalence of nonalcoholic fatty liver disease..., Tomah [/bib_ref] and it was present in local situations and the burden of clinical management for the healthcare sector and is proposed for daily clinical practical use. Particular reference to special groups was done whenever necessary.
Keywords: Egyptian, guidelines, MAFLD approximately 15.8% of children. [bib_ref] Prevalence, risk factors, and predictors of nonalcoholic fatty liver disease among schoolchildren:..., Alkassabany [/bib_ref] Another retrospective study of 2097 patients from large Egyptian tertiary care liver centers revealed that the leading cause of patient presentation is MAFLD (44.9%).Unfortunately, the awareness of patients and physicians in Egypt about the magnitude of the problem and its risks is not sufficient. [bib_ref] Capturing patient experience: A qualitative study of change from NAFLD to MAFLD..., Alem [/bib_ref] [bib_ref] Change from NAFLD to MAFLD increases the awareness of fatty liver disease..., Fouad [/bib_ref] Therefore, it is not surprising that NAFLD is seriously underdiagnosed in real-world settings, [bib_ref] Real-world data reveal a diagnostic gap in non-alcoholic fatty liver disease, Alexander [/bib_ref] [bib_ref] GPs' experiences and perceptions of early detection of liver disease: A qualitative..., Standing [/bib_ref] with most patients being diagnosed incidentally when cirrhosis has already developed. [bib_ref] Nonalcoholic fatty liver disease-related cirrhosis is commonly unrecognized and associated with hepatocellular..., Bertot [/bib_ref]
## Definition and diagnosis of mafld
According to the Middle East and North Africa consensus, [bib_ref] Nomenclature and definition of metabolic-associated fatty liver disease: A consensus from the..., Shiha [/bib_ref] the Egyptian guidelines endorse the proposal of the international consensus panel for the redefinition of fatty liver disease [bib_ref] Toward more accurate nomenclature for fatty liver diseases, Eslam [/bib_ref] [bib_ref] A new definition for metabolic dysfunction-associated fatty liver disease: An international expert..., Eslam [/bib_ref] [bib_ref] Defining paediatric metabolic (dysfunction)-associated fatty liver disease: An international expert consensus statement, Eslam [/bib_ref] The diagnosis of MAFLD is based on the presence of liver steatosis (detected by liver histology, imaging, or noninvasive biomarkers), together with the presence of at least one of three criteria, which include (ⅰ) overweight or obesity, (ⅱ) type 2 diabetes mellitus (T2DM), and (ⅲ) clinical evidence of metabolic dysfunction. An avalanche of evidence supports the superiority of the new definition compared to the old NAFLD definition. [bib_ref] The NAFLD-MAFLD debate: Eminence vs evidence, Fouad [/bib_ref] [bib_ref] MAFLD identifies patients with significant hepatic fibrosis better than NAFLD, Yamamura [/bib_ref] [bib_ref] Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: A nationwide..., Lee [/bib_ref] [bib_ref] MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized..., Tsutsumi [/bib_ref] In addition, the simplicity of the criteria render it suitable for resource-constrained settings [bib_ref] Nomenclature and definition of metabolic-associated fatty liver disease: A consensus from the..., Shiha [/bib_ref] [bib_ref] MAFLD identifies patients with significant hepatic fibrosis better than NAFLD, Yamamura [/bib_ref] [bib_ref] MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized..., Tsutsumi [/bib_ref] [bib_ref] The Latin American Association for the Study of the Liver (ALEH) position..., Mendez-Sanchez [/bib_ref] [bib_ref] The Asian Pacific Association for the Study of the Liver clinical practice..., Eslam [/bib_ref] [bib_ref] From NAFLD to MAFLD: A "redefining" moment for fatty liver disease, Zheng [/bib_ref] [ ].
## Natural history of mafld
Egypt had the highest global age-standardized death rate from cirrhosis in all the years from 1990 to 2017, which was 103.3 per 100,000, despite a 22.4% decrease from 1990. [bib_ref] The global, regional, and national burden of cirrhosis by cause in 195..., Sepanlou [/bib_ref] This decrease is likely driven by the rapid decrease in the HCV death rate. The decline is expected to continue over the next 5 years. However, the actual burden of MAFLD in Egypt is not fully characterized. Alarming numbers are emerging. In 2017, 12.8% of deaths due to cirrhosis in Egypt were caused by MAFLD and 6.5% were caused by other causes, most likely from undiagnosed MAFLD.
In addition, the age-standardized prevalence rates of compensated and decompensated cirrhosis due to MAFLD per 100,000 increased from 312. to 340 and 26 in 2017, respectively. Furthermore, the proportion of causes for disability-adjusted life years, a time-based measure that combines years of life lost due to premature mortality caused by MAFLD-related cirrhosis, in 2017 was 12%. [bib_ref] The global, regional, and national burden of cirrhosis by cause in 195..., Sepanlou [/bib_ref] MAFLD is currently progressively increasing as the main cause of hepatocellular carcinoma (HCC) globally. [bib_ref] Hepatocellular cancer: The impact of obesity, type 2 diabetes and a multidisciplinary..., Dyson [/bib_ref] The available data suggest that Egypt has one of the highest increases in the age-standardized incidence rate of MAFLD-related HCC globally, with an increase of 89.8% between 1990 and 2017. [bib_ref] The rising threat of hepatocellular carcinoma in the Middle East and North..., Sharafi [/bib_ref] Consistently, another study in Egypt showed that the annual proportions of MAFLD-related HCC increased significantly from 4.3% in 2010 to 20.6% in 2020, whereas HCV-related HCC declined from 94.8% to 76.7%.Compared to other liver diseases, a recent study showed that MAFLD-related HCC had a significantly higher percentage of death within 1 year of diagnosis and had approximately 5 months shorter survival time than HCC related to viral hepatitis (HCV/hepatitis B virus .Notably, a 2018 meta-analysis demonstrated that noncirrhotic patients with MAFLD had up to 261% increased risk of HCC compared to all other etiologies of liver disease. [bib_ref] Systematic review with meta-analysis: Risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without..., Stine [/bib_ref] Similarly, MAFLD was found to be the most rapidly growing indication for liver transplantation in multiple countries in the region [bib_ref] Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in..., Eshraghian [/bib_ref] ; for example, more than 63% of referred patients for liver transplantation in Kuwait in 2018-2019 had MAFLD-related cirrhosis. [bib_ref] The burden and clinical care pathways of nonalcoholic steatohepatitis in the Middle..., Hasan [/bib_ref] Though it would be expected that Egypt would have a similar trend, further studies are required to confirm this.
## Extrahepatic manifestations of mafld
MAFLD is a multisystem disease associated with a plethora of extrahepatic manifestations and comorbidities. [bib_ref] Extra-hepatic manifestations of nonalcoholic fatty liver disease: A review, Tariq [/bib_ref] MAFLD is associated with cardiovascular disease (CVD) [bib_ref] Extra-hepatic manifestations of nonalcoholic fatty liver disease: A review, Tariq [/bib_ref] and chronic kidney disease (CKD) [bib_ref] Association of non-alcoholic fatty liver disease with chronic kidney disease: A systematic..., Musso [/bib_ref] risk. In addition to liver cancer, MAFLD is implicated in the risk of various extra-hepatic cancers. [bib_ref] Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis, Targher [/bib_ref] CVD and malignancy represent the main causes of death in MAFLD patients, [bib_ref] Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease, Ong [/bib_ref] while baseline liver fibrosis is the strongest predictor. [bib_ref] Liver fibrosis, but no other histologic features, is associated with long-term outcomes..., Angulo [/bib_ref] [bib_ref] Fibrosis severity as a determinant of cause-specific mortality in patients with advanced..., Vilar-Gomez [/bib_ref] Therefore, physicians treating patients with MAFLD should be encouraged to evaluate and undertake risk factor and comorbidities management as part of a holistic approach to patient care. CVD risk can be assessed using risk scores (e.g., atherosclerotic cardiovascular disease risk estimator). MAFLD patients with a history of a cardiovascular event or presenting with clinically active CVD or evidence of metabolic comorbidities and/or severe liver disease, should be referred for evaluation by a cardiologist for further evaluation. Otherwise, patients who are negative or assessed as having low CVD risk can be re-evaluated every 2-3 years. [bib_ref] Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications, Francque [/bib_ref] The types and choice of medications for treatment of T2DM, hypertension, and dyslipidemia are beyond the scope of these recommendations and should be followed according to the specific disease guidelines.
## Recommendations
- MAFLD patients should be evaluated for CVD and referred to a cardiologist, if needed (A1) - Consideration of other extra-hepatic manifestations of MAFLD is recommended (B1).
## Screening for mafld
Screening for MAFLD by ultrasonography is recommended in at-risk populations, including those with overweight/ obesity, T2DM, or metabolic dysfunction. Patients with MAFLD should be evaluated for the presence of other metabolic comorbidities, such as T2DM, hypertension, and dyslipidemia and be treated appropriately.
## Recommendations
- Screening for MAFLD by ultrasonography is recommended in at-risk populations, including those with T2DM or metabolic dysfunction (A1). - Patients with MAFLD should be evaluated for the presence of other metabolic comorbidities, such as T2DM, hypertension, and dyslipidemia and be treated appropriately to reduce the risk of cardiovascular and kidney disease. (A1) : The Egyptian guidelines recommended an algorithm to diagnose MAFLD in suspected patients, and evaluation, management, and monitoring disease severity approach for confirmed subjects. The proposed model is a primary care-based multidisciplinary care model for MAFLD, whereas the initial identification of cases would mainly occur at primary care, with an attached appropriate referral pathway for specialist care, as illustrated.
## Noninvasive tests
Noninvasive modalities that could be used in clinical practice are needed for diagnosis of MAFLD, assessing disease severity, and monitoring disease progression and treatment response. [bib_ref] Noninvasive biomarkers in NAFLD and NASH-current progress and future promise, Wong [/bib_ref] In routine clinical practice, abdominal ultrasonography is commonly used and is usually sufficient for the detection of hepatic steatosis. [bib_ref] Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver:..., Hernaez [/bib_ref] However, it has poor sensitivity for detecting mild levels of steatosis.
The controlled attenuation parameter (CAP) is more sensitive than ultrasonography and is being increasingly utilized to assess liver fat and can be obtained simultaneously with a liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) (FibroScan). [bib_ref] Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing..., Karlas [/bib_ref] The optimal cut-off for identifying fatty liver by CAP was suggested by an earlier meta-analysis, to be 248 dB/m. [bib_ref] Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing..., Karlas [/bib_ref] However, subsequent studies suggested higher optimal cut-off points, 288 dB/M [bib_ref] Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard..., Caussy [/bib_ref] and 302 dB/M. [bib_ref] Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard..., Caussy [/bib_ref] Further studies in Egyptian population are required. In addition, an interquartile range of >30-40 dB/m has been suggested to be associated with less reliable CAP measurements. [bib_ref] Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard..., Caussy [/bib_ref] [bib_ref] Validity criteria for the diagnosis of fatty liver by M probe-based controlled..., Wong [/bib_ref] Probe selection also influences CAP values, and optimal cut points for the diagnosis of fatty liver are lower using the M probe versus the XL probe. [bib_ref] Prospective, same-day, direct comparison of controlled attenuation parameter with the M vs..., Caussy [/bib_ref] MRI-based techniques such as MRI-PDFF and proton-magnetic resonance spectroscopy (MRI-MRS) can detect small amounts of liver fat and is considered the gold standard to quantify liver fat. Currently, the main indication for liver fat fraction measurement by MRI is for clinical trials. [bib_ref] Noninvasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in..., Caussy [/bib_ref] Numerous steatosis simple scores have been proposed as an alternative method for the assessment of hepatic steatosis, particularly in large-population studies. In particular, the FLI, which includes BMI, waist circumference, triglycerides, and GGT, is widely used [bib_ref] The fatty liver index: A simple and accurate predictor of hepatic steatosis..., Bedogni [/bib_ref] and has been recently validated in a large cohort of 35,335 patients with MAFLD. [bib_ref] Blood biomarkers for the diagnosis of hepatic steatosis in metabolic dysfunction-associated fatty..., Xu [/bib_ref] Simple fibrosis scores only involve clinical and routine laboratory parameters, are widely validated and reproducible scores, and are inexpensive; these include the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), [bib_ref] A simple noninvasive index can predict both significant fibrosis and cirrhosis in..., Wai [/bib_ref] Fibrosis-4 index (FIB-4), [bib_ref] Development of a simple noninvasive index to predict significant fibrosis in patients..., Sterling [/bib_ref] and NAFLD fibrosis score (NFS). [bib_ref] The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in..., Angulo [/bib_ref] Patients can be defined as being at low or high risk for advanced fibrosis for each score according to the following cut-offs: APRI (0.5 and 1.5), FIB-4 (1.30 and 2.67), NFS (<−1.455 and > 0.67611). These cut-offs need to be further validated in Egyptian cohorts. These scores are well suited for use as an initial assessment in primary-care or resource-poor settings. [bib_ref] The utility of noninvasive scores in non-alcoholic fatty liver disease patients with..., Kaya [/bib_ref] [bib_ref] Clinical utility of noninvasive scores in assessing advanced hepatic fibrosis in patients..., Alkayyali [/bib_ref] Subjects with indeterminant results or high scores are to be referred to specialists for further evaluation to appropriately guide the management of patients.
Proprietary biomarkers of fibrosis include N-terminal type III collagen propeptide (Pro-C3). A Pro-C3 based algorithm, the ADAPT algorithm, that includes age, T2DM, and platelet count has shown high diagnostic accuracy for advanced fibrosis in tertiary hospitals [bib_ref] ADAPT: An algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced..., Daniels [/bib_ref] and general low-risk populations cohorts. [bib_ref] A sequential algorithm combining ADAPT and liver stiffness can stage metabolic-associated fatty..., Eslam [/bib_ref] Liver stiffness measurement (LSM) obtained through VCTE, which is commercially available as FibroScan, is increasingly used in Egypt. An M probe and XL probe are both available. The majority of MAFLD patients can achieve successful measurement with the XL probe. [bib_ref] Serial transient elastography examinations to monitor patients with type 2 diabetes: A..., Lee [/bib_ref] [bib_ref] Chronic hepatitis C patients with obesity: Do we need two operators for..., Shiha [/bib_ref] The quality criteria to guide its use are a minimum of 10 measurements, of which more than 60% should be valid, and the ratio of the median valid LSM to IQR should not exceed 0.3. Magnetic resonance elastography has higher accuracy and success rates compared to VCTE, but its wider use is limited by availability and cost. [bib_ref] Magnetic resonance imaging more accurately classifies steatosis and fibrosis in patients with..., Imajo [/bib_ref] [bib_ref] Magnetic resonance elastography vs transient elastography in detection of fibrosis and noninvasive..., Park [/bib_ref] The combination of LSM and simple fibrosis scores has the advantage of increasing accuracy and decreasing the percentage of patients classified as a gray zone. In contrast, there has not been any robust biomarker for steatohepatitis.
## Recommendations
- Noninvasive modalities that could be used in clinical practice are needed for diagnosis of MAFLD, assessing disease severity, and monitoring disease progression and treatment response (A1). - Abdominal ultrasonography is the recommended first-line tool for the detection of hepatic steatosis (A1). - Controlled attenuation parameter (CAP) measurement is a more sensitive tool than ultrasonography. Thus, if available, it can be used for both diagnosis and disease monitoring (B1). - Although considered the gold standard to quantify liver fat, MRI-based techniques are not recommended for routine clinical practice (A1). - The exclusion of high risk of significant fibrosis is acceptable using simple noninvasive biomarkers and scores of fibrosis (A2). - The confirmation of significant fibrosis can be done by liver stiffness measurement by VCTE and/or sequential combination with serum biomarkers/scores (A2). - As per the clinical judgment, liver biopsy could be required in some cases, particularly in patients with indeterminant (gray) range scores (B2). - There is no strong biomarker for steatohepatitis, and liver biopsy remains the only diagnostic test of choice (A1).
## Liver biopsy
With the high prevalence of MAFLD, biopsy evaluation is indicated mainly to confirm the diagnosis when the clinical picture is atypical, to aid in the assessment of prognosis when some cases fall into the gray zone, [bib_ref] Optimizing use of nonalcoholic fatty liver disease fibrosis score, fibrosis-4 score, and..., Chan [/bib_ref] to identify additional causes of liver disease, and to determine if a patient might benefit from an intervention.
The use of a 16-G or wider needle via a percutaneous approach under ultrasound guidance is recommended for the biopsy. An adequate histology specimen should comprise at least 10 portal tracts and be 2 cm or more long. Liver biopsy is limited by a) sampling error, b) inter-observer variability, and c) the potentially rare complications. [bib_ref] Liver biopsy, Spinzi [/bib_ref] There are at least three common systems to evaluate MAFLD biopsies, namely Brunt score, [bib_ref] Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions, Brunt [/bib_ref] the NAFLD activity score (NAS), [bib_ref] Design and validation of a histological scoring system for nonalcoholic fatty liver..., Kleiner [/bib_ref] and the fatty liver inhibition of progression (FLIP) algorithm and the steatosis, activity, and fibrosis (SAF) scoring system. Emerging evidence suggests that the SAF score provides a more robust histological assessment. [bib_ref] Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly..., Bedossa [/bib_ref] Recommendations:
- Indications for liver biopsy in patients with MAFLD (A1) - A typical feature of noninvasive tests is sowing indeterminate or unreliable results. - Assessment for dual-etiology liver diseases. - E t h i c a l l y a p p r o v e d r e s e a r c h o r clinical trials, including during bariatric surgery or cholecystectomy. - Liver biopsy reporting should be standardized using either the FLIP algorithm and SAF score or the NASH CRN system (B1).
# Mafld-related cirrhosis
The highest risk of hepatic complication is among those with cirrhosis and of nonhepatic complication is among patients with stage 3 fibrosis. [bib_ref] Fibrosis severity as a determinant of cause-specific mortality in patients with advanced..., Vilar-Gomez [/bib_ref] [bib_ref] Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease:..., Dulai [/bib_ref] Classification of cirrhosis depends on prognostic staging-compensated and decompensated cirrhosis [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: A systematic review..., D'amico [/bib_ref] [bib_ref] The epidemiology of cirrhosis in the United States: A population-based study, Scaglione [/bib_ref] -based on the presence or absence of clinically evident decompensating events such as jaundice, variceal hemorrhage, ascites, spontaneous bacterial peritonitis, or encephalopathy.
Patients with cirrhosis and past or present evidence of metabolic dysfunction that meet the criteria to diagnose MAFLD with either documentation of MAFLD on a previous liver biopsy or historical documentation of steatosis by hepatic imaging should be considered as having MAFLD-related cirrhosis, even in the absence of hepatic steatosis or typical histology of MAFLD at the time of presentation. [bib_ref] A new definition for metabolic dysfunction-associated fatty liver disease: An international expert..., Eslam [/bib_ref] Cirrhosis can be diagnosed by classic findings on ultrasonography, but the diagnosis may be missed when this is obscured by liver fat. In this context, liver stiffness measurement (LSM) can be used to diagnose cirrhosis and provide prognostic information in MAFLD patients in the appropriate clinical context, [bib_ref] Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty..., Wong [/bib_ref] with mortality rate being higher with increasing LSM. [bib_ref] Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness..., Boursier [/bib_ref] If LSM is not available, fibrosis scores can be used as an initial step to rule out patients who are less likely to have advanced fibrosis or cirrhosis and determine patients who need referral for LSM. [bib_ref] Optimizing use of nonalcoholic fatty liver disease fibrosis score, fibrosis-4 score, and..., Chan [/bib_ref] Aside from the prevention and treatment of decompensation events, cirrhosis management should focus on education, lifestyle modification, protecting the liver from further injury (e.g., through vaccination for viral hepatitis and avoidance of hepatotoxic medications), and care coordination; [bib_ref] Treatment of patients with cirrhosis, Ge [/bib_ref] moreover, it remains critical to avoid sarcopenia [ [fig_ref] Figure 2: The Egyptian guidelines recommended an algorithm to evaluate and manage patients with... [/fig_ref] ].
## Recommendations
- Patients with cirrhosis in the absence of current steatosis who meet the following criteria should still be considered as having MAFLD-related cirrhosis:
- Past or present evidence of meeting the criteria to diagnose MAFLD, with at least one of the following: 1) Historical documentation of MAFLD on a previous liver biopsy*. 2) Historical documentation of hepatic steatosis by imaging*. (B2) *History of past viral hepatitis should be considered as patients may have dual disease etiology.
## Diagnosis and monitoring for clinically significant portal hypertension and varices
The initial consequence of liver cirrhosis in general, or MAFLD-related cirrhosis in particular, is portal hypertension. [bib_ref] Relationship of steatosis grade and zonal location to histological features of steatohepatitis..., Chalasani [/bib_ref] The gold-standard for assessment of clinically significant portal hypertension is the direct measurement of HVPG, as this is invasive and not readily available. Alternatively, ultrasound is a feasible and safe technique for detecting morphological abnormalities associated with cirrhosis and an indicative measure of clinically significant portal hypertension. Computed tomography (CT) and MRI are other alternative tools. [bib_ref] New abdominal collaterals at ultrasound: A clue of progression of portal hypertension, Berzigotti [/bib_ref] Patients with MAFLD-related cirrhosis should be screened for gastroesophageal varices according to the Baveno VI criteria, as the prognosis is worse in those with gastroesophageal varices compared to those without. [bib_ref] Expanding the Baveno VI criteria for the screening of varices in patients..., Augustin [/bib_ref] [bib_ref] Performance of Baveno VI and expanded Baveno VI criteria for excluding high-risk..., Stafylidou [/bib_ref] The Baveno VI criteria have been recently validated in patients with MAFLD related cirrhosis. [bib_ref] Validation of Baveno VI and expanded Baveno VI criteria to identify high-risk..., Zheng [/bib_ref] Esophagogastroduodenoscopy (EGD) is required to confirm the existence and size of varices, though it is an invasive procedure with a risk of bleeding. [bib_ref] Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice..., Garcia-Tsao [/bib_ref] The assessment of LSM is an alternative accepted technique to rule out high-risk varices in patients with compensated cirrhosis. The interpretation of LSM data is as follows: LSM >15 kPa can diagnose cirrhosis, LSM = 10-15 kPa is suggestive of cirrhosis, and LSM <10 kPa in the absence of other clinical signs rules out cirrhosis. [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop:..., De Franchis [/bib_ref] [bib_ref] Predicting portal hypertension and variceal bleeding using non-invasive measurements of metabolic variables, Eslam [/bib_ref] Patients with LSM >15 kPa should be considered for surveillance for HCC, whereas those with LSM >20-25 kPa and/or thrombocytopenia, the use of EGD may be recommended for confirmation of diagnosis and prophylactic interventions in these patients. [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop:..., De Franchis [/bib_ref]
## Recommendations
- Screening by EGD for gastroesophageal varices is recommended in patients with MAFLD-associated cirrhosis unless previously diagnosed and treated (B2).
## Screening for hcc in patients with mafld
Abdominal ultrasound is the preferred screening tool for HCC due to its availability and cost-effectiveness. [bib_ref] The Asian Pacific Association for the Study of the Liver clinical practice..., Eslam [/bib_ref] [bib_ref] AGA clinical practice update on screening and surveillance for hepatocellular carcinoma in..., Loomba [/bib_ref] [bib_ref] Epidemiology and surveillance for hepatocellular carcinoma: New trends, Singal [/bib_ref] However, it has low sensitivity for detection of early-stage HCC (~47%); [bib_ref] Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in..., Tzartzeva [/bib_ref] therefore, simultaneous measurement of serum biomarker such as AFP is recommended. [bib_ref] Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in..., Tzartzeva [/bib_ref] [bib_ref] Tumor markers are more useful in patients undergoing surveillance for hepatocellular carcinoma..., Mikami [/bib_ref] Despite their high diagnostic efficacy, using dynamic imaging such as contrast-enhanced ultrasonography, computed tomography, and MRI for screening for HCC is not recommended as a surveillance modality due to the lack of wide availability and high cost, except for patients in whom the ultrasound quality is suboptimal due to obesity or excessive gas in the alimentary tract or when confirmation is required. [bib_ref] Non-enhanced magnetic resonance imaging as a surveillance tool for hepatocellular carcinoma: Comparison..., Park [/bib_ref] A 6-month screening interval is recommended, which is based on the tumor volume doubling-time of HCC. [bib_ref] Natural history of small untreated hepatocellular carcinoma in cirrhosis: A multivariate analysis..., Barbara [/bib_ref] A randomized controlled trial demonstrated the detection rate of early HCC and prognosis does not differ significantly with 3-or 6-monthly surveillance intervals; 6-monthly surveillance interval has been found to be better than a 12-month interval. [bib_ref] Semiannual surveillance is superior to annual surveillance for the detection of early..., Santi [/bib_ref] The targeted population for screening are MAFLD patients with cirrhosis. Although noncirrhotic patients with MAFLD are at high risk of HCC, [bib_ref] Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is..., Mittal [/bib_ref] the overall risk in the absence of cirrhosis is relatively low to justify the recommendation of screening in this group of patients, particularly with the very high prevalence of MAFLD.
## Recommendations
- Screening for HCC in MAFLD patients with cirrhosis through a combination of abdominal ultrasound and alpha-fetoprotein (AFP) every 6 months is recommended, as it improves overall survival; however, it is not recommended in noncirrhotic patients due to lack of evidence for cost-effectiveness (A1). - Computed tomography or magnetic resonance imaging may be needed if the ultrasound quality is inadequate (B2).
## Nonpharmacological management of mafld
Lifestyle modifications, including dietary change, weight loss, and exercise intervention, remain the cornerstone therapy and the first-line for this disease.
## Diet and lifestyle changes
In patients with MAFLD, lifestyle intervention programs and weight loss effectively lead to a reduction in hepatic steatosis, resolution of steatohepatitis, and regression of fibrosis, and improve a patient's quality of life in a dose-dependent manner.
The overall aim of lifestyle intervention should be for gradual weight loss (up to 1 kg/week) with losing 7%-10% of their body weight in obese patients and 5% in nonobese subjects as a primary target. There is no robust evidence to support a particular dietary approach for patients with MAFLD. Generally, a hypocaloric diet (500-1000-kcal deficit), with a daily protein intake of 1.2-1.5 g/kg of body weight/day is recommended. Notably, excess caloric restriction should be avoided as it can exacerbate the risk of sarcopenia, which is a poor predictor outcome in obese cirrhotic patients. Dietary plans should discourage the consumption of fructose and encourage adopting the "Mediterranean type diet" [bib_ref] Primary prevention of cardiovascular disease with a Mediterranean diet, Estruch [/bib_ref] and regular coffee drinking. [bib_ref] Coffee consumption and risk of nonalcoholic fatty liver disease: A systematic review..., Wijarnpreecha [/bib_ref] In real life, weight loss and more critically sustaining this effect is challenging. Using the 5 A's model (ask, advise, assess, assist, and arrange) may be useful to assess patients' needs and modify their behavior. Increasing clinic visit frequency [bib_ref] Weight loss in nonalcoholic fatty liver disease patients in an ambulatory care..., Dudekula [/bib_ref] and/or utilizing an internet-based approach for lifestyle changes [bib_ref] An internet-based approach for lifestyle changes in patients with NAFLD: Two-year effects..., Mazzotti [/bib_ref] have been proposed to maximize the efficacy of weight loss programs in patients with MAFLD.
Recent evidence suggests that alcohol use is associated with hepatic steatosis even in subjects with presumed NAFLD, according to current definitions. [bib_ref] Alcohol use is associated with hepatic steatosis among persons with presumed non-alcoholic..., Long [/bib_ref] In addition, alcohol intake within the limits of the current definition has been reported to increase significantly the risk for progression of fatty liver disease [bib_ref] Toward more accurate nomenclature for fatty liver diseases, Eslam [/bib_ref] [bib_ref] Nonheavy drinking and worsening of noninvasive fibrosis markers in nonalcoholic fatty liver..., Chang [/bib_ref] [bib_ref] Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver..., Blomdahl [/bib_ref] and increased risk of HCC. [bib_ref] Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease..., Aberg [/bib_ref] [bib_ref] The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic..., Ascha [/bib_ref] Exercise Regular physical activity and exercise have been demonstrated to have beneficial effects on the entire spectrum of MAFLD, including improvements in hepatic steatosis and health-related quality of life [bib_ref] A randomized controlled trial on the effectiveness of 8-week high-intensity interval exercise..., Abdelbasset [/bib_ref] and reduction in liver stiffness, portal hypertension, [bib_ref] High-intensity aerobic exercise improves both hepatic fat content and stiffness in sedentary..., Oh [/bib_ref] and risk of HCC. [bib_ref] Hepatocellular carcinoma and lifestyles, Saran [/bib_ref] There is no defined optimal frequency, intensity, duration, and type of physical activity/exercise for the induction of resolution of MAFLD. For the general adult population, physical activity guidelines recommend a total of ≥150 min/week of moderate-intensity exercise or 30 min/day for ≥5 days/week, or vigorous-intensity exercise for ≥75 min/week or ≥20 min/day on ≥3 days/ week. Resistance exercise on 2-3 days/week and flexibility exercises >2 days/week are also recommended. [bib_ref] Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and..., Garber [/bib_ref] A recent randomized clinical trial demonstrated that both vigorous and moderate exercise and aerobic and resistance exercise reduces hepatic steatosis equally in MAFLD, and the effect appeared to be largely mediated by weight loss. [bib_ref] Effects of moderate and vigorous exercise on nonalcoholic fatty liver disease: A..., Zhang [/bib_ref] [bib_ref] Effects of high-intensity interval and moderate-intensity continuous aerobic exercise on diabetic obese..., Abdelbasset [/bib_ref] Thus, generally, the selection of the type and duration of exercise should be tailored according to patients' preference and the likelihood of compliance. Resistance and moderate exercise may be more feasible than aerobic and vigorous exercise for MAFLD patients with poor fitness. Combined diet/exercise strategies containing a minimum 6 months of high-intensity lifestyle intervention followed by 1 year of a maintenance program are recommended.
## Recommendations
- Lifestyle changes, including combined healthy diet and exercise strategies are effective in normalization of liver enzymes levels and improvement of liver histology. (B1) - Weight loss is beneficial and recommended in patients with MAFLD, regardless of BMI. 7-10% and 5% weight loss is the target in the overweight/ obese and nonobese patients with MAFLD, respectively. (B1) - Physical activity without any pharmacotherapy is enough for MAFLD patients without steatohepatitis or fibrosis (B1) - There is no particular mandatory dietary approach, and dietary counseling should be individualized. Generally, energy restriction, Mediterranean-type diet, regular coffee drinking, and avoiding processed food and fructose are advisable. (B1) - Both vigorous and moderate exercise and aerobic exercise and resistance training reduce hepatic steatosis equally in MAFLD, though resistance exercise may be more feasible for patients with poor fitness. Recommendations should be individualized based on patient preferences to enhance long-term adherence. (B2)
## Bariatric and metabolic therapies (endoscopic approaches and surgery) for mafld
Though not an indication per se, MAFLD exists in 65%−90% of all patients who undertake weight loss surgery. [bib_ref] Prevalence of nonalcoholic steatohepatitis in Japanese patients with morbid obesity undergoing bariatric..., Seki [/bib_ref] [bib_ref] Liver disease in the morbidly obese: A review of 1000 consecutive patients..., Subichin [/bib_ref] Multiple retrospective and prospective observational cohort studies from Egypt [bib_ref] Long-term effects of one-anastomosis gastric bypass on liver histopathology in NAFLD cases:..., Salman [/bib_ref] [bib_ref] Effect of weight loss induced by laparoscopic sleeve gastrectomy on liver histology..., Salman [/bib_ref] showed consistent results with international findings, with meta-analyses [bib_ref] The role of bariatric surgery in the management of nonalcoholic fatty liver..., Aguilar-Olivos [/bib_ref] [bib_ref] The Effects of Metabolic Surgery on fatty liver disease and nonalcoholic steatohepatitis, Clanton [/bib_ref] [bib_ref] Bariatric surgery as potential treatment for nonalcoholic fatty liver disease: A future..., Hafeez [/bib_ref] suggesting that resolution of hepatic steatosis, steatohepatitis, and fibrosis was observed in >75% of patients. [bib_ref] Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis, Lassailly [/bib_ref] Special precautions are required when bariatric surgery is considered in patients with MAFLD-related cirrhosis due to the high perioperative risk with a suggested operative mortality of up to 16.3% in those with decompensated disease. [bib_ref] Increased perioperative mortality following bariatric surgery among patients with cirrhosis, Mosko [/bib_ref] Notably, in a recent Egyptian study of 132 cases with Child-A MAFLD-related cirrhosis, laparoscopic sleeve gastrectomy (LSG) was found to be safe and led to improvement of steatosis, steatohepatitis, and fibrosis, after 30-month follow-up. [bib_ref] Impact of laparoscopic sleeve gastrectomy on fibrosis stage in patients with child-A..., Salman [/bib_ref] The utility of endoscopic bariatric and metabolic therapies (EBMT), including intragastric balloons (IGBs) and endoscopic sleeve gastroplasty (ESG), as less invasive and safer interventions compared to the traditional operations are emerging and may represent an attractive option for patients with MAFLD. [bib_ref] Endoscopic bariatric and metabolic therapies for non-alcoholic fatty liver disease: Evidence and..., Salomone [/bib_ref] Therefore, based on the current evidence, bariatric surgery can be offered to patients with MAFLD only if the following two criteria are met: 1) BMI >40 kg/m 2 or BMI >35 kg/m 2 with obesity-related comorbidities; 2) absence of decompensated cirrhosis or evidence of concomitant portal hypertension. The utility and feasibility of bariatric surgery for patients with MAFLD and BMI ≤35 kg/m 2 is currently unclear, and further studies are required to clarify this aspect. Due to the shared pathogenic pathways between MAFLD and T2DM, several anti-diabetic medications have been investigated for the treatment of patients with MAFLD. [bib_ref] The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from..., Chalasani [/bib_ref] The beneficial effects of pioglitazone on hepatic histology in patients with and without T2DM has been reported in five small-randomized controlled trials. [bib_ref] Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis, Sanyal [/bib_ref] [bib_ref] Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type..., Cusi [/bib_ref] [bib_ref] A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis, Belfort [/bib_ref] [bib_ref] Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis, Aithal [/bib_ref] [bib_ref] Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2..., Bril [/bib_ref] However, due to multiple possible concerns with pioglitazone, including weight gain, edema, the development of bladder cancer, and a decrease in bone mineral density, this therapy is not widely used. [bib_ref] Pioglitazone use and risk of bladder cancer: A systematic literature review and..., Mehtala [/bib_ref] [bib_ref] Effect of pioglitazone on bone mineral density in patients with nonalcoholic steatohepatitis:..., Portillo-Sanchez [/bib_ref] Metformin does not improve hepatic histology in patients with MAFLD. [bib_ref] Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial, Haukeland [/bib_ref] [bib_ref] A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver..., Musso [/bib_ref] [bib_ref] Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver..., Lavine [/bib_ref] [bib_ref] Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis, Li [/bib_ref] However, it improves insulin resistance [bib_ref] Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial, Haukeland [/bib_ref] [bib_ref] Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver..., Lavine [/bib_ref] [bib_ref] Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis, Li [/bib_ref] and reduces the risk of HCC in these patients, though it should be noted that the studies have not been randomized or prospective. [bib_ref] Type 2 diabetes and metformin use associate with outcomes of patients with..., Vilar-Gomez [/bib_ref] [bib_ref] Meta-analysis: The efficacy of metformin and other anti-hyperglycemic agents in prolonging the..., Zhou [/bib_ref] Though some studies have shown that vitamin E can have some role in improving hepatic histology in patients with steatohepatitis, [bib_ref] Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis, Sanyal [/bib_ref] [bib_ref] Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic..., Harrison [/bib_ref] [bib_ref] Vitamin E and changes in serum alanine aminotransferase levels in patients with..., Hoofnagle [/bib_ref] [bib_ref] Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: A..., Sato [/bib_ref] other studies failed to confirm these findings. [bib_ref] Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2..., Bril [/bib_ref] [bib_ref] Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver..., Lavine [/bib_ref] [bib_ref] Does vitamin E improve the outcomes of pediatric nonalcoholic fatty liver disease?..., Sarkhy [/bib_ref] [bib_ref] Effect of vitamin E in non-alcoholic fatty liver disease: A systematic review..., Amanullah [/bib_ref] A recent study demonstrated that vitamin E decreases the risk of hepatic decompensation, transplant, and death in MAFLD patients with bridging fibrosis or cirrhosis. [bib_ref] Vitamin E improves transplant-free survival and hepatic decompensation among patients with nonalcoholic..., Vilar-Gomez [/bib_ref] The development of prostate cancer and hemorrhagic stroke is a possible concern of vitamin E therapy. [bib_ref] Vitamin E and the risk of prostate cancer: The selenium and vitamin..., Klein [/bib_ref] Although statins did not show beneficial effects on hepatic histology, [bib_ref] Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, Eslami [/bib_ref] they may reduce cardiovascular morbidity in patients with MAFLD. [bib_ref] Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, Eslami [/bib_ref] [bib_ref] Safety and efficacy of long-term statin treatment for cardiovascular events in patients..., Athyros [/bib_ref] Thus, statins can be used safely in patients with MAFLD with hyperlipidemia.
## Recommendations
Obeticholic acid (OCA) is a first-in-class selective farnesoid X receptor (FXR) agonist and represents the most advanced drug in development to date; however, it is not approved yet. [bib_ref] Obeticholic acid: Towards first approval for NASH, Eslam [/bib_ref] In terms of adverse events, the main adverse event of OCA was pruritus, which occurred in half of patients that received 25 mg daily. Another major caveat of OCA is the elevation in serum low-density lipid protein (LDL) and decrease in high-density lipid protein (HDL). Thus, statins should be considered in patients with MAFLD with hyperlipidemia or who receive OCA therapy. [bib_ref] Obeticholic acid: Towards first approval for NASH, Eslam [/bib_ref] There are many pharmacological agents under clinical trials in phase II and phase III development [] and beyond the scope of discussion in this guideline document.
## Recommendations
- Statins reduce cardiovascular morbidity and mortality and can be used in patients who receive obeticholic acid, if needed. (B1) - Vitamin E may improve histological markers of disease activity; however, there are some concerns about safety. (B2)
- Pioglitazone improves histological markers of MAFLD; however, there are some concerns about safety. (B2) - Metformin has no effect on hepatic histology but improves insulin resistance and may reduce the risk of HCC. (B2)
## Moni̇tori̇ng progress and response to treatment
Given that the severity of fibrosis is the major determinant of both hepatic-related outcomes and mortality, [bib_ref] Association between fibrosis stage and outcomes of patients with non-alcoholic fatty liver..., Taylor [/bib_ref] those with significant fibrosis need the closest monitoring and the following scheme is recommended and can mainly be undertaken at primary care for the stage with no or early fibrosis and using simple noninvasive scores of fibrosis:
Interval of follow-up 1) Patients without fibrosis can be monitored at 2-or 3-year intervals if they do not have concomitant metabolic risk factors or if there has been no worsening of these comorbidities. 2) Patients with fibrosis or evidence uncontrolled concomitant metabolic risk factors should be monitored on an annual basis 3) Patients with cirrhosis should undergo monitoring at 6-month intervals, including surveillance for HCC (please see the next section for details).
# Method of follow-up
With acknowledgment of the fact that there is no ideal biomarker of the score with a high predictive value for differentiating different stages of liver fibrosis, we recommend monitoring of fibrosis progression in the clinic by using noninvasive scores (NFS, FIB-4) and ideally if possible in combination with liver stiffness measurement by transient elastography [bib_ref] Simple noninvasive scores are clinically useful to exclude, not predict, advanced fibrosis:..., Kaya [/bib_ref] [bib_ref] The diagnostic utility of fibrosis-4 or nonalcoholic fatty liver disease fibrosis score..., Jafarov [/bib_ref] to increase the accuracy of prediction and minimize the gray zone.
## Recommendations
- Patients without fibrosis, concomitant metabolic risk factors, or the absence of worsening of metabolic risk factors can be monitored at intervals of 2 or 3 years. (C2) - Patients with fibrosis or concomitant metabolic risk factors should be monitored on an annual basis by using a combination of noninvasive scores and/or liver stiffness measurement. (C2) - Patients with cirrhosis should undergo monitoring at 6-month intervals, including surveillance for hepatocellular carcinoma. (A2)
## Patient reported outcomes in mafld
MAFLD was demonstrated to be associated with low health-related quality of life (HRQoL), independent of other demographics or metabolic comorbidities. [bib_ref] Reduced patient-reported outcome scores associate with level of fibrosis in patients with..., Younossi [/bib_ref] [bib_ref] Health-related quality of life in nonalcoholic fatty liver disease associates with hepatic..., Huber [/bib_ref] Instruments for assessing patient reported outcomes (PRO) include questionnaires that evaluate general HRQoL such as Chronic Liver Disease Questionnaire (CLDQ), the Short Form-36 (SF-36), and EuroQoL 5-Dimensions 5-Level (EQ-5D-5L), or disease-specific questionnaires such as NASH-CHECK and CLDQ-NASH. [bib_ref] Patient-reported outcomes and the economic effects of nonalcoholic fatty liver disease and..., Younossi [/bib_ref] [bib_ref] Measuring what matters to patients: The development of the NASH-CHECK, a new..., Doward [/bib_ref] [bib_ref] A disease-specific quality of life instrument for non-alcoholic fatty liver disease and..., Younossi [/bib_ref] Although these questionnaires have been translated into various languages and validated in various countries, these are yet to be well validated in Egypt, and how cultural variation may influence the PROs is not known.
## Recommendations:
- Patients with MAFLD seem to have worse HRQoL, physical, fatigue, and mental scores, compared to patients with other causes of chronic liver disease. (B2) - Integration of patient perspectives on the disease, quality of life, satisfaction, and compliance with lifestyle advice via patient-reported outcomes (PRO) is crucial for developing a holistic patient-centered model of care for MAFLD. (B2)
## Special groups
## Lean mafld
Although overweight/obesity is classically associated with the development and progression of MAFLD, a recent meta-analysis estimated that within the MAFLD population, 40.8% are non-obese and 19.2% are lean, without differences in the histological severity of disease between lean and obese patients. [bib_ref] Non-alcoholic fatty liver disease in non-obese individuals: The impact of metabolic health, Eslam [/bib_ref] [bib_ref] Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver..., Ye [/bib_ref] Non-obese patients with MAFLD may have a worse outcome and accelerated disease progression. [bib_ref] Characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease, Cruz [/bib_ref] [bib_ref] Lean NAFLD: A distinct entity shaped by differential metabolic adaptation, Chen [/bib_ref] [bib_ref] NAFLD in Lean Asians, Eslam [/bib_ref] Insulin resistance and altered body fat distribution rather than BMI could be better indicators of MAFLD in such patients and hence the importance of the new diagnostic criteria of MAFLD. [bib_ref] Non-alcoholic fatty liver disease in non-obese individuals: The impact of metabolic health, Eslam [/bib_ref] The management of nonobese subjects with MAFLD relies on lifestyle intervention through regular exercise and controlling metabolic comorbidities, irrespective of baseline BMI. A 3%-5% weight reduction may be sufficient in lean MAFLD. In addition, nonobese subjects were found to be more likely to maintain weight reduction and normal liver enzymes in the long term compared to obese subjects. [bib_ref] Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver..., Wong [/bib_ref] Recommendations:
- MAFLD can frequently exist in nonobese subjects. (B1) - Lifestyle intervention with regular exercise is effective in treating MAFLD and in improving overall fitness and metabolic co-morbidities irrespective of baseline BMI. (B1)
## Dual etiologies
As MAFLD is no longer a diagnosis of exclusion and it is now possible to diagnose its coexistence with other liver diseases such as HBV and HCV, meeting the criteria for a diagnosis of MAFLD plus one or more of the other diagnoses as the cause of chronic liver diseases at baseline or at follow-up, should be diagnosed as dual etiology liver disease.
These individuals are likely to have a different natural history and response to therapy than those with liver disease of a "single" etiology. [bib_ref] A new definition for metabolic dysfunction-associated fatty liver disease: An international expert..., Eslam [/bib_ref] With the high prevalence rates of MAFLD and viral hepatitis in Egypt, it is expected that these disease entities will frequently occur together.
In this regard, a recent study of more than 10,000 consecutive patients with HCV from Egypt estimated that nearly half of these patients have coexisting MAFLD, and this group of patients were at a higher risk of hepatic fibrosis compared to those with HCV.Recommendations - Patients with liver diseases such as ALD and viral hepatitis should be carefully evaluated for possible concurrent MAFLD and vice versa (A1). - Patients with MAFLD should be advised to avoid alcohol or at least to consume the lowest amount possible (B1). - MAFLD management and that of concomitant diseases should be as per the standard guidelines for each of the diseases (B1).
## Cured hcv or treated hbv subjects
MAFLD is emerging as a key cause for persistently abnormal liver tests, continuing to drive liver disease progression and offset the beneficial impact of profound virological suppression or sustained virological response and poor outcomes in individuals with chronic HBV and/or HCV infection on end-stage liver disease, HCC burden, and dropout rate from the liver transplant waiting list. [bib_ref] Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals, Noureddin [/bib_ref] [bib_ref] Liver steatosis is a strong predictor of mortality and cancer in chronic..., Peleg [/bib_ref] Treatment of MAFLD in this group should be considered the same as that for noninfected patients. In addition, multiple studies have demonstrated that direct acting antivirals-induced SVR is associated with weight gain, increased serum lipid levels, and hepatic steatosis. [bib_ref] MAFLD considerations as a part of the global hepatitis C elimination effort:..., Fouad [/bib_ref] Therefore, this group of patients may be more vulnerable to MAFLD-related complications.
## Recommendations
- Patients cured of HCV or having profound HBV virological suppression with MAFLD need monitoring because of the increased risk for progression to cirrhosis, development of HCC, as well as extrahepatic-related complications. (B1) - The exact monitoring schedule is yet to be defined, but these patients can be followed according to the recommendations of MAFLD single etiology. (B2) - Deterioration of lipid profiles and increase in weight and hepatic steatosis are frequently overlooked post-SVR. Clinicians should actively find, monitor these parameters, and intervene as appropriate, to reduce cardio-cerebral vascular disease risk. (B1)
## Ramadan fasting
Restriction in meal-consuming timing has emerged as a potential promising dietary approach for the management of obesity and dysmetabolic diseases, including MAFLD. Ramadan fasting has been reported in a study from Egypt on 83 patients with MAFLD to lead to a reduction of the severity of hepatic steatosis and liver enzymes. [bib_ref] Ramadan fasting improves liver function and total cholesterol in patients with nonalcoholic..., Ebrahimi [/bib_ref] Another study showed a direct effect of Ramadan fasting on improving noninvasive measures of fibrosis as well as on inflammatory markers and insulin sensitivity. [bib_ref] The impact of Ramadan fasting on fatty liver disease severity: A retrospective..., Mari [/bib_ref] In addition, both preclinical animal studies and human clinical trials have demonstrated that intermittent fasting has wide-spectrum benefits for many health conditions, including MAFLD. [bib_ref] Effects of intermittent fasting on health, aging, and disease, De Cabo [/bib_ref] Recommendations Ramadan fasting is advisable with plethoric beneficial effects in patients with MAFLD (A2).
## Management of mafld-related hcc
Metabolic risk factor modification could contribute to the optimum management of patients with MAFLD-related HCC; physical activity has been found to have a positive impact on HCC-related survival. [bib_ref] Impact of cancer rehabilitation on the prognosis of patients with hepatocellular carcinoma, Hashida [/bib_ref] However, as sarcopenia is reported to be a prognostic factor for patients with HCC, [bib_ref] Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular..., Harimoto [/bib_ref] [bib_ref] intramuscular fat deposition, and visceral adiposity independently predict the outcomes of hepatocellular..., Fujiwara [/bib_ref] [bib_ref] Sarcopenia is a poor prognostic factor following hepatic resection in patients aged..., Harimoto [/bib_ref] [bib_ref] Prognostic significance of sarcopenia in patients with hepatocellular carcinoma undergoing sorafenib therapy, Nishikawa [/bib_ref] [bib_ref] Sarcopenia predicts prognosis in patients with newly diagnosed hepatocellular carcinoma, independent of..., Ha [/bib_ref] [bib_ref] Sarcopenia impairs prognosis of patients with hepatocellular carcinoma: The role of liver..., Imai [/bib_ref] [bib_ref] Impact of pre-sarcopenia in sorafenib treatment for advanced hepatocellular carcinoma, Takada [/bib_ref] [bib_ref] Sarcopenia and intramuscular fat deposition are associated with poor survival in Indonesian..., Mardian [/bib_ref] careful consideration of body composition, including skeletal muscle mass and body fat, is crucial when recommending treating patients with HCC and particularly when recommending physical activity.
T2DM is a risk factor for HCC, and metformin has been demonstrated to significantly reduce the risk of HCC in MAFLD patients with HbA1c levels of >7.0% [bib_ref] Type 2 diabetes and metformin use associate with outcomes of patients with..., Vilar-Gomez [/bib_ref] and extend the survival of HCC patients with T2DM after the curative treatment of HCC. [bib_ref] Meta-analysis: The efficacy of metformin and other anti-hyperglycemic agents in prolonging the..., Zhou [/bib_ref] Thus, in MAFLD-related HCC patients with T2DM, metformin with life-style intervention may be recommended. However, further prospective, well-controlled randomized studies including Egyptian patients are required before any strong recommendation can be made.
## Recommendations:
- Metformin and lifestyle intervention could be beneficial in MAFLD-related HCC patients, particularly patients with T2DM. (B1) - Careful consideration of sarcopenia as a prognostic factor and appropriate nutritional therapy is recommended. (C2)
## Liver transplantation for mafld
MAFLD is emerging as the leading indication for liver transplantation (LT). The related comorbidities with MAFLD directly impact patient evaluation and selection, waitlist morbidity, mortality, and eventually post-transplant outcomes. Although LT is a radical treatment for cirrhosis, it does not treat these underlying comorbidities; therefore, this population is maintained at an increased risk for CVD and postoperative morbidity after LT. [bib_ref] Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic..., Yalamanchili [/bib_ref] Thus, a careful cardiovascular evaluation is mandatory. Survival after MAFLD-associated liver transplant has been reported to be similar to those for other causes of liver disease. [bib_ref] Outcomes of liver transplantation for nonalcoholic steatohepatitis: A systematic review and meta-analysis, Wang [/bib_ref] On the contrary, the main causes of mortality in patients with MAFLD following LT are sepsis and cardiovascular disease. [bib_ref] Is there disparity between risk and incidence of cardiovascular disease after liver..., Neal [/bib_ref] The increasing prevalence of MAFLD in the general population corresponds directly with the increasing prevalence of MAFLD in both the deceased and living donor pools. The use of steatotic livers has been associated with an increased risk of graft failure and/or impaired graft function. [bib_ref] Liver transplantation using fatty livers: Always feasible?, Mccormack [/bib_ref] The optimal regime in MAFLD recipients is unclear. Strategies to control associated comorbidities before LT should be prioritized to favorably impact waitlist mortality, decrease the rate of recurrent or de novo MAFLD after LT, and improve post-transplant outcome. In addition, immunosuppression including steroids and calcineurins inhibitors can cause or worsen modifiable risk factors and therefore should be minimized. Statins should be encouraged post-LT in those with dyslipidemia and/or pre-existing CVD and may be associated with a survival benefit. [bib_ref] The impact of coronary artery disease and statins on survival after liver..., Patel [/bib_ref] Recommendations - Liver transplantation should be considered in appropriately selected MAFLD patients with decompensated liver disease or HCC. (B1) - Patients with MAFLD have a high risk of presence of pre-existing CVD and hence should be thoroughly assessed prior to listing for transplantation and followed up afterwards.. (B1)
# Conclusion
The burden of MAFLD is rapidly increasing in Egypt and is emerging as a leading cause of chronic liver disease, HCC, and liver transplantation. In addition, it is intimately associated with numerous systemic complications such as T2DM, CVD, CKD, and multiple cancers. In our region, dual etiology, particularly with viral hepatitis, is common and challenging. The Egyptian guideline document for MAFLD is aimed to provide simple and practical recommendations for the assessment and management for the general population along with special populations with MAFLD. Fibrosis is the single major risk factor of all hepatic and extra-hepatic complications of MAFLD, with numerous noninvasive tools for assessment of fibrosis available and increasingly used. Holistic multidisciplinary and patient-centered approaches are needed to provide optimal care for patients with MAFLD. These models should aim to tackle the entire spectrum of the disease that includes not only the resolution of hepatic steatosis and liver injury but also the amelioration of the associated systemic metabolic milieu and control the accompanied comorbidities that aggravate the risk of cardiovascular and other extra-hepatic complications, with patient-reported outcomes being at the core. Lifestyle intervention, including dietary changes and structured exercise, remains the holy grail of management, with an armamentarium of therapeutic options expected to be available over the next few years. In the extreme of the spectrum of the disease, bariatric (metabolic) surgery may be indicated. MAFLD patients with cirrhosis should be considered for surveillance for varices and HCC. Multiple gaps in our knowledge on MAFLD are identified, and a joint effort by various stakeholders for gathering more evidence is the only way forward for the full adoption of these recommendations and tackling this growing burden.
## Research priorities and unmet needs in the field
We recommend the following research priorities to improve MAFLD-related health outcomes in Egypt:
- Serum tests and risk stratification algorithms for staging MAFLD and validating the cut-offs of noninvasive scores of fibrosis in the Egyptian MAFLD population. - Studies to establish and test the efficacy of task shifting and referral pathways based on the MAFLD diagnostic criteria. - Identifying the characteristics of patients with dual disease (MAFLD and HCV; MAFLD and HBV). - Characterization of the genetic architecture of MAFLD in this region would be required. - Studies to compare the diagnostic accuracy, costeffectiveness, and patient outcomes reported using the NAFLD and MAFLD diagnostic criteria in Egyptian cohorts. - Relative to their proportion of the global MAFLD population, Egypt is underrepresented in ongoing clinical trials for pharmaceutical treatments. Thus, more clinical trials in Egyptian populations are necessary.
## Ethical approval and informed consent
Nil.
## Financial support and sponsorship
Nil.
## Conflicts of interest
There are no conflicts of interest.
[fig] Figure 2: The Egyptian guidelines recommended an algorithm to evaluate and manage patients with MAFLD-related compensated and decompensated cirrhosis. [/fig]
[fig] •: Bariatric surgery can be offered to patients with MAFLD only if the following two criteria are met: 1) BMI >40 kg/m 2 or BMI >35 kg/m 2 with obesity-related comorbidities; 2) absence of decompensated cirrhosis or evidence of concomitant portal hypertension. (B1) The utility and feasibility of bariatric surgery for patients with MAFLD and BMI ≤35 kg/m 2 is currently unclear. (C2) Bariatric (metabolic) surgery improves all MAFLD parameters, including reduction of liver fat, resolution of steatohepatitis, and regression of fibrosis. (B1) The decision for offering bariatric (metabolic) surgery for patients with cirrhosis should be individualized because of the high risk of post-operative complications. (C1) PHARMACOLOGICAL TREATMENT [/fig]
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The landscape of chronic liver disease in Egypt has drastically changed over the past few decades. The prevalence of metabolic-associated fatty liver disease (MAFLD) has risen to alarming levels. Despite the magnitude of the problem, no regional guidelines have been developed to tackle this disease. This document provides the clinical practice guidelines of the key Egyptian opinion leaders on MAFLD screening, diagnosis, and management, and covers various aspects in the management of MAFLD. The document considers our local situations and the burden of clinical management for the healthcare sector and is proposed for daily clinical practical use. Particular reference to special groups was done whenever necessary.
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2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease
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2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease
PreambleSince 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, based on systematic methods to evaluate and classify evidence, provide a cornerstone of quality cardiovascular care.In response to reports from the Institute of Medicine 1,2 and a mandate to evaluate new knowledge and maintain relevance at the point of care, the ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) modified its methodology.[3][4][5]The relationships among guidelines, data standards, appropriate use criteria, and performance measures are addressed elsewhere. 5Intended Use-Practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease. The focus is on medical practice in the United States, but guidelines developed in collaboration with other organizations may have a broader target. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients' interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. Guidelines are reviewed annually by the Task Force and are official policy of the ACC and AHA. Each guideline is considered current until it is updated, revised, or superseded by published addenda, statements of clarification, focused updates, or revised full-text guidelines. To ensure that guidelines remain current, new data are reviewed biannually to determine whether recommendations should be modified. In general, full revisions are posted in 5-year cycles.[3][4][5][6]Modernization-Processes have evolved to support the evolution of guidelines as "living documents" that can be dynamically updated. This process delineates a recommendation to address a specific clinical question, followed by concise text (ideally <250 words) and hyperlinked to supportive evidence. This approach accommodates time constraints on busy clinicians and facilitates easier access to recommendations via electronic search engines and other evolving technology.Evidence Review-Writing committee members review the literature; weigh the quality of evidence for or against particular tests, treatments, or procedures; and estimate expected health outcomes. In developing recommendations, the writing committee uses evidence-based methodologies that are based on all available data. 3-7 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only selected references are cited.The Task Force recognizes the need for objective, independent Evidence Review Committees (ERCs) that include methodologists, epidemiologists, clinicians, and biostatisticians who systematically survey, abstract, and assess the evidence to address systematic review questions posed in the PICOTS format (P=population, I=intervention, C=comparator, O=outcome, T=timing, S=setting). 2,4-6 Practical considerations, including time and resource constraints, limit et al.the ERCs to evidence that is relevant to key clinical questions and lends itself to systematic review and analysis that could affect the strength of corresponding recommendations.Guideline-Directed Management and Treatment-The term "guideline-directed management and therapy" (GDMT) refers to care defined mainly by ACC/AHA Class I recommendations. For these and all recommended drug treatment regimens, the reader should confirm dosage with product insert material and carefully evaluate for contraindications and interactions. Recommendations are limited to treatments, drugs, and devices approved for clinical use in the United States.Class of Recommendation and Level of Evidence-TheClass of Recommendation (COR; ie, the strength of the recommendation) encompasses the anticipated magnitude and certainty of benefit in proportion to risk. The Level of Evidence (LOE) rates evidence supporting the effect of the intervention on the basis of the type, quality, quantity, and consistency of data from clinical trials and other reports(Table 1). 3-5 Unless otherwise stated, recommendations are sequenced by COR and then by LOE. Where comparative data exist, preferred strategies take precedence. When >1 drug, strategy, or therapy exists within the same COR and LOE and no comparative data are available, options are listed alphabetically.Relationships With Industry and Other Entities-The ACC and AHA sponsor the guidelines without commercial support, and members volunteer their time. The Task Force zealously avoids actual, potential, or perceived conflicts of interest that might arise through relationships with industry or other entities (RWI). All writing committee members and reviewers are required to disclose current industry relationships or personal interests, from 12 months before initiation of the writing effort. Management of RWI involves selecting a balanced writing committee and assuring that the chair and a majority of committee members have no relevant RWI (Appendix 1). Members are restricted with regard to writing or voting on sections to which their RWI apply. For transparency, members' comprehensive disclosure information is available online. Comprehensive disclosure information for the Task Force is also available online.The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds representing different geographic regions, sexes, ethnicities, intellectual perspectives/biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators.Individualizing Care in Patients With Associated Conditions and Comorbidities-Managing patients with multiple conditions can be complex, especially when recommendations applicable to coexisting illnesses are discordant or interacting. 8 The guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances. The recommendations should not replace clinical judgment.Clinical Implementation-Management in accordance with guideline recommendations is effective only when followed. Adherence to recommendations can be enhanced by shared decision making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities. Consequently, circumstances may arise in which deviations from these guidelines are appropriate. et al.the literature searches used for the existing evidence reviews, so the ERC concluded that no additional systematic review was necessary to address either of these critical questions.A third systematic review question was then identified: 3) Is one revascularization strategy (endovascular or surgical) associated with improved cardiovascular and limb-related outcomes in patients with critical limb ischemia (CLI)? This question had also been the subject of a high-quality systematic review that synthesized evidence from observational data and an RCT 14 ; additional RCTs addressing this question are ongoing. [15][16][17] The writing committee and the Task Force decided to expand the survey to include more relevant randomized and observational studies. Based on evaluation of this additional evidence the ERC decided that further systematic review was not needed to inform the writing committee on this question. Hence, the ERC and writing committee concluded that available systematic reviews could be used to inform the development of recommendations addressing each of the 3 systematic review questions specified above. The members of the Task Force and writing committee thank the members of the ERC that began this process and their willingness to participate in this volunteer effort. They include Aruna Pradhan, MD, MPH (ERC Chair);
# Introduction
## Methodology and evidence review
The recommendations listed in this guideline are, whenever possible, evidence based. An initial extensive evidence review, which included literature derived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline, was conducted from January through September 2015. Key search words included but were not limited to the following: acute limb ischemia, angioplasty, ankle-brachial index, anticoagulation, antiplatelet therapy, atypical leg symptoms, blood pressure lowering/hypertension, bypass graft/bypass grafting/ surgical bypass, cilostazol, claudication/intermittent claudication, critical limb ischemia/ severe limb ischemia, diabetes, diagnostic testing, endovascular therapy, exercise rehabilitation/exercise therapy/exercise training/supervised exercise, lower extremity/foot wound/ulcer, peripheral artery disease/peripheral arterial disease/peripheral vascular disease/ lower extremity arterial disease, smoking/smoking cessation, statin, stenting, and vascular surgery. Additional relevant studies published through September 2016, during the guideline writing process, were also considered by the writing committee, and added to the evidence tables when appropriate. The final evidence tables included in the Online Data Supplement summarize the evidence utilized by the writing committee to formulate recommendations.
Additionally, the writing committee reviewed documents related to lower extremity peripheral artery disease (PAD) previously published by the ACC and AHA. 9,10 References selected and published in this document are representative and not all-inclusive.
As stated in the Preamble, the ACC/AHA guideline methodology provides for commissioning an independent ERC to address systematic review questions (PI-COTS format) to inform recommendations developed by the writing committee. All other guideline recommendations (not based on the systematic review questions) were also subjected to an extensive evidence review process. For this guideline, the writing committee in conjunction with the Task Force and ERC Chair identified the following systematic review questions: 1) Is antiplatelet therapy beneficial for prevention of cardiovascular events in the patient with symptomatic or asymptomatic lower extremity PAD? 2) What is the effect of revascularization, compared with optimal medical therapy and exercise training, on functional outcome and quality of life (QoL) among patients with claudication? Each question has been the subject of recently published, systematic evidence reviews. The quality of these evidence reviews was appraised by the ACC/AHA methodologist and a vendor contracted to support this process (Doctor Evidence [Santa Monica, CA]). Few substantive randomized or nonrandomized studies had been published after the end date of The symptoms and signs of PAD are variable. Patients with PAD may experience the classic symptom of claudication or may present with advanced disease, including CLI. Studies have demonstrated that the majority of patients with confirmed PAD do not have typical claudication but have other non-joint-related limb symptoms or are asymptomatic. 53,55 Atypical lower extremity symptoms related to PAD may include pain or discomfort that begins at rest but et al. Circulation. Author manuscript; available in PMC 2017 September 21.
## Va author manuscript
VA Author Manuscript VA Author Manuscript worsens with exertion, pain or discomfort that does not stop an individual from walking, and pain or discomfort that begins with exertion but is not alleviated within 10 minutes of rest. Patients with PAD who do not have typical claudication but have other leg symptoms, or who are asymptomatic, have been shown to have functional impairment comparable to patients with claudication. Thus, all patients at increased risk of PAD should be asked not only about claudication but also about other exertional non-joint-related limb symptoms and perceived walking impairment.
## I b-nr
Patients at increased risk of PAD [fig_ref] Table 4: Patients at Increased Risk of PADAge ≥65 y Age 50-64 y, with... [/fig_ref] should undergo vascular examination, including palpation of lower extremity pulses (ie, femoral, popliteal, dorsalis pedis, and posterior tibial), auscultation for femoral bruits, and inspection of the legs and feet. See Online Data Supplements.
A thorough lower extremity vascular examination and careful inspection of the legs and feet are important components of the clinical assessment for PAD. To perform a thorough examination, legs and feet are examined with lower garments (pants/skirt, shoes, and socks) removed. Examination findings suggestive of PAD are shown in [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref]. Lower extremity pulses should be assessed and rated as follows: 0, absent; 1, diminished; 2, normal; or 3, bounding. Reproducibility of pulse assessment is better for detection of normal versus absent pulse than for normal versus diminished pulse. Absence of the dorsalis pedis pulse is less accurate for diagnosis of PAD than is absence of the posterior tibial pulse because the dorsalis pedis pulse can be absent on examination in a significant percentage of healthy patients. The presence of multiple abnormal physical findings (ie, multiple pulse abnormalities, bruits) increases the likelihood of confirmed PAD. Abnormal physical findings, such as a pulse abnormality, require confirmation with the ankle-brachial index (ABI) to establish the diagnosis of PAD. Similarly, an entirely normal pulse examination and absence of bruits decreases the likelihood of confirmed PAD. The presence of nonhealing lower extremity wounds may be a sign of CLI. Findings of cool or discolored skin and delayed capillary refill are not reliable for PAD diagnosis. To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing (Section 3), generally with the ABI as the initial test.
## I b-nr
Patients with PAD should undergo noninvasive blood pressure measurement in both arms at least once during the initial assessment. See Online Data Supplement 1.
An inter-arm blood pressure difference of >15 to 20 mm Hg is abnormal and suggestive of subclavian (or innominate) artery stenosis. Patients with PAD are at increased risk of subclavian artery stenosis. Measuring blood pressure in both arms identifies the arm with the highest systolic pressure, a requirement for accurate measurement of the ABI. Identification of unequal blood pressures in the arms also allows for more accurate measurement of blood pressure in the treatment of hypertension (ie, blood pressure is taken at the arm with higher measurements). Although a difference in arm systolic pressures of >15 to 20 mm Hg suggests subclavian (or innominate) artery stenosis, in the absence of symptoms (eg, arm claudication or symptoms of vertebral artery steal), no further imaging or intervention is warranted.
## Diagnostic testing for the patient with suspected lower extremity pad
(Claudication or CLI) [bib_ref] Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines, Accf/Aha Task Force On Practice [/bib_ref]
## .1. resting abi for diagnosing pad: recommendations
Recommendations for Resting ABI for Diagnosing PAD
## Cor loe recommendations
## I b-nr
In patients with history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref] , the resting ABI, with or without segmental pressures and waveforms, is recommended to establish the diagnosis. [bib_ref] Comparison of lower limb arterial assessments using colorduplex ultrasound and ankle/brachial pressure..., Allen [/bib_ref] [bib_ref] ROC analysis of noninvasive tests for peripheral arterial disease, Lijmer [/bib_ref] [bib_ref] Sensitivity and specificity of ankle-brachial index for detecting angiographic stenosis of peripheral..., Guo [/bib_ref] [bib_ref] Diagnostic utility of the two methods of ankle brachial index in the..., Niazi [/bib_ref] See Online Data Supplement 4.
The resting ABI is obtained by measuring systolic blood pressures at the arms (brachial arteries) and ankles (dorsalis pedis and posterior tibial arteries) in the supine position by using a Doppler device. The ABI of each leg is calculated by dividing the higher of the dorsalis pedis or posterior tibial pressure by the higher of the right or left arm blood pressure. In patients with a history or physical examination suggestive of PAD, the ABI has good validity as a first-line test in the diagnosis of PAD, as shown by vascular imaging, with sensitivities ranging from 68% to 84% and specificities from 84% to 99%. [bib_ref] ROC analysis of noninvasive tests for peripheral arterial disease, Lijmer [/bib_ref] [bib_ref] Sensitivity and specificity of ankle-brachial index for detecting angiographic stenosis of peripheral..., Guo [/bib_ref] [bib_ref] Diagnostic utility of the two methods of ankle brachial index in the..., Niazi [/bib_ref] Those with ABI 0.91 to 0.99 may possibly have PAD and should undergo exercise ABI, if the clinical suspicion of PAD is significant [fig_ref] Table 4: Patients at Increased Risk of PADAge ≥65 y Age 50-64 y, with... [/fig_ref]. [bib_ref] Critical evaluation of stress testing in the diagnosis of peripheral vascular disease, Ouriel [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] Values >1.40 indicate that the arteries were not able to be compressed, which is more common among individuals with diabetes mellitus and/or advanced chronic kidney disease. In the setting of noncompressible ABI values, additional imaging can be used to diagnose PAD if the clinical suspicion is significant [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref]. [bib_ref] The association between elevated ankle systolic pressures and peripheral occlusive arterial disease..., Aboyans [/bib_ref] These cutpoints for ABI interpretation have been previously proposed and represent a reasonable standardized categorization. 27
## Iia b-nr
In patients at increased risk of PAD [fig_ref] Table 4: Patients at Increased Risk of PADAge ≥65 y Age 50-64 y, with... [/fig_ref] but without history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref] , measurement of the resting ABI is reasonable. 54,55, See Online Data Supplements 3 and 4.
The ABI test is noninvasive, is simple to perform, and has minimal risks, making it suitable for use in asymptomatic individuals. Previous studies have demonstrated a significant prevalence of abnormal resting ABI among asymptomatic patients with risk factors for PAD. 55,79,95 A significant body of evidence demonstrates that patients with an abnormal ABI who are asymptomatic have poorer cardiovascular morbidity and mortality outcomes than do patients with normal ABI. [bib_ref] Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral..., Diehm [/bib_ref] [bib_ref] Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events..., Flowkes [/bib_ref] [bib_ref] Prevalence and association between risk factors, stroke subtypes, and abnormal ankle brachial..., Ratanakorn [/bib_ref] [bib_ref] Association of asymptomatic peripheral arterial disease with vascular events in patients with..., Sen [/bib_ref] [bib_ref] Asymptomatic peripheral arterial disease in type 2 diabetes patients: a 10-year follow-up..., Bundó [/bib_ref] [bib_ref] Prognostic usefulness of clinical and subclinical peripheral arterial disease in men with..., Bouisset [/bib_ref] While there is no conclusive evidence that aspirin treatment changes cardiovascular or limb outcomes in this population, in 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes. [bib_ref] The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial..., Belch [/bib_ref] [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] [bib_ref] A systematic review for the screening for peripheral arterial disease in asymptomatic..., Alahdab [/bib_ref] [bib_ref] The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction..., Lin [/bib_ref] There is also evidence that asymptomatic patients with a low resting ABI have a poorer functional status and a more rapid rate of functional decline than do patients with a normal ABI. 54,88-92 Although physical activity has been shown to be associated with improvement in functional status in patients with asymptomatic PAD, 93,94 the benefit of resting ABI testing to identify asymptomatic patients who are at increased risk of functional decline and may benefit from structured exercise programs remains to be determined.
## Iii: no benefit b-nr
In patients not at increased risk of PAD [fig_ref] Table 4: Patients at Increased Risk of PADAge ≥65 y Age 50-64 y, with... [/fig_ref] and without history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref] , the ABI is not recommended. See Online Data Supplement 4.
The prevalence of PAD among individuals without risk factors for atherosclerosis and who are <50 years of age is low. Data from population-based cohort studies have demonstrated a low prevalence (approximately 1%) of abnormal resting ABI among individuals <50 years of age. In the NHANES (National Health and Nutrition Study), approximately 95% of participants with an abnormal resting ABI had at least 1 risk factor for atherosclerosis. The yield of ABI testing among younger, asymptomatic individuals without risk factors for atherosclerosis is low, and these patients should not be routinely tested for PAD. 95,98
## Physiological testing: recommendations
Recommendations for Physiological Testing COR LOE Recommendations I B-NR Toe-brachial index (TBI) should be measured to diagnose patients with suspected PAD when the ABI is greater than 1.40. [bib_ref] The association between elevated ankle systolic pressures and peripheral occlusive arterial disease..., Aboyans [/bib_ref] See Online Data Supplement 5.
TBI is a noninvasive test that is useful to evaluate for PAD in patents with noncompressible arteries, which cause an artificial elevation of the ABI. 99,100,102,103 A TBI ≤0.70 is abnormal and diagnostic of PAD because the digital arteries are rarely noncompressible. 99-102,104, [bib_ref] Utility of toe-brachial index for diagnosis of peripheral artery disease, Park [/bib_ref] Patients with longstanding diabetes mellitus [bib_ref] The association between elevated ankle systolic pressures and peripheral occlusive arterial disease..., Aboyans [/bib_ref] or advanced chronic kidney disease [bib_ref] Vascular calcification in chronic kidney disease, Covic [/bib_ref]
## Va author manuscript
VA Author Manuscript PAD in these patients with noncompressible arteries who have history or physical examination findings suggestive of PAD [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref].
## I b-nr
Patients with exertional non-joint-related leg symptoms and normal or borderline resting ABI (>0.90 and ≤1.40) should undergo exercise treadmill ABI testing to evaluate for PAD. [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolaï [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] See Online Data Supplement 5.
Exercise treadmill ABI testing is important to objectively measure symptom limitations and diagnose PAD. [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolaï [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] It is useful in establishing the diagnosis of lower extremity PAD in the symptomatic patient when resting ABIs are normal or borderline and to differentiate claudication from pseudoclaudication in individuals with exertional leg symptoms. If the postexercise treadmill ABI is normal, alternative causes of leg pain are considered [fig_ref] Table 6: Alternative Diagnoses for Leg Pain or Claudication With Normal Physiological Testing [/fig_ref]. If a treadmill is not available, the pedal plantarflexion ABI test is a reasonable alternative because the results correlate well with treadmill ABIs [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref]. 111
## Iia b-nr
In patients with PAD and an abnormal resting ABI (≤0.90), exercise treadmill ABI testing can be useful to objectively assess functional status. [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolaï [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] See Online Data Supplement 5.
In patients with PAD, exercise treadmill ABI testing can objectively assess symptoms, measure change in ABI in response to exercise, and assess functional status [bib_ref] Vascular laboratory criteria for the management of peripheral vascular disease of the..., Raines [/bib_ref] [bib_ref] Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial..., Stein [/bib_ref] [bib_ref] Discordant diagnosis of lower extremity peripheral artery disease using American Heart Association..., Mahe [/bib_ref] [bib_ref] Reliability of treadmill testing in peripheral arterial disease: a meta-regression analysis, Nicolaï [/bib_ref] [bib_ref] Standard exercise test to assess peripheral arterial disease, Laing [/bib_ref] [bib_ref] The relationship between calf blood flow and ankle blood pressure in patients..., Sumner [/bib_ref] [fig_ref] Figure 1: Diagnostic Testing for Suspected PAD [/fig_ref]. It can be useful to correlate exertional lower extremity symptoms to a decline in ABI after treadmill exercise. Exercise treadmill ABI testing can document the magnitude of symptom limitation in patients with PAD and provide objective data that can demonstrate the safety of exercise and help to individualize exercise prescriptions in patients with PAD before initiation of a formal program of structured exercise training. Exercise ABI may also be used to objectively measure the functional improvement obtained in response to claudication treatment (eg, structured exercise program or revascularization). Administration of a 6-minute walk test in a corridor is a reasonable alternative to treadmill ABI testing for assessment of functional status. 54
## Iia b-nr
In patients with normal (1.00-1.40) or borderline (0.91-0.99) ABI in the setting of nonhealing wounds or gangrene, it is reasonable to diagnose CLI by using TBI with waveforms, transcutaneous oxygen pressure (TcPO 2 ), or skin perfusion pressure (SPP). [bib_ref] Transcutaneous oxygen pressure measurements in diabetic and non-diabetic patients clinically suspected of..., Biotteau [/bib_ref] [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] [bib_ref] Skin perfusion pressure measurement is valuable in the diagnosis of critical limb..., Castronuovo [/bib_ref] [bib_ref] Validation of the relationship between ankle-brachial and toe-brachial indices and infra-genicular arterial..., Bunte [/bib_ref] [bib_ref] An analysis of IN.PACT DEEP randomized trial on the limitations of the..., Shishehbor [/bib_ref] See Online Data Supplement 5.
The toe pressure and TBI may be discordant with the ABI 0.90 to 1.40 in some patients with diabetes mellitus and a nonhealing wound . [bib_ref] Validation of the relationship between ankle-brachial and toe-brachial indices and infra-genicular arterial..., Bunte [/bib_ref] [bib_ref] An analysis of IN.PACT DEEP randomized trial on the limitations of the..., Shishehbor [/bib_ref] A TBI ≤0.70 is considered diagnostic of PAD. 101,104,105 Doppler or plethysmographic waveforms taken at the toe supplement the toe pressure and TBI measurement and may be severely dampened in the setting of CLI. The likelihood of wound healing decreases with toe pressure <30 mm Hg. 100 Perfusion assessment measures (ie, TBI with waveforms, TcPO 2 , SPP) are obtained in a warm room to prevent arterial vasoconstriction in response to the cold. TcPO 2 measurements are performed with a standardized protocol and are taken at multiple sites. [bib_ref] Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based..., Fife [/bib_ref] Correlation between TBI, TcPO 2 , and SPP has been reported. [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] TcPO 2 >30 mm Hg has been used to predict ulcer healing. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] SPP ≥30 to 50 mm Hg is associated with increased likelihood of wound healing. [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] If perfusion measures are normal or only mildly impaired, alternative causes of the nonhealing wounds are considered [fig_ref] Table 7: Alternative Diagnoses for Nonhealing Wounds With Normal Physiological Testing [/fig_ref]. TcPO 2 and SPP can be used in angiosome-targeted assessment for revascularization. 119
## Iia b-nr
In patients with PAD with an abnormal ABI (≤0.90) or with noncompressible arteries (ABI >1.40 and TBI ≤0.70) in the setting of nonhealing wounds or gangrene, TBI with waveforms, TcPO 2 , or SPP can be useful to evaluate local perfusion. [bib_ref] Transcutaneous oxygen pressure measurements in diabetic and non-diabetic patients clinically suspected of..., Biotteau [/bib_ref] [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] [bib_ref] Skin perfusion pressure measurement is valuable in the diagnosis of critical limb..., Castronuovo [/bib_ref] [bib_ref] Validation of the relationship between ankle-brachial and toe-brachial indices and infra-genicular arterial..., Bunte [/bib_ref] [bib_ref] An analysis of IN.PACT DEEP randomized trial on the limitations of the..., Shishehbor [/bib_ref] See Online Data Supplement 5.
Perfusion assessment measures (eg, TBI with waveforms, TcPO 2 , SPP) can be useful when the ABI is only mildly reduced (eg, ABI 0.70-0.90) to determine whether factors other than PAD may be contributing to impaired wound healing . These perfusion assessment measures are obtained in a warm room to prevent arterial vasoconstriction in response to the cold. TcPO 2 measurements are performed with a standardized protocol and are taken at multiple sites. [bib_ref] Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based..., Fife [/bib_ref] The likelihood of wound healing decreases with toe pressure <30 mm Hg. There is correlation between TBI, TcPO 2 , and SPP. TcPO 2 >30 mm Hg has been used to predict ulcer healing. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] SPP ≥30 to 50 mm Hg is associated with increased likelihood of wound healing. [bib_ref] Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs-comparison..., Yamada [/bib_ref] TcPO 2 and SPP can be used in angiosome-targeted assessment for revascularization. [bib_ref] Angiosome-targeted infrapopliteal endovascular revascularization for treatment of diabetic foot ulcers, Söderstrom [/bib_ref] Additional perfusion assessment may also be useful for patients with nonhealing wounds or gangrene who have noncompressible arteries (ABI >1.40) but who have a diagnosis of PAD that is based on an abnormal TBI (ABI ≤0.70).
## I b-nr
Duplex ultrasound, computed tomography angiography (CTA), or magnetic resonance angiography (MRA) of the lower extremities is useful to diagnose anatomic location and severity of stenosis for patients with symptomatic PAD in whom revascularization is considered. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] [bib_ref] Diagnostic accuracy of 64 multidetector computed tomographic angiography in peripheral vascular disease, Shareghi [/bib_ref] [bib_ref] MDCT compared with digital subtraction angiography for assessment of lower extremity arterial..., Ota [/bib_ref] [bib_ref] Summary receiver operating characteristic curves as a technique for meta-analysis of the..., De Vries [/bib_ref] See Online Data Supplement 6.
For symptomatic patients in whom ABI/TBI confirms PAD and in whom revascularization is considered, additional imaging with duplex ultrasonography, CTA, or MRA is useful to develop an individualized treatment plan, including assistance in selection of vascular access sites, identification of significant lesions, and determination of the feasibility of and modality for invasive treatment. All 3 of these noninvasive imaging methods have good sensitivity and specificity as compared with invasive angiography. [bib_ref] Comparison of contrast-enhanced multi-station MR angiography and digital subtraction angiography of the..., Burbelko [/bib_ref] [bib_ref] Diagnostic accuracy of 64 multidetector computed tomographic angiography in peripheral vascular disease, Shareghi [/bib_ref] [bib_ref] MDCT compared with digital subtraction angiography for assessment of lower extremity arterial..., Ota [/bib_ref] [bib_ref] Summary receiver operating characteristic curves as a technique for meta-analysis of the..., De Vries [/bib_ref] Renal function does not affect the safety of duplex ultrasonography, although duplex offers lower spatial resolution than CTA and MRA in the setting of arterial calcification. The tomographic data from CTA and MRA afford 3dimensional reconstruction of the vessels examined. The iodinated contrast used in CTA confers risk of contrast-induced nephropathy and (rarely) severe allergic reaction [bib_ref] Side effects of radiographic contrast media: pathogenesis, risk factors, and prevention, Andreucci [/bib_ref] [bib_ref] Contrast induced nephropathy: updated ESUR Contrast Media Safety Committee guidelines, Stacul [/bib_ref] ; CTA uses ionizing radiation. MRA does not use ionizing radiation; however, gadolinium contrast used frequently in MRA studies confers risk of nephrogenic systemic sclerosis for patients with advanced renal dysfunction and is therefore contraindicated in this population. The choice of the examination should be determined in an individualized approach to the anatomic assessment for each patient, including risk-benefit assessment of each study type. If these noninvasive tests are nondiagnostic, then invasive angiography may be required to delineate anatomy and plan revascularization.
## I c-eo
Invasive angiography is useful for patients with CLI in whom revascularization is considered.
## N/a
By definition, CLI results from extensive PAD that limits tissue perfusion. Because timely diagnosis and treatment are essential to preserve tissue viability in CLI, it is often most effective and expeditious to pursue invasive angiography with endovascular revascularization directly, without delay and potential risk of additional noninvasive imaging.
## Iia c-eo
Invasive angiography is reasonable for patients with lifestyle-limiting claudication with an inadequate response to GDMT for whom revascularization is considered.
## N/a
For patients with lifestyle-limiting claudication despite GDMT (including structured exercise therapy) for whom revascularization is being considered, proceeding directly to invasive angiography for anatomic assessment and to determine revascularization strategy is reasonable. In certain clinical settings, noninvasive imaging studies for anatomic assessment (ie, duplex ultrasound, CTA, or MRA) may not be available because of lack of local resources or expertise. In addition, there are clinical scenarios in which noninvasive studies for anatomic assessment may be perceived to confer greater risk to the patient than invasive angiography (eg, patient with advanced chronic kidney disease for whom contrast dose for invasive angiography would be lower than that required for CTA).
## Iia
## B-nr
A screening duplex ultrasound for abdominal aortic aneurysm (AAA) is reasonable in patients with symptomatic PAD. See Online Data Supplement 8.
PAD has been recognized as a risk factor for AAA. In observational studies, the prevalence of AAA (aortic diameter ≥3 cm) was higher in patients with symptomatic PAD than in the general population 127,129 and in a population of patients with atherosclerotic risk factors. The prevalence of AAA among patients with PAD increased with age, beginning in patients ≥55 years of age, and was highest in patients ≥75 years of age. There are no data on AAA screening in patients with asymptomatic PAD. This recommendation refers to screening patients with symptomatic PAD for AAA regardless of patient age, sex, smoking history, or family history of AAA. Recommendations for screening the general population with risk factors for AAA (based on age, sex, smoking history, and family history) have been previously published. 9
## Screening for asymptomatic atherosclerosis in other arterial beds (coronary, carotid, and renal arteries)
The prevalence of atherosclerosis in the coronary, carotid, and renal arteries is higher in patients with PAD than in those without pad. 128,130-135 However, intensive atherosclerosis risk factor modification in patients with PAD is justified regardless of the presence of disease in other arterial beds. Thus, the only justification for screening for disease in other arterial beds is if revascularization results in a reduced risk of myocardial infarction (MI), stroke, or death, and this has never been shown. Currently, there is no evidence to demonstrate that screening all patients with PAD for asymptomatic atherosclerosis in other arterial beds improves clinical outcome. Intensive treatment of risk factors through GDMT is the principle method for preventing adverse cardiovascular ischemic events from asymptomatic disease in other arterial beds. Patients with PAD (ie, ABI ≤0.90) who do not have claudication may have leg symptoms atypical for claudication or may be too functionally limited to allow for adequate leg symptom assessment. Patients with PAD without claudication are at increased cardiovascular risk. [bib_ref] Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral..., Diehm [/bib_ref] Subgroup analysis in a trial evaluating asymptomatic patients did not show an effect of aspirin in patients with an abnormally low ABI (<0.80 or ≤0.90). [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] However, the trial was not powered to analyze subgroups, and the uncertainty of the result does not rule out the possibility that aspirin could provide benefit in such patients, especially in those at increased risk of cardiovascular events. Another trial that included asymptomatic patients was too small to derive meaningful conclusions. 140
## Medical therapy for the patient with pad
IIb B-R In asymptomatic patients with borderline ABI (0.91-0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain. [bib_ref] The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial..., Belch [/bib_ref] [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] See Online Data Supplement 13.
In asymptomatic patients with an abnormal or borderline ABI, 2 RCTs found that aspirin had no effect in reducing cardiovascular events [bib_ref] The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial: factorial..., Belch [/bib_ref] [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] and might increase bleeding. [bib_ref] Aspirin for prevention of cardiovascular events in a general population screened for..., Flowkes [/bib_ref] However, the trials were not powered to examine patients with borderline ABI separately. Given that cardiovascular risk is lower in patients with borderline ABI than in those with abnormal ABI, [bib_ref] Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events..., Flowkes [/bib_ref] it would be unlikely that aspirin would have a meaningful effect in this subgroup when there was no evidence of an effect in the total trial populations.
## Iib b-r
The effectiveness of dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established. [bib_ref] Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in..., Bhatt [/bib_ref] See Online Data Supplement 13.
Based on findings from a subset of patients with PAD in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, DAPT with aspirin plus clopidogrel may be considered for patients with PAD at particularly high risk of cardiovascular ischemic events who are not at high risk of bleeding. 143, [bib_ref] Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in..., Bhatt [/bib_ref] Currently, there are sparse data on newer P2Y 12 antagonists for PAD. There is uncertainty about the net benefit of long-term DAPT for patients with PAD-specifically the balance of risks of cardiovascular ischemic events versus major bleeding. Additional clinical trials are needed in the population with PAD. Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD. 20
IIb C-LD DAPT (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization. [bib_ref] Management of peripheral arterial interventions with mono or dual antiplatelet therapy-the MIRROR..., Tepe [/bib_ref] [bib_ref] Association of dual-antiplatelet therapy with reduced major adverse cardiovascular events in patients..., Armstrong [/bib_ref] [bib_ref] Twelve-month results of a randomized trial comparing mono with dual antiplatelet therapy..., Strobl [/bib_ref] [bib_ref] CASPAR Writing Committee. Results of the randomized, placebocontrolled Clopidogrel and Acetylsalicylic Acid..., Belch [/bib_ref] See Online Data Supplements 13 and 14.
There are sparse data on DAPT after lower extremity revascularization. Still, DAPT is prescribed in up to 55% of patients after endovascular revascularization for CLI. [bib_ref] Association of dual-antiplatelet therapy with reduced major adverse cardiovascular events in patients..., Armstrong [/bib_ref] One small RCT of aspirin or aspirin plus clopidogrel in patients undergoing endovascular revascularization demonstrated that patients with DAPT had fewer repeat revascularization procedures for clinical symptoms. [bib_ref] Management of peripheral arterial interventions with mono or dual antiplatelet therapy-the MIRROR..., Tepe [/bib_ref] A subsequent small RCT of aspirin plus placebo or aspirin plus clopidogrel in patients after endovascular revascularization also showed a decrease in the need for repeat revascularization at 6 months in patients receiving clopidogrel. [bib_ref] Twelve-month results of a randomized trial comparing mono with dual antiplatelet therapy..., Strobl [/bib_ref] An RCT of aspirin plus placebo or aspirin plus clopidogrel in patients who underwent below-knee bypass graft showed a decrease in limb-related events only in the prespecified subgroup of patients with prosthetic bypass grafts. [bib_ref] CASPAR Writing Committee. Results of the randomized, placebocontrolled Clopidogrel and Acetylsalicylic Acid..., Belch [/bib_ref] Refer to the DAPT guideline focused update for DAPT recommendations specifically for CAD. 20
IIb B-R The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] This novel antagonist of protease-activated receptor-1 added to existing antiplatelet therapy reduced the risk of cardiovascular ischemic events in patients with atherosclerosis who were receiving standard therapy in an RCT. [bib_ref] Vorapaxar in the secondary prevention of atherothrombotic events, Morrow [/bib_ref] [bib_ref] Efficacy and safety of vorapaxar with and without a thienopyridine for secondary..., Bohula [/bib_ref] However, it also increased the risk of moderate or severe bleeding. Although the cardiovascular benefit was not demonstrated in the subgroup with symptomatic PAD, there was a reduction in limb-related events with vorapaxar, specifically in acute limb ischemia (ALI) and peripheral revascularization. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] [bib_ref] Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery..., Bonaca [/bib_ref] More than half of ALI events in the PAD subset were due to thrombosis of lower extremity bypass grafts. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] Unfortunately, the benefit in limb events in patients with PAD was accompanied by an increased risk of bleeding. [bib_ref] Vorapaxar in patients with peripheral artery disease: results from TRA2oP-TIMI 50, Bonaca [/bib_ref] [bib_ref] Acute limb ischemia and outcomes with vorapaxar in patients with peripheral artery..., Bonaca [/bib_ref] Therefore, the overall clinical benefit of vorapaxar in patients with PAD is uncertain. Statin therapy improves both cardiovascular and limb outcomes in patients with PAD.In a subgroup of 6748 patients with PAD in the HPS (Heart Protection Study), simvastatin 40 mg daily reduced the rate of first major vascular event by 22% relative to placebo.In a multinational registry, statin use among patients with PAD reduced 4-year adverse limb-related events (ie, worsening claudication, new CLI, new lower extremity revascularization, new ischemic amputation) compared with no statin. [bib_ref] Statin therapy and long-term adverse limb outcomes in patients with peripheral artery..., Kumbhani [/bib_ref] Use of simvastatin in the HPS reduced relative risk of peripheral vascular events (including noncoronary revascularization, aneurysm repair, major amputation, or PAD death) compared with placebo.In Medicare patients undergoing lower extremity revascularization, 1-year limb salvage rates were improved among those receiving statin medication. [bib_ref] Preoperative statins and limb salvage after lower extremity revascularization in the Medicare..., Vogel [/bib_ref] In a multicenter RCT, use of atorvastatin 80 mg daily improved pain-free walking time and community-based walking at 12 months compared with placebo. [bib_ref] Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial..., Mohler [/bib_ref] In 1 cohort study of 5480 patients with asymptomatic PAD, statin treatment improved cardiovascular outcomes. Guidelines for dosing of statin medications have been previously published. 24
## Statin agents: recommendation
## Antihypertensive agents: recommendations
## Recommendations for antihypertensive agents
## Cor loe recommendations
I A Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death. [bib_ref] Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings..., Bavry [/bib_ref] [bib_ref] Cardioprotective medication is associated with improved survival in patients with peripheral arterial..., Feringa [/bib_ref] [bib_ref] The HOPE Study (Heart Outcomes Prevention Evaluation), Sleight [/bib_ref] [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] See Online Data Supplements 17 and 18.
Treatment of elevated blood pressure is indicated to lower the risk of cardiovascular events.Target blood pressure and selection of antihypertensive therapy should be consistent with current published guidelines for hypertension management. Concerns have been raised that antihypertensive therapy may reduce limb perfusion. However, multiple studies have demonstrated that blood pressure treatment, including the use of beta blockers, does not worsen claudication symptoms or impair functional status in patients with PAD. [bib_ref] Effect of nebivolol vs. hydrochlorothiazide on the walking capacity in hypertensive patients..., Diehm [/bib_ref] [bib_ref] Beta blockers for peripheral arterial disease, Paravastu [/bib_ref] [bib_ref] β-Blockers in patients with intermittent claudication and arterial hypertension: results from the..., Espinola-Klein [/bib_ref] There is no evidence that one class of antihypertensive medication or strategy is superior for blood pressure lowering in PAD. [bib_ref] Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings..., Bavry [/bib_ref] [bib_ref] Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT, Piller [/bib_ref] [bib_ref] Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan..., Zanchetti [/bib_ref] An updated multisocietal guideline on the management of high blood pressure is anticipated in 2017.
## Iia a
The use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD. [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] [bib_ref] Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients...., Yusuf [/bib_ref] See Online Data Supplement 17.
The effect of ramipril versus placebo on cardiovascular events was studied in high-risk patients free of heart failure in the HOPE (Heart Outcomes Prevention Evaluation) trial. [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] [bib_ref] Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients...., Yusuf [/bib_ref] Patients were normotensive on average at the time of enrollment. In a subgroup of 4051 patients with PAD, ramipril reduced the risk of MI, stroke, or vascular death by 25%, similar to the efficacy in the entire study population. [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] [bib_ref] Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients...., Yusuf [/bib_ref] The efficacy was similar in patients with PAD with symptomatic disease and asymptomatic low ABI. [bib_ref] Impact of ramipril in patients with evidence of clinical or subclinical peripheral..., Ostergren [/bib_ref] Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial) compared telmisartan, ramipril, and combination therapy in patients with cardiovascular disease, including PAD, and/or diabetes mellitus. [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] All 3 treatments had similar cardiovascular event rates with higher rates of adverse events (including hypotension, syncope, and renal failure) in the combination-therapy group. The efficacy of telmisartan was similar in the subgroup of 3468 patients with PAD, which supports the use of angiotensin-receptor blockers as an alternative to angiotensin-converting enzyme inhibitors. [bib_ref] Telmisartan, ramipril, or both in patients at high risk for vascular events, Yusuf [/bib_ref] The effect of angiotensin-receptor blockers in asymptomatic PAD has not been studied.
## Smoking cessation: recommendations
## Recommendations for smoking cessation
## Cor loe recommendations
I A Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit. [bib_ref] Effectiveness of a smoking cessation program for peripheral artery disease patients: a..., Hennrikus [/bib_ref] [bib_ref] Physician advice for smoking cessation, Stead [/bib_ref] [bib_ref] Variation in smoking cessation after vascular operations, Hoel [/bib_ref] See Online Data Supplements 19 and 20.
Tobacco use is a strong risk factor for the development and progression of PAD. [bib_ref] Influence of smoking on incidence and prevalence of peripheral arterial disease, Willigendael [/bib_ref] [bib_ref] The contribution of tobacco use to high health care utilization and medical..., Duval [/bib_ref] Sparse evidence exists with regard to the association of novel tobacco product use, including electronic cigarettes, and PAD. [bib_ref] Electronic cigarettes: a policy statement from the, Bhatnagar [/bib_ref] Observational studies suggest that smoking cessation is associated with lower rates of cardiovascular ischemic events, limb-related events, bypass graft failure, amputation, and death in patients with PAD. [bib_ref] Variation in smoking cessation after vascular operations, Hoel [/bib_ref] [bib_ref] Smoking cessation is associated with decreased mortality and improved amputation-free survival among..., Armstrong [/bib_ref] [bib_ref] Association of smoking cessation and weight change with cardiovascular disease among adults..., Clair [/bib_ref] [bib_ref] Preoperative smoking is associated with early graft failure after infrainguinal bypass surgery, Selvarajah [/bib_ref] Clinician advice increases quit rates, which supports simple provider-based measures as a component of smoking cessation programs. 22,171,179
## I a
Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (ie, varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program. [bib_ref] Effectiveness of a smoking cessation program for peripheral artery disease patients: a..., Hennrikus [/bib_ref] [bib_ref] Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular..., Rigotti [/bib_ref] [bib_ref] Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized..., Rigotti [/bib_ref] [bib_ref] Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre,..., Tonstad [/bib_ref] See Online Data Supplements 19 and 20.
Coordinated smoking cessation interventions that include nonpharmacological and pharmacological approaches have the greatest efficacy. An RCT of a follow-up program and smoking cessation medications provided to hospitalized patients, including those with PAD, demonstrated a modest increase in quit rates. [bib_ref] Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized..., Rigotti [/bib_ref] In an RCT of patients with PAD specifically, a comprehensive smoking cessation program combining counseling and pharmacological agents increased the rates of smoking cessation to 21.3%, compared with 6.8% with standard advice. [bib_ref] Effectiveness of a smoking cessation program for peripheral artery disease patients: a..., Hennrikus [/bib_ref] Three pharmacological approaches (ie, varenicline, bupropion, and nicotine replacement therapy) used alone or in combination all increase smoking cessation rates. [bib_ref] Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular..., Rigotti [/bib_ref] [bib_ref] Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre,..., Tonstad [/bib_ref] Two meta-analyses of RCTs of smoking cessation medications showed no evidence of increased cardiovascular event rates with nicotine replacement, bupropion, or varenicline. [bib_ref] Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis, Mills [/bib_ref] [bib_ref] Risk of cardiovascular serious adverse events associated with varenicline use for tobacco..., Prochaska [/bib_ref] Sparse data suggest that electronic cigarettes have no benefit on smoking cessation rates. 179
## I b-nr
Patients with PAD should avoid exposure to environmental tobacco smoke at work, at home, and in public places. [bib_ref] Association between smoke-free legislation and hospitalizations for cardiac, cerebrovascular, and respiratory diseases:..., Tan [/bib_ref] [bib_ref] Association between level of exposure to secondhand smoke and peripheral arterial disease:..., Lu [/bib_ref] See Online Data Supplement 20.
Passive smoke exposure has been associated with the development of PAD. [bib_ref] Association between level of exposure to secondhand smoke and peripheral arterial disease:..., Lu [/bib_ref] Observational studies have shown lower cardiovascular and cerebrovascular event rates in the general population after enactment of smoke-free legislation. [bib_ref] Association between smoke-free legislation and hospitalizations for cardiac, cerebrovascular, and respiratory diseases:..., Tan [/bib_ref] The effects of avoidance of passive smoke exposure on limb-related events are not known. [bib_ref] Association of elevated fasting glucose with lower patency and increased major adverse..., Singh [/bib_ref] [bib_ref] The influence of glycemic control on the prognosis of Japanese patients undergoing..., Takahara [/bib_ref] See Online Data Supplement 22.
## Glycemic control: recommendations
In a cohort of 1974 participants with diabetes mellitus from the Strong Heart Study, compared with patients without PAD, patients with PAD and a Hg A1c level <6.5% had lower ageadjusted odds of major amputation compared to patients with PAD and hemoglobin A1c 6.5% to 9.5% and hemoglobin A1c >9.5%. [bib_ref] Relationship of high and low ankle brachial index to all-cause and cardiovascular..., Resnick [/bib_ref] Glycemic control is particularly important for patients with PAD and diabetes mellitus who have CLI. Single-center observational studies have demonstrated improved limb-related outcomes, including lower rates of major amputation and improved patency after infrapopliteal intervention, among patients with CLI who have more optimized glycemic control parameters compared with patients with inferior glycemic control. [bib_ref] Association of elevated fasting glucose with lower patency and increased major adverse..., Singh [/bib_ref] [bib_ref] The influence of glycemic control on the prognosis of Japanese patients undergoing..., Takahara [/bib_ref]
## Oral anticoagulation: recommendations
## Recommendations for oral anticoagulation
## Cor loe recommendations
IIb B-R The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain. [bib_ref] Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk..., Sarac [/bib_ref] [bib_ref] Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery, Bedenis [/bib_ref] See Online Data Supplements 23 and 24.
Two RCTs evaluating the effectiveness of oral anticoagulation (warfarin) in improving lower extremity bypass patency demonstrated improved patency among the subgroup of patients with autogenous vein bypass grafts. [bib_ref] Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk..., Sarac [/bib_ref] However, a Cochrane systematic review showed no patency benefit with the use of anticoagulation compared with antiplatelet therapy. [bib_ref] Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery, Bedenis [/bib_ref] All RCTs and observational studies evaluating the effect of anticoagulants on bypass patency demonstrated increased bleeding complications associated with anticoagulant use. One RCT evaluating the effectiveness of oral anticoagulation (warfarin) in addition to aspirin in improving lower extremity bypass patency demonstrated improved patency in a subgroup of patients with 6-mm polytetrafluoroethylene (known as PTFE) bypass graft. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref] Randomization to anticoagulation plus aspirin was associated with increased risk of death and major hemorrhage versus aspirin alone.
## Iii: harm
A Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref] [bib_ref] Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, Alonso-Coello [/bib_ref] [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] See Online Data Supplements 23 and 24
RCTs and observational studies have uniformly demonstrated that oral anticoagulation therapy aimed at decreasing major cardiovascular ischemic events provided no benefit and resulted in increased morbidity. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref] [bib_ref] Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, Alonso-Coello [/bib_ref] [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] In the WAVE (Warfarin Antiplatelet Vascular Evaluation) trial of patients with atherosclerotic vascular disease, including PAD, there was no difference in cardiovascular ischemic events among patients randomized to oral anticoagulation and antiplatelet therapy versus antiplatelet therapy alone. [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] In addition, there was an increase in bleeding endpoints including lifethreatening and intracranial bleeding. [bib_ref] Oral anticoagulant and antiplatelet therapy and peripheral arterial disease, Anand [/bib_ref] One RCT demonstrated increased death rate among patients randomized to warfarin plus aspirin versus aspirin alone after lower extremity bypass grafting. [bib_ref] Department of Veterans Affairs Cooporative Study #362Benefits, morbidity, and mortality associated with..., Johnson [/bib_ref]
## Cilostazol: recommendation
Recommendation for Cilostazol COR LOE Recommendation I A Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication. [bib_ref] Cilostazol for intermittent claudication, Bedenis [/bib_ref] [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] See Online Data Supplement 25.
In a Cochrane review including 15 double-blind RCTs with a total of 3718 participants, cilostazol was associated with improvement in claudication symptoms but no changes in et al.
## Page 15
Circulation. Author manuscript; available in PMC 2017 September 21. cardiovascular deaths or QoL when compared with placebo. [bib_ref] Cilostazol for intermittent claudication, Bedenis [/bib_ref] In 1 RCT, cilostazol was more effective than pentoxifylline or placebo. [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] Side effects include headache, abnormal stool (diarrhea), dizziness, and palpitations. Cilostazol is contraindicated in patients with congestive heart failure.In 1 trial, 20% of patients discontinued cilostazol within 3 months. 202
## Pentoxifylline: recommendation
Recommendation for Pentoxifylline COR LOE Recommendation III: No Benefit B-R Pentoxifylline is not effective for treatment of claudication. [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] [bib_ref] Pentoxifylline for intermittent claudication, Salhiyyah [/bib_ref] See Online Data Supplement 26.
In a Cochrane review of 24 studies with 3377 participants, there was large variability in study design and results between individual studies, and therefore the review's effectiveness was unclear. [bib_ref] Pentoxifylline for intermittent claudication, Salhiyyah [/bib_ref] Pentoxifylline was shown to be generally well tolerated. [bib_ref] Pentoxifylline for intermittent claudication, Salhiyyah [/bib_ref] In a multicenter RCT of pentoxifylline, cilostazol, or placebo for patients with moderate-to-severe claudication, there was no difference between pentoxifylline and placebo in the primary endpoint of maximal walking distance. [bib_ref] A comparison of cilostazol and pentoxifylline for treating intermittent claudication, Dawson [/bib_ref] Therefore, pentoxifylline is not recommended as treatment for claudication.
## Chelation therapy: recommendation
Recommendation for Chelation Therapy
## Cor loe recommendation
## Iii: no benefit b-r chelation therapy (eg, ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication. 204
See Online Data Supplement 27.
In a Cochrane review of 5 studies with 260 participants, chelation therapy showed no significant difference in symptoms (maximal and pain-free walking distance) compared with placebo. 204
## Homocysteine lowering: recommendation
## Recommendation for homocysteine lowering
## Cor loe recommendation
## Iii: no benefit b-r
B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended. [bib_ref] Rationale, design and baseline characteristics of a large, simple, randomized trial of..., Lonn [/bib_ref] [bib_ref] Homocysteine lowering with folic acid and B vitamins in vascular disease, Lonn [/bib_ref] [bib_ref] Homocysteine and peripheral arterial disease: systematic review and meta-analysis, Khandanpour [/bib_ref] See Online Data Supplements 28 and 29.
Although patients with PAD have been shown to have increased plasma homocysteine levels compared with patients without PAD, there is no evidence that B-complex vitamin supplementation improves clinical outcomes in patients with PAD. [bib_ref] Homocysteine and peripheral arterial disease: systematic review and meta-analysis, Khandanpour [/bib_ref] The HOPE-2 trial randomized 5522 patients with atherosclerotic vascular disease, including symptomatic PAD, or diabetes mellitus with additional risk factors to receive folic acid/vitamin B6/vitamin B12 or placebo. [bib_ref] Rationale, design and baseline characteristics of a large, simple, randomized trial of..., Lonn [/bib_ref] [bib_ref] Homocysteine lowering with folic acid and B vitamins in vascular disease, Lonn [/bib_ref] Despite lowering of homocysteine levels in the vitamin supplementation arm, there was no improvement in the primary endpoint of cardiovascular death, MI, or stroke. Observational studies have demonstrated reduced cardiovascular event rates among patients with cardiovascular disease who have received an influenza vaccination. Two RCTs that enrolled patients with CAD demonstrated a benefit of an influenza vaccination on the prevention of cardiovascular events, particularly coronary ischemic events. [bib_ref] Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS)..., Gurfinkel [/bib_ref] [bib_ref] Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery..., Ciszewski [/bib_ref] Although these trials did not specifically enroll participants with PAD, a majority of patients with PAD also have CAD. On the basis of this evidence, an annual influenza vaccination is recommended as a component of medical therapy for patients with PAD.
## Influenza vaccination: recommendation
## Structured exercise therapy: recommendations
Structured exercise therapy is an important element of care for the patient with PAD. Components of structured exercise programs for PAD are outlined in . The data supporting the efficacy of supervised exercise training as an initial treatment for claudication continue to develop and remain convincing, building on many earlier RCTs. 40-46,48,210,211 Trials with long-term follow-up from 18 months 37,38 to 7 years 36 have demonstrated a persistent benefit of supervised exercise in patients with claudication. Data also support a benefit of supervised exercise for patients with symptomatic PAD and diabetes mellitus. [bib_ref] Diabetes status differentiates endothelial function and plasma nitrite response to exercise stress..., Allen [/bib_ref] The risk-benefit ratio for supervised exercise in PAD is favorable, with an excellent safety profile in patients screened for absolute contraindications to exercise such as exercise-limiting cardiovascular disease, amputation or wheelchair confinement, and other major comorbidities that would preclude exercise. 36,39,49,213-216 Despite the health benefits associated with supervised exercise in patients with PAD, initiating and maintaining a high level of adherence remain challenging. Frequent contact with patients both when performing exercise in the supervised setting and at home has been somewhat effective in promoting retention. 37,38 I B-R A supervised exercise program should be discussed as a treatment option for claudication before possible revascularization. See Online Data Supplement 32.
## Recommendations for structured exercise
The CLEVER (Claudication: Exercise Versus Endoluminal Revascularization) trial randomized patients with symptomatic aortoiliac PAD and showed comparable benefits for supervised exercise and stent revascularization at 6 and 18 months, with each therapy being superior to optimal medical care. 37,38 Overall, the safety profile for supervised exercise was excellent. An RCT that compared 7-year effectiveness of supervised exercise or endovascular revascularization in patients with stable claudication with iliac or femoropopliteal disease found no differences in improved walking and QoL outcomes. Although more secondary interventions occurred in the exercise group, the total number of interventions was greater in the endovascular revascularization group. Collectively, these studies provide strong support for offering patients a supervised exercise program for reducing claudication symptoms and for improving functional status and QoL.
A 3-month RCT that compared percutaneous transluminal angioplasty (PTA), supervised exercise, and combined treatment for claudication found that both supervised exercise and PTA improved clinical and QoL outcomes, whereas PTA plus supervised exercise produced greater benefits than either therapy alone. [bib_ref] Early outcomes from a randomized, controlled trial of supervised exercise, angioplasty, and..., Mazari [/bib_ref] The ERASE (Endovascular Revascularization and Supervised Exercise) study randomized participants with claudication to endovascular revascularization plus supervised exercise or supervised exercise alone. After 1 year, patients in both groups had significant improvements in walking distances and health-related QoL, with greater improvements in the combined-therapy group. [bib_ref] Endovascular revascularization and supervised exercise for peripheral artery disease and intermittent claudication:..., Fakhry [/bib_ref] Collectively, these studies support the continued provision of supervised exercise to patients with claudication, whether as a monotherapy or combined with revascularization. Unstructured community-based or home-based walking programs that consist of providing general recommendations to patients with claudication to simply walk more are not efficacious. 50 Studies supporting structured community-or home-based programs for patients with symptomatic PAD (claudication and/or leg symptoms atypical for claudication) are more recent than studies supporting supervised exercise programs, and have provided strong evidence in support of the community-or home-based approach. 47,49,51,88,94,213 For example, the GOALS (Group Oriented Arterial Leg Study) trial 94 included patients with confirmed PAD with and without claudication (atypical lower extremity symptoms or no symptoms) and showed increases in several parameters of functional status for both of these patient cohort subgroups, versus nonexercising controls, after 6 months, 88 with improvement maintained at 12 months. 94
As with supervised exercise programs, despite proven benefit, initiating and maintaining a high level of adherence to community-or home-based exercise programs remains challenging. Studies that have incorporated behavioral change techniques, such as health coaching and activity tracking used in supervised settings, appear to reduce attrition and promote higher levels of adherence, thereby improving functional and QoL outcomes, both short term and long term. Hg, white blood cell count >12 000 or <4000/mcL or >10% immature forms). 226 Probe-tobone test is moderately predictive for osteomyelitis but is not pathognomonic. 227
## Iia c-ld in patients with pad and signs of foot infection, prompt referral to an interdisciplinary care team (
## N/a
A history of foot ulcers, foot infections, or amputation identifies patients with a very high (>10%) yearly incidence of recurrent ulcers. 231 Examination includes a visual inspection for foot ulcers (full-thickness epithelial defects) and structural (bony) deformities, monofilament testing for sensory neuropathy, and palpation for pedal pulses.
## Revascularization for claudication
An individualized approach to revascularization for claudication is recommended for each patient to optimize outcome. Revascularization is but one component of care for the patient with claudication, as each patient should have a customized care plan that also includes medical therapy (Section 5), structured exercise therapy (Section 6), and care to minimize tissue loss (Section 7). If a strategy of revascularization for claudication is undertaken, the revascularization strategy should be evidence based and can include endovascular revascularization, surgery, or both.
Because of the variability of ischemic limb symptoms and impact of these symptoms on functional status and QoL, patients should be selected for revascularization on the basis of severity of their symptoms. Factors to consider include a significant disability as assessed by the patient, adequacy of response to medical and structured exercise therapy, status of comorbid conditions, and a favorable risk-benefit ratio. Patient preferences and goals of care are important considerations in the evaluation for revascularization. The revascularization strategy should have a reasonable likelihood of providing durable relief of symptoms. A general recommendation for revascularization as a treatment option for claudication is provided below followed by specific recommendations for endovascular (Section 8. A minority of patients with claudication (estimated at <10% to 15% over 5 years or more) will progress to CLI. 234-237 Therefore, the role of revascularization in claudication is improvement in claudication symptoms and functional status, and consequently in QoL, rather than limb salvage. Revascularization is reasonable when the patient who is being treated with GDMT (including structured exercise therapy) presents with persistent lifestyle-limiting claudication. 12,37,38,232,233 Lifestyle-limiting claudication is defined by the patient rather than by any test. It includes impairment of activities of daily living and/ or vocational and/or recreational activities due to claudication. There should be clear discussion with the patient about expected risks and benefits of revascularization, as well as discussion of the durability of proposed procedures.
## Endovascular revascularization for claudication: recommendations-
Endovascular techniques to treat claudication include balloon dilation (angioplasty), stents, and atherectomy. These techniques continue to involve and now include covered stents, drug-eluting stents (DES), cutting balloons, and drug-coated balloons. The technique chosen for endovascular treatment is related to lesion characteristics (eg, anatomic location, lesion length, degree of calcification) and operator experience. Assessment of the appropriateness of specific endovascular techniques for specific lesions for the treatment of claudication is beyond the scope of this document.
Revascularization is performed on lesions that are deemed to be hemodynamically significant, and stenoses selected for endovascular treatment should have a reasonable likelihood of limiting perfusion to the distal limb. Stenoses of 50% to 75% diameter by angiography may not be hemodynamically significant, and resting or provoked intravascular pressure measurements may be used to determine whether lesions are significant. The durability of endovascular treatment for claudication is directly related to vessel patency. Long-term patency is greater in the iliac artery than in the femoropopliteal segment. Furthermore, durability is diminished with greater lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poorquality runoff, diabetes mellitus, chronic kidney disease, renal failure, and smoking. The choice of endovascular therapy as a revascularization approach for claudication due to femoropopliteal disease therefore should include a discussion of outcomes, addressing the risk of restenosis and repeat intervention, particularly for lesions with poor likelihood of long-term durability.
## Iib c-ld
The usefulness of endovascular procedures as a revascularization option for patients with claudication due to isolated infrapopliteal artery disease is unknown. [bib_ref] Paclitaxel-coated balloon angioplasty versus drugeluting stenting for the treatment of infrapopliteal long-segment..., Siablis [/bib_ref] See Online Data Supplement 35.
Isolated infrapopliteal disease is unlikely to cause claudication. Incidence of in-stent restenosis is high and long-term benefit lacking with bare-metal stenting of the infrapopliteal arteries. Studies that have enrolled patients with claudication as well as CLI have demonstrated a benefit of DES versus bare-metal stents or versus drug-coated balloons for revascularization of infrapopliteal lesions. 257,258 However, these differences were mainly for patency and restenosis endpoints, and neither of these studies included patient-oriented outcomes, such as walking function or QoL parameters. Additional efficacy data on the use of infrapopliteal drug-coated balloon or DES for the treatment of claudication are likely to be published in the near future. There are no data to support a practice paradigm of performing endovascular procedures on patients with PAD for the purpose of preventing progression of claudication symptoms to CLI. Reported rates of amputation or progression to CLI from prospective cohort studies of patients with claudication are <10% to 15% over 5 years or more, and increased mortality rate associated with claudication is usually the result of cardiovascular events rather than limb-related events. [bib_ref] Intermittent claudication. Incidence in the Framingham Study, Kannel [/bib_ref] Similarly, there are no data to support revascularization in patients with asymptomatic PAD. Procedural risks include bleeding, renal failure from contrast-induced nephropathy, and the possibility of adverse limb outcomes. [bib_ref] Trends in the national outcomes and costs for claudication and limb threatening..., Sachs [/bib_ref] [bib_ref] Predictors of distal embolization in peripheral percutaneous interventions: a report from a..., Shammas [/bib_ref] [bib_ref] Complications of lower-limb percutaneous transluminal angioplasty: a prospective analysis of 410 procedures..., Matsi [/bib_ref] Therefore, the known risks of endovascular procedures outweigh any hypothetical benefit of preventing progression from asymptomatic PAD or claudication to CLI.
## Surgical revascularization for claudication: recommendations
## Recommendations for surgical revascularization for claudication
## Cor loe recommendations
I A When surgical revascularization is performed, bypass to the popliteal artery with autogenous vein is recommended in preference to prosthetic graft material. [bib_ref] Prospective controlled study of polytetrafluoroethylene versus saphenous vein in claudicant patients with..., Aburahma [/bib_ref] [bib_ref] Femoropopliteal bypass with either adequate ipsilater-al reversed saphenous vein or obligatory polytetrafluoroethylene, Archie [/bib_ref] [bib_ref] Ten years after arterial bypass surgery for claudication: venous bypass is the..., Eugster [/bib_ref] [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] [bib_ref] Patency results of percutaneous and surgical revascularization for femoropopliteal arterial disease, Hunink [/bib_ref] [bib_ref] Comparative evaluation of externally supported Dacron and polytetrafluoroethylene prosthetic bypasses for femorofemoral..., Johnson [/bib_ref] [bib_ref] Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a..., Klinkert [/bib_ref] [bib_ref] Graft type for femoro-popliteal bypass surgery, Twine [/bib_ref] [bib_ref] Meta-analysis of femoropopliteal bypass grafts for lower extremity arterial insufficiency, Pereira [/bib_ref] See Online Data Supplements 37 and 38.
The superficial femoral and proximal popliteal arteries are the most common anatomic sites of stenosis or occlusion among individuals with claudication. Femoral-popliteal bypass is therefore one of the most common surgical procedures for claudication and may be performed under general or regional anesthesia. The type of conduit and site of et al.
## Page 21
Circulation. Author manuscript; available in PMC 2017 September 21.
popliteal artery anastomosis (above versus below knee) are major determinants of outcomes associated with femoral-popliteal bypass. Systematic reviews and metaanalyses have identified a clear and consistent primary patency benefit for autogenous vein versus to prosthetic grafts for popliteal artery bypass. [bib_ref] Graft type for femoro-popliteal bypass surgery, Twine [/bib_ref] [bib_ref] Meta-analysis of femoropopliteal bypass grafts for lower extremity arterial insufficiency, Pereira [/bib_ref] Prosthetic grafts to the popliteal artery above the knee have reduced patency rates and increased rates of repeat intervention. [bib_ref] Prospective controlled study of polytetrafluoroethylene versus saphenous vein in claudicant patients with..., Aburahma [/bib_ref] [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] [bib_ref] Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a..., Klinkert [/bib_ref] [bib_ref] A comparative evaluation of polytetrafluoroethylene, umbilical vein, and saphenous vein bypass grafts..., Johnson [/bib_ref] Sparse evidence suggests a long-term patency advantage for Dacron over polytetrafluoroethylene (known as PTFE) graft for above-knee bypass, [bib_ref] Graft type for femoro-popliteal bypass surgery, Twine [/bib_ref] although this finding has not been consistently demonstrated in all RCTs. [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] Claudication does not commonly progress to CLI. Reported rates of amputation or progression to CLI from prospective cohort studies of patients with claudication are <10% to 15% for 5 years or more, and increased mortality rate associated with claudication is usually the result of cardiovascular events rather than limb-related events. 234-237, [bib_ref] Intermittent claudication. Incidence in the Framingham Study, Kannel [/bib_ref] Surgical intervention should not be performed primarily to prevent disease progression, given the risk of adverse perioperative events without potential for significant benefit. Similarly, there are no data to support surgical revascularization in patients with asymptomatic PAD to prevent progression to CLI.
## Management of cli
Patients with CLI are at increased risk of amputation and major cardiovascular ischemic events. Care of the patient with CLI includes evaluation for revascularization and wound healing therapies, with the objective to minimize tissue loss, completely heal wounds, and preserve a functional foot. Medical therapy to prevent cardiovascular ischemic events is also an important component of care for the patient with CLI (Section 5). Patients with CLI are at high risk of major cardiovascular ischemic events, as well as nonhealing wounds and major amputation. In a systematic review of 13 studies of patients with CLI who did not receive revascularization, which included patients enrolled in medical and angiogenic therapy trials, there was a 22% all-cause mortality rate and a 22% rate of major amputation at a median follow-up of 12 months. [bib_ref] The natural history of untreated severe or critical limb ischemia, Dabrh [/bib_ref] The goal of surgical or endovascular revascularization is to provide in-line blood flow to the foot through at least 1 patent artery, which will help decrease ischemic pain and allow healing of any wounds, while preserving a functional limb. Multiple RCTs comparing contemporary surgical and endovascular treatment for patients with CLI are ongoing. 15-17 Revascularization is not warranted in the setting of a nonviable limb.
## Revascularization for cli: recommendations
## I c-eo
An evaluation for revascularization options should be performed by an interdisciplinary care team [fig_ref] Table 9: can be beneficial [/fig_ref] before amputation in the patient with CLI.
## N/a
Patients with CLI should be evaluated by an interdisciplinary care team. Before amputation, evaluation generally includes imaging for assessment of revascularization options (eg, duplex ultrasound, CTA, MRA, or catheter-based angiogram). The objective of this strategy is to minimize tissue loss and preserve a functional limb with revascularization.
## Endovascular revascularization for cli: recommendations
## Iia c-ld
A staged approach to endovascular procedures is reasonable in patients with ischemic rest pain. [bib_ref] Complex endovascular treatment for critical limb ischemia in poor surgical candidates: a..., Gray [/bib_ref] [bib_ref] Analysis of outcomes following failed endovascular treatment of chronic limb ischemia, Ryer [/bib_ref] N/A For patients with multilevel disease who suffer from ischemic rest pain, in-flow lesions are generally addressed first. [bib_ref] Complex endovascular treatment for critical limb ischemia in poor surgical candidates: a..., Gray [/bib_ref] [bib_ref] Analysis of outcomes following failed endovascular treatment of chronic limb ischemia, Ryer [/bib_ref] Depending on procedural characteristics, including contrast volume used, radiation exposure, and procedure time, out-flow lesions can be addressed in the same setting or at a later time if symptoms persist. This strategy for ischemic rest pain is distinct from the strategy recommended for CLI in the patient with a nonhealing wound or gangrene. In that scenario, restoration of direct in-line flow to the foot is essential for wound healing.
IIa B-R Evaluation of lesion characteristics can be useful in selecting the endovascular approach for CLI. [bib_ref] Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon..., Schillinger [/bib_ref] See Online Data Supplement 39.
The lesion characteristics to consider include length, anatomic location, and extent of occlusive disease. For example, if an adequate angioplasty result can be achieved with PTA alone for short (<10 cm) stenoses in the femoropopliteal segment, then stent placement is not necessary. [bib_ref] Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon..., Schillinger [/bib_ref] Presence of thrombosis or calcification at the lesion site will also affect the endovascular approach. In general, the advantages of DES and drug-coated balloons over PTA alone or bare-metal stents are more consistent in the femoropopliteal segment than for infrapopliteal interventions. 257,258,299-309 However, these differences are mainly for patency, restenosis, and repeat-revascularization endpoints. Most studies were underpowered or did not examine other patient-oriented outcomes, such as amputation or wound healing in CLI. Endovascular techniques continue to evolve rapidly, and there has been limited literature comparing techniques with regard to clinically significant outcomes, such as amputation or wound healing. During the past decade, the goal of care with regard to endovascular therapy for the treatment of nonhealing wounds due to CLI has been establishment of direct in-line blood flow to the affected limb. The angiosome concept has also been described in the literature in relation to the treatment of nonhealing wounds. Angiosome-directed treatment entails establishing direct blood flow to the infrapopliteal artery directly responsible for perfusing the region of the leg or foot with the nonhealing wound. Multiple retrospective studies and 1 small nonrandomized prospective study assessing the efficacy of this concept have been published. [bib_ref] Angiosome-targeted infrapopliteal endovascular revascularization for treatment of diabetic foot ulcers, Söderstrom [/bib_ref] [bib_ref] Results of infrapopliteal endovascular procedures performed in diabetic patients with critical limb..., Acín [/bib_ref] [bib_ref] Selective primary angioplasty following an angiosome model of reperfusion in the treatment..., Alexandrescu [/bib_ref] [bib_ref] Factors influencing wound healing of critical ischaemic foot after bypass surgery: is..., Azuma [/bib_ref] [bib_ref] Endovascular treatment of diabetic foot in a selected population of patients with..., Fossaceca [/bib_ref] [bib_ref] Long-term results of direct and indirect endovascular revascularization based on the angiosome..., Iida [/bib_ref] [bib_ref] Outcomes of angiosome and non-angiosome targeted revascularization in critical lower limb ischemia, Kabra [/bib_ref] [bib_ref] Utility of direct angiosome revascularization and runoff scores in predicting outcomes in..., Kret [/bib_ref] [bib_ref] Long-term outcomes of direct and indirect below-the-knee open revascularization based on the..., Lejay [/bib_ref] [bib_ref] Revascularization of a specific angiosome for limb salvage: does the target artery..., Neville [/bib_ref] [bib_ref] Importance of the six angio-somes concept through arterialarterial connections in CLI, Osawa [/bib_ref] [bib_ref] The impact of arterial pedal arch quality and angiosome revascularization on foot..., Rashid [/bib_ref] [bib_ref] The role of foot collateral vessels on ulcer healing and limb salvage..., Varela [/bib_ref] Metaanalyses of these studies found improved wound healing and limb salvage with angiosomeguided therapy but cautioned that the quality of the evidence was low. [bib_ref] Systematic review and meta-analysis of direct versus indirect angiosomal revascularisation of infrapopliteal..., Bosanquet [/bib_ref] [bib_ref] Angiosome-targeted lower limb revascularization for ischemic foot wounds: systematic review and metaanalysis, Biancari [/bib_ref] Although the angiosome concept is theoretically satisfying, randomized data comparing the establishment of in-line flow versus angiosome-guided therapy have yet to be published. Furthermore, there is no evidence yet to demonstrate the potential benefit of treating additional infrapopliteal arteries once in-line flow has been established in one artery, regardless of angiosome. Important considerations with regard to angiosome-guided therapy include the potential for longer procedural times, more contrast exposure, and more technically complex procedures. The impact of all these factors needs to be weighed against the likelihood of a technically successful procedure providing hypothetical added benefit over the establishment of in-line blood flow. Many large RCTs have demonstrated that bypasses above the knee should be autogenous vein either reversed or in situ vein. [bib_ref] Prospective controlled study of polytetrafluoroethylene versus saphenous vein in claudicant patients with..., Aburahma [/bib_ref] [bib_ref] Prosthetic above-knee femoropopliteal bypass grafting: five-year results of a randomized trial, Green [/bib_ref] [bib_ref] Vein versus polytetrafluoroethylene in above-knee femoropopliteal bypass grafting: five-year results of a..., Klinkert [/bib_ref] [bib_ref] A comparative evaluation of polytetrafluoroethylene, umbilical vein, and saphenous vein bypass grafts..., Johnson [/bib_ref] There are large single-center trials showing the efficacy of autogenous vein to distal tibial vessels. [bib_ref] Present status of infrainguinal arterial bypass procedures following an all autogenous policy-long-term..., Eugster [/bib_ref] [bib_ref] Contemporary outcomes for open infrainguinal bypass in the endovascular era, Reifsnyder [/bib_ref] In addition, composite sequential femoropopliteal-tibial bypass and bypass to an isolated popliteal arterial segment that has collateral out flow to the foot are both acceptable methods of revascularization and should be considered when no other form of bypass with adequate autogenous conduit is possible. [bib_ref] Autogenous composite vein bypass graft for infrainguinal arterial reconstruction, Chew [/bib_ref] [bib_ref] Preferred strategies for secondary infrainguinal bypass: lessons learned from 300 consecutive reoperations, Belkin [/bib_ref] I C-LD Surgical procedures are recommended to establish in-line blood flow to the foot in patients with nonhealing wounds or gangrene. [bib_ref] A comparison of in situ and reversed saphenous vein grafts for infrainguinal..., Fogle [/bib_ref] [bib_ref] In-situ saphenous vein arterial bypass for the treatment of limb ischemia, Leather [/bib_ref] [bib_ref] Present status of reversed vein bypass grafting: five-year results of a modern..., Taylor [/bib_ref] See Online Data Supplement 42.
## Surgical revascularization for cli: recommendations
In patients presenting with nonhealing ulcers or gangrene, surgical procedures should be performed to establish in-line blood flow to the foot. [bib_ref] A comparison of in situ and reversed saphenous vein grafts for infrainguinal..., Fogle [/bib_ref] [bib_ref] In-situ saphenous vein arterial bypass for the treatment of limb ischemia, Leather [/bib_ref] [bib_ref] Present status of reversed vein bypass grafting: five-year results of a modern..., Taylor [/bib_ref] Table 10 addresses factors that may prompt a surgical approach to the patient with CLI.
## Iia b-nr
In patients with CLI for whom endovascular revascularization has failed and a suitable autogenous vein is not available, prosthetic material can be effective for bypass to the below-knee popliteal and tibial arteries. [bib_ref] Prior failed ipsilateral percutaneous endovascular intervention in patients with critical limb ischemia..., Nolan [/bib_ref] [bib_ref] Lower extremity autologous vein bypass for critical limb ischemia is not adversely..., Santo [/bib_ref] [bib_ref] Pedal bypass surgery after crural endovascular intervention, Uhl [/bib_ref] See Online Data Supplement 42.
There are studies demonstrating that patients for whom endovascular treatment for CLI has failed can be treated successfully with autogenous vein bypass graft 332,333 or prosthetic material. [bib_ref] Prior failed ipsilateral percutaneous endovascular intervention in patients with critical limb ischemia..., Nolan [/bib_ref] Although autogenous vein is the preferred conduit for surgical revascularization, prosthetic conduit is a secondary option for patients with CLI without suitable saphenous vein who require surgical revascularization.
## Iia c-ld
A staged approach to surgical procedures is reasonable in patients with ischemic rest pain. [bib_ref] The role of common femoral artery endarterectomy in the endovascular era, Nishibe [/bib_ref] [bib_ref] Long-term results of a hybrid revascularization procedure for peripheral arterial disease, Okadome [/bib_ref] [bib_ref] Hybrid and open surgery of Trans-Atlantic Inter-Society II type C and D..., Starodubtsev [/bib_ref] N/A It is reasonable to perform a staged approach to revascularization in patients with ischemic rest pain with multilevel disease. For example, aortoiliac (inflow) disease may be treated first with endovascular treatment or by surgical reconstruction, depending on lesion characteristics, patient comorbidities, and patient preference. [bib_ref] Seven-year approach evolution of the aortoiliac occlusive disease endovascular treatment, Kasemi [/bib_ref] The management of patients with CLI and nonhealing wounds should include coordinated efforts for both revascularization and wound healing, because the risk of limb-threatening infections remains until complete wound healing is achieved. The structure and activities of interdisciplinary care teams for CLI may vary according to several factors, including the local availability of resources. Previous groups have described various combinations of activities of this team, which are in addition to revascularization and include functions such as wound care, infection management, orthotics, and prosthetics (see Online Data Supplement 34a for a complete list of functions). Coordination of these activities and some degree of organized team structure are recommended, as opposed to ad hoc or unstructured referrals among various specialty clinicians not involved in interdisciplinary care.
Ambulatory patients with PAD and nonhealing foot ulcers should be considered for efforts to prevent amputation. The components of this effort may include revascularization, offloading, treatment of infection, and wound care. The long-term outcome of the limb is excellent when complete wound healing can be achieved. [bib_ref] Prognosis of critical limb ischemia patients with tissue loss after achievement of..., Kobayashi [/bib_ref] Revascularization should be coordinated with the efforts of clinicians who manage foot infections, provide offloading, and achieve complete wound healing, either through medical therapy, surgical options, or a combination thereof. Coordinated and timely interdisciplinary care can achieve excellent limb outcomes for patients with PAD and nonhealing foot wounds. 229,339-341
## I c-ld
In patients with CLI, wound care after revascularization should be performed with the goal of complete wound healing. [bib_ref] Prognosis of critical limb ischemia patients with tissue loss after achievement of..., Kobayashi [/bib_ref] See Online Data Supplement 44.
A comprehensive plan for treatment of CLI must include a plan for achieving an intact skin surface on a functional foot. One study demonstrated a limb salvage rate of 100% at 3 years in a cohort of patients with CLI who achieved complete wound healing with endovascular revascularization and dedicated wound care. [bib_ref] Prognosis of critical limb ischemia patients with tissue loss after achievement of..., Kobayashi [/bib_ref] Before revascularization, the interdisciplinary care team should devise a plan to achieve the goal of complete wound healing. After successful revascularization, most patients with gangrene of the foot are evaluated for minor amputation with staged/delayed primary closure or surgical reconstruction when feasible. [bib_ref] Surgical complications associated with primary closure in patients with diabetic foot osteomyelitis, García-Morales [/bib_ref] [bib_ref] Clinical outcomes after closed, staged, and open forefoot amputations, Berceli [/bib_ref] [bib_ref] Outcome of limited forefoot amputation with primary closure in patients with diabetes, Shaikh [/bib_ref] Negative-pressure wound therapy dressings are helpful to achieve wound healing after revascularization and minor (ie, digit or partial foot) amputation when primary or delayed secondary closure is not feasible. [bib_ref] Diabetic Foot Study ConsortiumNegative pressure wound therapy after partial diabetic foot amputation:..., Armstrong [/bib_ref] [bib_ref] Negative-pressure wound therapy versus standard wound dressing in the treatment of diabetic..., Sepúlveda [/bib_ref] Spontaneous amputation, or autoamputation, of gangrenous digits should be reserved for palliation in patients without options for revascularization. [bib_ref] Diabetic Foot Study ConsortiumNegative pressure wound therapy after partial diabetic foot amputation:..., Armstrong [/bib_ref] [bib_ref] Minor amputation and palliative wound care as a strategy to avoid major..., Barshes [/bib_ref] [bib_ref] Awaiting autoamputation: a primary management strategy for toe gangrene in diabetic foot..., Fikri [/bib_ref] Other evidence-based guidelines relevant to those with nonhealing foot wounds following revascularization cover the full spectrum of diabetic foot problems 349 or separately consider the management of infection, 225,350 offloading, [bib_ref] Footwear and offloading interventions to prevent and heal foot ulcers and reduce..., Bus [/bib_ref] and wound care. [bib_ref] IWGDF guidance on use of interventions to enhance the healing of chronic..., Game [/bib_ref] To date, there are no RCTs or high-quality studies that have focused on wound healing adjuncts in limbs with severe PAD (eg, topical cytokine ointments, skin substitutes, cell-based therapies intended to optimize wound healing).
## Iib b-nr
In patients with CLI, intermittent pneumatic compression (arterial pump) devices may be considered to augment wound healing and/or ameliorate severe ischemic rest pain. [bib_ref] A systematic review of intermittent pneumatic compression for critical limb ischaemia, Moran [/bib_ref] See Online Data Supplement 44.
A systematic review of studies that used intermittent pneumatic compression devices specifically designed to augment arterial perfusion of the lower extremities suggests that these may provide modest clinical benefit (specifically, decreased amputation rates and improved QoL) in patients with CLI who were ineligible for revascularization. [bib_ref] A systematic review of intermittent pneumatic compression for critical limb ischaemia, Moran [/bib_ref] The potential benefit appears to outweigh the low risk associated with the use of these devices. The literature evaluating the utility of hyperbaric oxygen therapy has focused on patients without severe PAD and has not demonstrated a long-term benefit on wound healing or improving amputation-free survival when compared with sham treatment. [bib_ref] Hyperbaric oxygen therapy for chronic wounds, Kranke [/bib_ref] There are no published studies evaluating the role of hyperbaric oxygen therapy for patients with nonreconstructible PAD. One small RCT that focused on patients with foot ulcers and PAD (ABI <0.80 or TBI <0.70) for whom no revascularization was planned demonstrated a significant decrease in ulcer area at 6 weeks, but no significant differences in ulcer size at 6 months, complete ulcer healing at 6 weeks or 6 months, and major or minor amputations. [bib_ref] The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers:..., Abidia [/bib_ref] Further research on the utility of hyperbaric oxygen therapy in this context is needed.
## Iib c-ld
## Iii: no benefit b-r prostanoids are not indicated in patients with cli. 356
See Online Data Supplement 43.
A systematic review and meta-analysis concluded that RCTs have not demonstrated meaningful long-term clinical benefit from the administration of prostanoids to patients with CLI attributable to nonreconstructible PAD. 356
## Management of ali
ALI is one of the most treatable and potentially devastating presentations of PAD. Timely recognition of arterial occlusion as the cause of an ischemic, cold, painful leg is crucial to successful treatment. The writing committee has used a standard definition of ALI in which symptom duration is <2 weeks (
## Clinical presentation of ali: recommendations
## Recommendations for clinical presentation of ali
## Cor loe recommendations
## I c-eo
Patients with ALI should be emergently evaluated by a clinician with sufficient experience to assess limb viability and implement appropriate therapy.
## N/a
Patients with ALI should be rapidly evaluated by a vascular specialist if one is available. Depending on local clinical expertise, the vascular specialist may be a vascular surgeon, interventional radiologist, cardiologist, or a general surgeon with specialized training and experience in treating PAD. If such expertise is not locally or rapidly available, there should be strong consideration of transfer of the patient to a facility with such resources. The more advanced the degree of ischemia, the more rapidly the communication (including communication about potential patient transfer) needs to occur.
## I c-ld
In patients with suspected ALI, initial clinical evaluation should rapidly assess limb viability and potential for salvage and does not require imaging. [bib_ref] Outcomes of lower extremity bypass performed for acute limb ischemia, Baril [/bib_ref] [bib_ref] Patient delay is the main cause of treatment delay in acute limb..., Londero [/bib_ref] [bib_ref] Analysis of associated diseases in patients with acute critical lower limb ischemia, Manojlović [/bib_ref] [bib_ref] The impact of prolonged lower limb ischemia on amputation, mortality, and functional..., Duval [/bib_ref] [bib_ref] Update experience of surgery for acute limb ischaemia in a district general..., Morris-Stiff [/bib_ref] See Online Data Supplements 45 and 46.
ALI is a medical emergency and must be recognized rapidly. The time constraint is due to the period that skeletal muscle will tolerate ischemia-roughly 4 to 6 hours. [bib_ref] The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review, Blaisdell [/bib_ref] A rapid assessment of limb viability and ability to restore arterial blood flow should be performed by a clinician able to either complete the revascularization or triage the patient. [bib_ref] Patient delay is the main cause of treatment delay in acute limb..., Londero [/bib_ref] Lower extremity symptoms in ALI can include both pain and loss of function. The longer these symptoms are present, the less likely the possibility of limb salvage. [bib_ref] The impact of prolonged lower limb ischemia on amputation, mortality, and functional..., Duval [/bib_ref] [bib_ref] Update experience of surgery for acute limb ischaemia in a district general..., Morris-Stiff [/bib_ref] Clinical assessment must include symptom duration, pain intensity, and motor and sensory deficit severity to distinguish a threatened from a nonviable extremity [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref]. The bedside assessment should include arterial and venous examination with a handheld continuous-wave Doppler because of the inaccuracy of pulse palpation. The loss of dopplerable arterial signal indicates that the limb is threatened. [bib_ref] Heparin-induced thrombocytopenia causing graft thrombosis and bowel ischemia postendovascular aneurysm repair, Altoijry [/bib_ref] [bib_ref] Catheter-directed thrombolysis of acute lower extremity arterial thrombosis in a patient with..., Turba [/bib_ref] In this situation, a direct thrombin inhibitor is given, rather than heparin, if heparin-induced thrombocytopenia with thrombosis is suspected.
## Revascularization for ali: recommendations
## Recommendations for revascularization for ali
## Cor loe recommendations
## I c-ld in patients with ali, the revascularization strategy should be determined by local resources and patient factors (eg, etiology and degree of ischemia). 367-369
See Online Data Supplement 47.
For marginally or immediately threatened limbs (Category IIa and IIb ALI [ [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref] , revascularization should be performed emergently (within 6 hours). For viable limbs (Category I ALI [ [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref] , revascularization should be performed an on urgent basis (within 6-24 hours). The revascularization strategy can range from catheter-directed thrombolysis to surgical thromboembolectomy. Available facilities and clinical expertise are factors that should be considered when determining the revascularization strategy. The technique that will provide the most rapid restoration of arterial flow with the least risk to the patient should be selected. For example, catheter-directed thrombolysis can provide rapid restoration of arterial flow to a viable or marginally threatened limb, particularly in the setting of recent occlusion, thrombosis of synthetic grafts, and stent thrombosis. [bib_ref] Results of a prospective, randomized trial of surgery versus thrombolysis for occluded..., Comerota [/bib_ref] If this is not available locally, surgical options for timely revascularization should be considered, along with the feasibility of timely transfer to a facility with the necessary expertise.
I A Catheter-based thrombolysis is effective for patients with ALI and a salvageable limb. [bib_ref] Results of a prospective, randomized trial of surgery versus thrombolysis for occluded..., Comerota [/bib_ref] [bib_ref] Assessment of peripheral intraarterial thrombolysis versus surgical revascularization in acute lower-limb ischemia:..., Diffin [/bib_ref] have demonstrated similar limb salvage rates between the 2 approaches but better survival with catheter-based therapy. The survival advantage of catheter-based therapy may be at least in part attributable to multiple comorbidities found among the population of patients who present with ALI. Increased comorbidities are likely to contribute to increased perioperative risk. Several of the RCTs included patients with relatively chronic ischemia. Acuity and severity are both factors in the decision to consider thrombolysis. 367,369-371 I C-LD Amputation should be performed as the first procedure in patients with a nonsalvageable limb. [bib_ref] Metabolic consequences of acute limb ischemia and their clinical implications, Eliason [/bib_ref] [bib_ref] Contemporary management of acute limb ischemia: factors associated with amputation and in-hospital..., Henke [/bib_ref] See Online Data Supplement 48.
For patients with Category III ALI [fig_ref] Figure 3: Diagnosis and Management of ALI [/fig_ref] , amputation should be performed as the index procedure. Prolonged duration of ischemia is the most common factor in patients requiring amputation for treatment of ALI. The risks associated with reconstruction outweigh the potential benefit in a limb that is already insensate or immobile because of prolonged ischemia. The lower extremity muscles reside in compartments, surrounded by fascia and bones. Reperfusion to ischemic muscles can cause cellular edema, resulting in increased compartment pressure. When compartment pressure is >30 mm Hg, there is capillary and venule compression that leads to malperfusion of the muscle; this is compartment syndrome. Fasciotomy is indicated when the compartment pressure increases. Measurement of intracompartment pressure is not always easily accessible. In such cases, evaluation for fasciotomy is prompted by development of increased pain, tense muscle, or nerve injury. Fasciotomy should be considered for patients with Category IIb ischemia for whom the time to revascularization is >4 hours.
## Iia b-nr
In patients with ALI with a salvageable limb, percutaneous mechanical thrombectomy can be useful as adjunctive therapy to thrombolysis. [bib_ref] Treatment of acute limb ischemia with a percutaneous mechanical thrombectomy-based endovascular approach:..., Ansel [/bib_ref] [bib_ref] Percutaneous isolated pharmaco-mechanical thrombolysis-thrombectomy system for the management of acute arterial limb..., Gupta [/bib_ref] [bib_ref] Rheolytic thrombectomy in the treatment of acute limbthreatening ischemia: immediate results and..., Silva [/bib_ref] [bib_ref] Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia, Taha [/bib_ref] [bib_ref] Rheolytic pharmacom-echanical thrombectomy for the management of acute limb ischemia: results from..., Leung [/bib_ref] See Online Data Supplements 49 and 50.
Multiple nonrandomized studies have suggested that percutaneous mechanical thrombectomy in combination with pharmacological therapy can be beneficial in the treatment of threatened limbs. [bib_ref] Treatment of acute limb ischemia with a percutaneous mechanical thrombectomy-based endovascular approach:..., Ansel [/bib_ref] [bib_ref] Percutaneous isolated pharmaco-mechanical thrombolysis-thrombectomy system for the management of acute arterial limb..., Gupta [/bib_ref] [bib_ref] Rheolytic thrombectomy in the treatment of acute limbthreatening ischemia: immediate results and..., Silva [/bib_ref] [bib_ref] Comparative effectiveness of endovascular versus surgical revascularization for acute lower extremity ischemia, Taha [/bib_ref] [bib_ref] Rheolytic pharmacom-echanical thrombectomy for the management of acute limb ischemia: results from..., Leung [/bib_ref] IIa C-LD In patients with ALI due to embolism and with a salvageable limb, surgical thromboembolectomy can be effective. [bib_ref] Factors affecting long-term outcomes after thromboembolectomy for acute lower limb ischemia, Zaraca [/bib_ref] [bib_ref] Management of non-traumatic acute limb ischemia and predictors of outcome in 270..., Topal [/bib_ref] [bib_ref] A method for extraction of arterial emboli and thrombi, Fogarty [/bib_ref] See Online Data Supplements 49 and 50.
Patients with arterial embolism and an absent pulse ipsilateral to the ischemic limb can be treated by exposure of an artery in the affected limb and balloon-catheter thromboembolectomy. These patients may benefit from adjunctive intraoperative fibrinolytics. In the event that thromboembolectomy does not restore arterial flow, bypass can be performed. [bib_ref] A method for extraction of arterial emboli and thrombi, Fogarty [/bib_ref] [bib_ref] Clinical practice. Acute limb ischemia, Creager [/bib_ref] [bib_ref] Proper evaluation and management of acute embolic versus thrombotic limb ischemia, O'connell [/bib_ref] IIb C-LD The usefulness of ultrasound-accelerated catheter-based thrombolysis for patients with ALI with a salvageable limb is unknown. [bib_ref] Initial results of catheter-directed ultrasoundaccelerated thrombolysis for thromboembolic obstructions of the aortofemoral..., Schrijver [/bib_ref] [bib_ref] Ultrasound-accelerated thrombolysis for lower extremity ischemia: multicenter experience and literature review, Schrijver [/bib_ref] [bib_ref] Dutch randomized trial comparing standard catheter-directed thrombolysis versus ultrasound-accelerated thrombolysis for thromboembolic..., Schrijver [/bib_ref] See Online Data Supplements 47 and 50.
The use of ultrasound-accelerated catheter delivery of thrombolytic agents has been published in case series [bib_ref] Initial results of catheter-directed ultrasoundaccelerated thrombolysis for thromboembolic obstructions of the aortofemoral..., Schrijver [/bib_ref] and retrospective analyses. [bib_ref] Ultrasound-accelerated thrombolysis for lower extremity ischemia: multicenter experience and literature review, Schrijver [/bib_ref] However, the single RCT comparing this technique to standard catheter-based thrombolytic therapy failed to demonstrate a difference in outcomes, including bleeding, despite a lower total amount of lytic delivered. 386
## Diagnostic evaluation of the cause of ali: recommendations
## I c-eo
Patients with PAD who have undergone lower extremity revascularization (surgical and/or endovascular) should be followed up with periodic clinical evaluation and ABI measurement.
## N/a
In addition to the clinical evaluation of cardiovascular risk factors, functional status, and adherence to medical therapy and smoking cessation, patients with PAD who have previously undergone lower extremity revascularization (surgical and/or endovascular) require additional ongoing assessment and care. Follow-up visits after revascularization should include reassessment of the patient's limb symptoms and interval change in functional status, as well as participation in a structured exercise program. Pulse examination and ABI are included in the assessment. A change in ABI of 0.15 is considered clinically significant. 388 [bib_ref] Secondary interventions in patients with autologous infrainguinal bypass grafts strongly improve patency..., Jongsma [/bib_ref] [bib_ref] The natural history of stenoses within lower limb arterial bypass grafts using..., Carter [/bib_ref] [bib_ref] Does a completely accomplished duplex-based surveillance prevent vein-graft failure?, Ihlberg [/bib_ref] [bib_ref] Prospective validation of threshold criteria for intervention in infrainguinal vein grafts undergoing..., Westerband [/bib_ref] [bib_ref] Femoropopliteal-crural graft patency is improved by an intensive surveillance program: a prospective..., Lundell [/bib_ref] [bib_ref] The importance of routine surveillance of distal bypass grafts with duplex scanning:..., Mills [/bib_ref] [bib_ref] A low flow velocity predicts failure of femoropopliteal and femorotibial bypass grafts, Bandyk [/bib_ref] See Online Data Supplements 51 and 52.
## Iia b-r duplex ultrasound can be beneficial for routine surveillance of infrainguinal, autogenous vein bypass grafts in patients with pad.
A general surveillance schedule may be at 4 to 6 weeks, 6 months, and 12 months in the first year and yearly thereafter. It is important that testing frequency is individualized to the patient, type of arterial bypass, and any prior duplex scan findings. Duplex graft surveillance focuses on the identification of high-grade stenosis (eg, peak systolic velocity >300 cm/s and peak systolic velocity ratio across the stenosis >3.5) or impending graft failure (eg, PSV <40 cm/s). [bib_ref] Prospective validation of threshold criteria for intervention in infrainguinal vein grafts undergoing..., Westerband [/bib_ref] [bib_ref] A low flow velocity predicts failure of femoropopliteal and femorotibial bypass grafts, Bandyk [/bib_ref] Detection of a graft stenosis prompts the consideration of further revascularization to treat the stenosis and maintain graft patency. Duplex may detect significant stenoses that may not be detected by a decline in ABI. [bib_ref] The importance of routine surveillance of distal bypass grafts with duplex scanning:..., Mills [/bib_ref] Although case series have demonstrated high rates of primary assisted patency with a duplex ultrasoundsurveillance strategy, RCTs of duplex surveillance versus clinical surveillance with the ABI have demonstrated mixed results in terms of a benefit on patency and limb outcomes. [bib_ref] Does a completely accomplished duplex-based surveillance prevent vein-graft failure?, Ihlberg [/bib_ref] [bib_ref] Femoropopliteal-crural graft patency is improved by an intensive surveillance program: a prospective..., Lundell [/bib_ref] [bib_ref] Is duplex surveillance of value after leg vein bypass grafting? Principal results..., Davies [/bib_ref] IIa C-LD Duplex ultrasound is reasonable for routine surveillance after endovascular procedures in patients with PAD. [bib_ref] Utility of duplex surveillance following iliac artery angioplasty and primary stenting, Back [/bib_ref] [bib_ref] Duplex evaluation following femoropopliteal angioplasty and stenting: criteria and utility of surveillance, Baril [/bib_ref] [bib_ref] Duplex ultrasound diagnosis of failing stent grafts placed for occlusive disease, Troutman [/bib_ref] See Online Data Supplement 52.
Studies have developed duplex ultrasound diagnostic criteria for diagnosing restenosis at the site of endovascular revascularization. Diagnostic criteria need to be customized to the location (eg, iliac or superficial femoral artery) and type of intervention (eg, angioplasty, uncovered stent, or covered stent). The optimal timing for surveillance after endovascular procedures is unclear. [bib_ref] Utility of duplex surveillance following iliac artery angioplasty and primary stenting, Back [/bib_ref] [bib_ref] Duplex evaluation following femoropopliteal angioplasty and stenting: criteria and utility of surveillance, Baril [/bib_ref] [bib_ref] Duplex ultrasound diagnosis of failing stent grafts placed for occlusive disease, Troutman [/bib_ref] There are limited outcome data on routine duplex surveillance versus clinical surveillance plus the ABI after endovascular revascularization. [bib_ref] Utility of duplex surveillance following iliac artery angioplasty and primary stenting, Back [/bib_ref] [bib_ref] Duplex evaluation following femoropopliteal angioplasty and stenting: criteria and utility of surveillance, Baril [/bib_ref] [bib_ref] Duplex ultrasound diagnosis of failing stent grafts placed for occlusive disease, Troutman [/bib_ref] The value of duplex ultrasound may be greater in cases with higher rates of restenosis, such as after interventions to treat very long lesions or occlusions. 400 Duplex ultrasound of prosthetic bypass grafts may be used to characterize mid-graft velocity, because low velocities can predict impending graft failure. [bib_ref] The relative importance of graft surveillance and warfarin therapy in infrainguinal prosthetic..., Brumberg [/bib_ref] [bib_ref] Should duplex ultrasonography be performed for surveillance of femoropopliteal and femorotibial arterial..., Calligaro [/bib_ref] [bib_ref] Duplex ultrasound criteria for femorofemoral bypass revision, Stone [/bib_ref] Outcome studies of duplex surveillance of prosthetic grafts have not shown consistent benefit. [bib_ref] Femoropopliteal-crural graft patency is improved by an intensive surveillance program: a prospective..., Lundell [/bib_ref] [bib_ref] The relative importance of graft surveillance and warfarin therapy in infrainguinal prosthetic..., Brumberg [/bib_ref] [bib_ref] Should duplex ultrasonography be performed for surveillance of femoropopliteal and femorotibial arterial..., Calligaro [/bib_ref] [bib_ref] Duplex ultrasound criteria for femorofemoral bypass revision, Stone [/bib_ref] One RCT of duplex versus clinical surveillance with the ABI for femoropopliteal grafts did not show a benefit of duplex on outcome in the subset of patients with prosthetic grafts, though there was a benefit of duplex surveillance for vein bypass grafts. 393
## Iib b-r the effectiveness of duplex ultrasound for routine surveillance of infrainguinal prosthetic bypass grafts in patients with
## Evidence gaps and future research directions
In performing the evidence review and in developing the present guidelines, the writing committee identified the following critical evidence gaps and future directions for PADrelated research:
- Basic science and translational studies to better understand the vascular biology of endovascular therapies and bypass grafting and to develop new methods for preventing restenosis after revascularization.
- Determination of risk factors for progression from asymptomatic PAD to symptomatic disease, including CLI.
- RCTs needed to determine the value of using the ABI to identify asymptomatic patients with PAD for therapies to reduce cardiovascular risk (eg, antiplatelet agents, statins, and other therapies).
- Advancement in PAD diagnostics, such as technologies for simplified yet highly accurate measurement of the ABI and tools for more reliable noninvasive perfusion assessment in CLI.
- Comparative-effectiveness studies to determine the optimal antiplatelet therapy (drug or drugs and dosage) for prevention of cardiovascular and limb-related events in patients with PAD.
- Development of additional medical therapies for claudication-an area of unmet medical need with a currently limited research pipeline. [bib_ref] Clinical trials in peripheral vascular disease: pipeline and trial designs: an evaluation..., Subherwal [/bib_ref] - Studies to investigate the role of dietary intervention, in addition to statin therapy, to improve outcome and modify the natural history of PAD.
- Additional research to identify the best community-or home-based exercise programs for patients with PAD to maximize functional status and improve QoL, as well as the role of such exercise programs before or in addition to revascularization.
- Development and validation of improved clinical classification systems for PAD that incorporate symptoms, anatomic factors, and patient-specific risk factors and can be used to predict clinical outcome and optimize treatment approach. An example of a recently developed classification system is the Society for Vascular Surgery limb classification system, based on wound, ischemia, and foot infection (WIfI), which has been validated in different populations and may permit more meaningful prognosis in patients with CLI. [bib_ref] Predictive ability of the Society for Vascular Surgery Wound, Ischemia, and foot..., Darling [/bib_ref] balloons and DES. Studies should include patient-centered end-points, such as functional parameters, time to wound healing, and QoL, in addition to standard patency-focused outcomes. These studies could then be incorporated into valuebased clinical algorithms for approach to revascularization for claudication and CLI.
- Additional studies to demonstrate the impact of multisocietal registries on clinical outcomes and appropriate use. At present, these include the Vascular Quality Initiative (VQI), the National Cardiovascular Data Registry Peripheral Vascular Intervention Registry™ (PVI Registry™), and the National Radiology Data Registry for Interventional Radiology (NRDR). These registries provide an opportunity to obtain "real-world" data on surgical and endovascular procedures for PAD and to improve quality by providing feedback to participating centers. Future efforts should incorporate these registries into interventional RCTs and postmarketing studies of PAD-related devices.
## Advocacy priorities
The writing committee identified 3 priorities for multi-societal advocacy initiatives to improve health care for patients with PAD. First, the writing committee supports the availability of the ABI as the initial diagnostic test to establish the diagnosis of PAD in patients with history or physical examination findings suggestive of PAD [fig_ref] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity... [/fig_ref].
Although the ABI test is generally reimbursed by third-party payers for patients with classic claudication or lower extremity wounds, payers may not provide reimbursement for the ABI with other findings suggestive of PAD, such as lower extremity pulse abnormalities or femoral bruits. The writing committee affirms the importance of confirming the diagnosis of PAD in such patients to allow for GDMT as delineated in this document. Second, the writing committee supports the vital importance of insuring access to supervised exercise programs for patients with PAD. Although extensive high-quality evidence supports supervised exercise programs to improve functional status and QoL, only a minority of patients with PAD participate in such programs because of lack of reimbursement by third-party payers. Third, the writing committee recognizes the need for incorporation of patient-centered outcomes into the process of regulatory approval of new medical therapies and revascularization technologies. For revascularization technologies, regulatory approval is driven primarily by data on angiographic efficacy (ie, target lesion patency) and safety endpoints. The nature of the functional limitation associated with PAD warrants the incorporation of patient-centered outcomes, such as functional parameters and QoL, into the efficacy outcomes for the approval process.
# Supplementary material
Refer to Web version on PubMed Central for supplementary material.Definition of PAD Key Terms
## Term definition
Claudication Fatigue, discomfort, cramping, or pain of vascular origin in the muscles of the lower extremities that is consistently induced by exercise and consistently relieved by rest (within 10 min).
Acute limb ischemia (ALI) Acute (<2 wk), severe hypoperfusion of the limb characterized by these features: pain, pallor, pulselessness, poikilothermia (cold), paresthesias, and paralysis.
One of these categories of ALI is assigned (Section 10):
## I.
Viable-Limb is not immediately threatened; no sensory loss; no muscle weakness; audible arterial and venous Doppler.
## Ii.
Threatened-Mild-to-moderate sensory or motor loss; inaudible arterial Doppler; audible venous Doppler; may be further divided into IIa (marginally threatened) or IIb (immediately threatened).
## Iii.
Irreversible-Major tissue loss or permanent nerve damage inevitable; profound sensory loss, anesthetic; profound muscle weakness or paralysis (rigor); inaudible arterial and venous Doppler. Tissue loss Type of tissue loss:
Minor-nonhealing ulcer, focal gangrene with diffuse pedal ischemia. Major-extending above transmetatarsal level; functional foot no longer salvageable. 33
Critical limb ischemia (CLI) A condition characterized by chronic (≥2 wk) ischemic rest pain, nonhealing wound/ulcers, or gangrene in 1 or both legs attributable to objectively proven arterial occlusive disease.
The diagnosis of CLI is a constellation of both symptoms and signs. Arterial disease can be proved objectively with ABI, TBI, TcPO 2 , or skin perfusion pressure. Supplementary parameters, such as absolute ankle and toe pressures and pulse volume recordings, may also be used to assess for significant arterial occlusive disease. However, a very low ABI or TBI does not necessarily mean the patient has CLI. The term CLI implies chronicity and is to be distinguished from ALI. 35
In-line blood flow Direct arterial flow to the foot, excluding collaterals.
Functional status Patient's ability to perform normal daily activities required to meet basic needs, fulfill usual roles, and maintain health and well-being. Walking ability is a component of functional status.
Nonviable limb Condition of extremity (or portion of extremity) in which loss of motor function, neurological function, and tissue integrity cannot be restored with treatment.
Salvageable limb Condition of extremity with potential to secure viability and preserve motor function to the weight-bearing portion of the foot if treated.
Structured exercise program Planned program that provides individualized recommendations for type, frequency, intensity, and duration of exercise.
Program provides recommendations for exercise progression to assure that the body is consistently challenged to increase exercise intensity and levels as functional status improves over time.
There are 2 types of structured exercise program for patients with PAD:
## 1.
Supervised exercise program
## 2.
Structured community-or home-based exercise program Supervised exercise program Structured exercise program that takes place in a hospital or outpatient facility in which intermittent walking exercise is used as the treatment modality.
Program can be standalone or can be made available within a cardiac rehabilitation program.
Program is directly supervised by qualified healthcare provider(s).
Training is performed for a minimum of 30 to 45 min per session, in sessions performed at least 3 times/wk for a minimum of 12 wk. 36-46 Patients may not initially achieve these targets, and a treatment goal is to progress to these levels over time.
Circulation. Author manuscript; available in PMC 2017 September 21. et al.
## Page 63
## Term definition
Training involves intermittent bouts of walking to moderate-to-maximum claudication, alternating with periods of rest.
Warm-up and cool-down periods precede and follow each session of walking.
Structured community-or homebased exercise program Structured exercise program that takes place in the personal setting of the patient rather than in a clinical setting. 41,47-51
Program is self-directed with the guidance of healthcare providers who prescribe an exercise regimen similar to that of a supervised program.
Patient counseling ensures that patients understand how to begin the program, how to maintain the program, and how to progress the difficulty of the walking (by increasing distance or speed).
Program may incorporate behavioral change techniques, such as health coaching and/or use of activity monitors.
## Emergency versus urgent
An emergency procedure is one in which life or limb is threatened if the patient is not in the operating room or interventional suite and/or where there is time for no or very limited clinical evaluation, typically within <6 h.
An urgent procedure is one in which there may be time for a limited clinical evaluation, usually when life or limb is threatened if the patient is not in the operating room or interventional suite, typically between 6 and 24 h.
Interdisciplinary care team A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD.
For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care. [fig_ref] Table 9: can be beneficial [/fig_ref] Interdisciplinary Care Team for PAD A team of professionals representing different disciplines to assist in the evaluation and management of the patient with PAD. For the care of patients with CLI, the interdisciplinary care team should include individuals who are skilled in endovascular revascularization, surgical revascularization, wound healing therapies and foot surgery, and medical evaluation and care.
Interdisciplinary care team members may include:
## Examples
Factors associated with technical failure or poor durability with endovascular treatment Lesion involving common femoral artery, including origin of deep femoral artery Long segment lesion involving the below-knee popliteal and/or infrapopliteal arteries in a patient with suitable single-segment autogenous vein conduit Diffuse multilevel disease that would require endovascular revascularization at multiple anatomic levels Small-diameter target artery proximal to site of stenosis or densely calcified lesion at location of endovascular treatment Endovascular treatment likely to preclude or complicate subsequent achievement of in-line blood flow through surgical revascularization Single-vessel runoff distal to ankle
## Findings that favor consideration of endovascular revascularization
## Examples
The presence of patient comorbidities may place patients at increased risk of perioperative complications from surgical revascularization. In these patients, an endovascular-first approach should be used regardless of anatomy Patient comorbidities, including coronary ischemia, cardiomyopathy, congestive heart failure, severe lung disease, and chronic kidney disease Patients with rest pain and disease at multiple levels may undergo a staged approach as part of endovascular-first approach
In-flow disease can be addressed first, and out-flow disease can be addressed in a staged manner, when required, if clinical factors or patient safety prevent addressing all diseased segments at one setting
[fig] Figure 1: Diagnostic Testing for Suspected PAD [/fig]
[fig] Figure 3: Diagnosis and Management of ALI [/fig]
[table] Table 9: can be beneficial.[228][229][230] The EuroDIALE (European Study Group on Diabetes and the Lower Extremity) study demonstrated that the presence of both PAD and foot infection conferred a nearly 3-fold higher risk of leg amputation than either infection or PAD alone.228 The treatment of deep soft-tissue infection typically requires prompt surgical drainage; vascular imaging and expeditious revascularization generally follow. Experienced clinical teams have reported very good outcomes when this is performed in a coordinated and timely fashion. 229,230 Previous groups have described various combinations of functions of interdisciplinary care teams (See Online Data Supplement 34a for a complete list of functions). See Section 9.2 for recommendations related to the role of the interdisciplinary care team in wound healing therapies for CLI.Although there are limited data to support patient education about self-foot examination and foot care for patients with diabetes mellitus, there are no data that have evaluated this practice in a population of patients with PAD but without diabetes mellitus. Nonetheless, this is a very low-risk intervention with potential for benefit. Educational efforts generally include teaching patients about healthy foot behaviors (eg, daily inspection of feet; foot care and hygiene, including appropriate toenail cutting strategies; avoidance of barefoot walking), the selection of appropriately fitting shoes, and the importance of seeking medical attention for new foot problems. 223IIaC-EO Biannual foot examination by a clinician is reasonable for patients with PAD and diabetes mellitus. [/table]
[table] Table 3: 33,34 Category I refers to viable limbs that are not immediately threatened. Category II refers to threatened limbs. Category IIa limbs are marginally threatened and salvageable, if promptly treated. Category IIb are immediately threatened limbs that require immediate revascularization if salvage is to be accomplished. Category III are irreversibly damaged limbs, in which case resultant major tissue loss or permanent nerve damage is inevitable.34 [/table]
[table] Table 2: Important Guideline PolicyACC/AHA Guideline policy relevant to the management of lower extremity PAD [/table]
[table] Table 4: Patients at Increased Risk of PADAge ≥65 y Age 50-64 y, with risk factors for atherosclerosis (eg, diabetes mellitus, history of smoking, hyperlipidemia, hypertension) or family history of PAD 63Age <50 y, with diabetes mellitus and 1 additional risk factor for atherosclerosis Individuals with known atherosclerotic disease in another vascular bed (eg, coronary, carotid, subclavian, renal, mesenteric artery stenosis, or AAA) AAA indicates abdominal aortic aneurysm; PAD, peripheral artery disease.Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 5: History and/or Physical Examination Findings Suggestive of PADClaudicationOther non-joint-related exertional lower extremity symptoms (not typical of claudication)Other suggestive lower extremity physical findings (eg, elevation pallor/dependent rubor) PAD indicates peripheral artery disease.Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 6: Alternative Diagnoses for Leg Pain or Claudication With Normal Physiological Testing (Not PAD-Related)Modified from Norgren L et al. 35 PAD indicates peripheral artery disease. Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 7: Alternative Diagnoses for Nonhealing Wounds With Normal Physiological Testing (Not PAD-Related)Develops in regions of skin changes due to chronic venous disease and local venous hypertension Typically wet (ie, wound drainage) rather than dry lesion Thrombotic (eg, antiphospholipid antibody syndrome, Sneddon's syndrome, warfarin skin necrosis, disseminated intravascular coagulation, livedoid vasculitis, protein C or S deficiency, prolonged vasospasm) Medication direct toxicity (eg, doxorubicin, hydroxyurea, some tyrosine kinase inhibitors)NeuropathicPressure zones of footHyperkeratosis surrounds the ulcer Diabetes mellitus with peripheral neuropathy Peripheral neuropathy without diabetes mellitus Leprosy Autoimmune injury Toes, foot, leg With blisters (eg, pemphigoid, pemphigus, epidermolysis bullosa) Without blisters (eg, dermatomyositis, lupus, scleroderma) PAD indicates peripheral artery disease. Circulation. Author manuscript; available in PMC 2017 September 21. [/table]
[table] Table 10: Therapy for CLI: Findings That Prompt Consideration of Surgical or Endovascular Revascularization Findings That Favor Consideration of Surgical Revascularization [/table]
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Preamble Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, based on systematic methods to evaluate and classify evidence, provide a cornerstone of quality cardiovascular care. In response to reports from the Institute of Medicine1,2 and a mandate to evaluate new knowledge and maintain relevance at the point of care, the ACC/AHA Task Force on Clinical Practice Guidelines (Task Force) modified its methodology.3–5 The relationships among guidelines, data standards, appropriate use criteria, and performance measures are addressed elsewhere.5 Intended Use Practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease. The focus is on medical practice in the United States, but guidelines developed in collaboration with other organizations may have a broader target. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients' interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. Guidelines are reviewed annually by the Task Force and are official policy of the ACC and AHA. Each guideline is considered current until it is updated, revised, or superseded by published addenda, statements of clarification, focused updates, or revised full-text guidelines. To ensure that guidelines remain current, new data are reviewed biannually to determine whether recommendations should be modified. In general, full revisions are posted in 5-year cycles.3–6 Modernization Processes have evolved to support the evolution of guidelines as “living documents” that can be dynamically updated. This process delineates a recommendation to address a specific clinical question, followed by concise text (ideally <250 words) and hyperlinked to supportive evidence. This approach accommodates time constraints on busy clinicians and facilitates easier access to recommendations via electronic search engines and other evolving technology. Evidence Review Writing committee members review the literature; weigh the quality of evidence for or against particular tests, treatments, or procedures; and estimate expected health outcomes. In developing recommendations, the writing committee uses evidence-based methodologies that are based on all available data.3–7 Literature searches focus on randomized controlled trials (RCTs) but also include registries, nonrandomized comparative and descriptive studies, case series, cohort studies, systematic reviews, and expert opinion. Only selected references are cited. The Task Force recognizes the need for objective, independent Evidence Review Committees (ERCs) that include methodologists, epidemiologists, clinicians, and biostatisticians who systematically survey, abstract, and assess the evidence to address systematic review questions posed in the PICOTS format (P=population, I=intervention, C=comparator, O=outcome, T=timing, S=setting).2,4–6 Practical considerations, including time and resource constraints, limit the ERCs to evidence that is relevant to key clinical questions and lends itself to systematic review and analysis that could affect the strength of corresponding recommendations. Guideline-Directed Management and Treatment The term “guideline-directed management and therapy” (GDMT) refers to care defined mainly by ACC/AHA Class I recommendations. For these and all recommended drug treatment regimens, the reader should confirm dosage with product insert material and carefully evaluate for contraindications and interactions. Recommendations are limited to treatments, drugs, and devices approved for clinical use in the United States. Class of Recommendation and Level of Evidence The Class of Recommendation (COR; ie, the strength of the recommendation) encompasses the anticipated magnitude and certainty of benefit in proportion to risk. The Level of Evidence (LOE) rates evidence supporting the effect of the intervention on the basis of the type, quality, quantity, and consistency of data from clinical trials and other reports (Table 1).3–5 Unless otherwise stated, recommendations are sequenced by COR and then by LOE. Where comparative data exist, preferred strategies take precedence. When >1 drug, strategy, or therapy exists within the same COR and LOE and no comparative data are available, options are listed alphabetically. Relationships With Industry and Other Entities The ACC and AHA sponsor the guidelines without commercial support, and members volunteer their time. The Task Force zealously avoids actual, potential, or perceived conflicts of interest that might arise through relationships with industry or other entities (RWI). All writing committee members and reviewers are required to disclose current industry relationships or personal interests, from 12 months before initiation of the writing effort. Management of RWI involves selecting a balanced writing committee and assuring that the chair and a majority of committee members have no relevant RWI (Appendix 1). Members are restricted with regard to writing or voting on sections to which their RWI apply. For transparency, members' comprehensive disclosure information is available online. Comprehensive disclosure information for the Task Force is also available online. The Task Force strives to avoid bias by selecting experts from a broad array of backgrounds representing different geographic regions, sexes, ethnicities, intellectual perspectives/biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators. Individualizing Care in Patients With Associated Conditions and
Comorbidities Managing patients with multiple conditions can be complex, especially when recommendations applicable to coexisting illnesses are discordant or interacting.8 The guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances. The recommendations should not replace clinical judgment. Clinical Implementation Management in accordance with guideline recommendations is effective only when followed. Adherence to recommendations can be enhanced by shared decision making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities. Consequently, circumstances may arise in which deviations from these guidelines are appropriate.
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The Australian Institute of Sport (AIS) and National Eating Disorders Collaboration (NEDC) position statement on disordered eating in high performance sport
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The Australian Institute of Sport (AIS) and National Eating Disorders Collaboration (NEDC) position statement on disordered eating in high performance sport
Identification, evaluation and management of disordered eating (DE) is complex. DE exists along the spectrum from optimised nutrition through to clinical eating disorders (EDs). Individual athletes can move back and forth along the spectrum of eating behaviour at any point in time over their career and within different stages of a training cycle. Athletes are more likely to present with DE than a clinical ED. Overall, there is a higher prevalence of DE and EDs in athletes compared with non-athletes. Additionally, athletes participating in aesthetic, gravitational and weight-class sports are at higher risk of DE and EDs than those in sports without these characteristics. The evaluation and management of DE requires a cohesive team of professional practitioners consisting of, at minimum, a doctor, a sports dietitian and a psychologist, termed within this statement as the core multidisciplinary team. The Australian Institute of Sport and the National Eating Disorders Collaboration have collaborated to provide this position statement, containing guidelines for athletes, coaches, support staff, clinicians and sporting organisations. The guidelines support the prevention and early identification of DE, and promote timely intervention to optimise nutrition for performance in a safe, supported, purposeful and individualised manner. This position statement is a call to action to all involved in sport to be aware of poor self-image and poor body image among athletes. The practical recommendations should guide the clinical management of DE in high performance sport. bACkground position statement.
The Australian Institute of Sport (AIS) and National Eating Disorders Collaboration (NEDC) position statement on disordered eating in high performance sport Introduction
The Australian Institute of Sport (AIS) is Australia's peak high performance sport agency. The National Eating Disorders Collaboration (NEDC), an initiative of the Australian Government Department of Health, promotes nationally consistent, evidencebased responses to disordered eating (DE) and eating disorders (EDs) in Australia. Both organisations are committed to ensuring the safety and welfare of all high performance athletes. A high performance athlete is considered to be any athlete within the performance pathway ranging from junior and senior elite level and including para and able-bodied athletes. From here on, the high performance athlete will be referred to as the athlete.
The AIS and NEDC have collaborated to provide these guidelines for athletes, coaches, support staff, clinicians and sporting organisations. The guidelines support the prevention and recognition of DE, and promote early intervention to optimise nutrition for performance in a safe, supported, purposeful and individualised manner. This position statement is a call to action to all involved in sport to be aware of poor self-image and poor body image among athletes. Sporting organisations should develop sport-specific positions and guidelines that foster a healthy sport system for athletes. The practical recommendations in this document are intended to guide the clinical management of DE in high performance sport, putting in place a core multidisciplinary team (CMT) comprised of the doctor, sports dietitian and psychologist. The clinical treatment and management of EDs is outside the scope of this document. There are further resources available in the National Practice Standards for Eating Disorders,the Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of EDs (2014) [bib_ref] Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for..., Hay [/bib_ref] and the UK National Institute for Health and Care Excellence guideline on EDs recognition and treatment (2017).In addition, the Australia and New Zealand Academy for EDs is due to publish Clinical Practice and Training Standards in 2020.
## De in athletes
DE in an athlete sits on a spectrum between optimised nutrition and an ED . An individual with DE may regularly engage in behaviours such as skipping meals, compulsive eating, compulsive exercise and/or restrictive eating but without fully meeting the criteria for an ED. Comparisons between EDs and DE are shown in table 1. DE may involve short-term restrictive diets, which progress to chronic energy or nutrient restriction, binge eating, active and passive dehydration, use of laxatives, diuretics, vomiting, and diet pills with or without excessive training. Individual athletes can move back and forth along the spectrum of eating behaviour at any point in time over their career and within different stages of a training cycle (eg, during the off-season, preseason, when injured). Athletes are more likely to present with DE than a clinical ED. [bib_ref] National athletic trainers' association position statement: preventing, detecting, and managing disordered eating..., Bonci [/bib_ref] [bib_ref] Mental health in elite athletes: international Olympic Committee consensus statement (2019), Reardon [/bib_ref] [bib_ref] Prevalence of eating disorders in elite athletes is higher than in the..., Sundgot-Borgen [/bib_ref] However, there are health and performance implications regardless of where an athlete falls Consensus statement The spectrum of eating behaviour in the high performance athlete from optimised nutrition to disordered eating to eating disorders. DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Characteristics of eating disorders versus disordered eating in elite athletes (reprinted with permission from The IOC Consensus Statement on Mental Health in Elite Sport 5 )
## Eating disorders disordered eating
Restricting, bingeing or purging often occur multiple times per week Pathogenic behaviours used to control weight (eg, occasional restricting, use of diet pills, bingeing, purging or use of saunas or 'sweat runs') may occur but not with regularity
Obsessions with thoughts of food and eating occur much of the time Thoughts of food and eating do not occupy most of the day Eating patterns and obsessions preclude normal functioning in life activities Functioning usually remains intact Preoccupation with 'healthy eating' leads to significant dietary restriction There may be preoccupation with 'healthy eating' or significant attention to caloric or nutritional parameters of most foods eaten but intake remains acceptable Excessive exercise beyond that recommended by coaches may be explicitly used as a frequent means of purging carbs While exercise may not be regularly used in excessive amount to purge calories, there may be a cognitive focus on burning calories when exercising along the spectrum and risks increase when DE worsens into a diagnosed ED. DE and low energy availability (LEA) can occur together, or in isolation (figure 2). Identification of one necessitates the investigation of the other. LEA may be difficult to recognise since an athlete may be stable in weight but deficient in energy. Added complexity in working with athletes comes from sport-specific pressures and individual comorbidities as well as cultural, familial, individual and genetic/biochemical factors. 9
## Health and performance consequences of de behaviours
In addressing the health and performance consequences of DE or EDs, health must be the priority. One of the health risks of DE or EDs is the potential development of relative energy deficiency in sport (RED-S). [bib_ref] IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update, Mountjoy [/bib_ref] In addition to the direct impairment of physiological and psychological function, DE can increase the risk of illness and injury, compromise training quality and consistency, and indirectly interfere with competition goals. [bib_ref] The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in..., Mountjoy [/bib_ref] Consequences of DE behaviours may include electrolyte imbalances, dehydration, nutritional deficiencies, gastrointestinal problems (dental, gingival, bleeding, ulceration, bloating, constipation) and mental health issues (depression, anxiety, personality disorders, substance abuse, self-harm and suicidal ideation).If DE is in conjunction with LEA, there may be suppression of physiological processes, resulting in impairments of bone health, menstrual function, endocrine, metabolic and haematological status, growth and development, psychological well-being, and cardiovascular, gastrointestinal and immunological systems. The long-term consequences of LEA are particularly critical to the adolescent athlete, affecting the accrual of peak bone mineral density (BMD) and stature, and neurological 13 and reproductive system development. [bib_ref] How to minimise the health risks to athletes who compete in weight-sensitive..., Sundgot-Borgen [/bib_ref] Performance consequences of DE may arise from interrupted or less effective training (eg, increased illness and injury, reductions in training capacity, recovery and adaptation) as well as acute impairments on competition day from inadequate fuelling for the event (eg, reduction in coordination, concentration, mood, strength and endurance). 9
## Prevalence and contributing factors to de in athletes
DE can occur in any athlete, in any sport, at any time, crossing boundaries of gender, age, body size, culture, socioeconomic background, athletic calibre and ability. The estimated prevalence of DE and/or EDs in athletes ranges from 0% to 19% in men and 6% to 45% in women. [bib_ref] Mental health in elite athletes: international Olympic Committee consensus statement (2019), Reardon [/bib_ref] Overall, there is a higher prevalence of DE and EDs in athletes compared with non-athletes 14 but sport-specific demands and individual characteristics of the athlete lead to a wide variation in prevalence of DE and EDs across different sports. [bib_ref] Energy availability in athletes, Loucks [/bib_ref] Much of the prevalence data regarding DE in athletes originates from studies of Scandinavian cohorts and North American collegiate athletes, predominantly featuring Caucasian and able-bodied populations. There is a paucity of prevalence data in para-athletes with further research and understanding required to adequately address and inform best practice in this population. [bib_ref] Low energy availability, menstrual dysfunction, and low bone mineral density in individuals..., Blauwet [/bib_ref] An environment in which there is pressure to either lose or gain weight and/or to maintain meticulous control of body composition may contribute to an increased prevalence of DE and EDs. Athletes may be underweight, normal weight or overweight, irrespective of DE or EDs. Personal attributes which underpin successful performance, combined with the sport environment may leave athletes vulnerable to DE. Three categories of sports, defined as aesthetically judged, gravitational and weight class, are consistently identified as high risk for the development of DE and EDs. [bib_ref] How to minimise the health risks to athletes who compete in weight-sensitive..., Sundgot-Borgen [/bib_ref] Risk factors for DE and EDs in high performance athletes are shown in table 2.
## Early identification, assessment and monitoring early identification of de
DE in athletes can occur at any time; both precipitating, or being precipitated by, challenges in the athlete's life as well as occurring during a time of successful performance. 14 While there is a growing openness and support for mental health concerns in elite sport,barriers to early identification and treatment of DE and EDs still exist. Athletes' shame, stigma and fear of discrimination prevent them from disclosing problematic behaviour and seeking help, whereas limited knowledge about ED symptoms and reluctance to ask specifically about eating problems inhibit providers' detection of DE and EDs. [bib_ref] Position of the American dietetic association: nutrition intervention in the treatment of..., Ozier [/bib_ref] It is widely accepted that the early identification and appropriate management of DE leads to better outcomes. [bib_ref] Risks of all-cause and suicide mortality in mental disorders: a meta-review, Chesney [/bib_ref] EDs have one of the highest mortality rates among all mental illnesses, which underscores the importance of prevention efforts, timely detection and specialised treatment. [bib_ref] Understanding eating disorders in elite gymnastics: ethical and conceptual challenges, Tan [/bib_ref] Everyone in the sport system has a role to play in recognition and early intervention, and anyone can refer athletes to, and/ or consult with, any member of the CMT (doctor, sports dietitian and psychologist) for further assessment and support.It is important for all personnel involved in the sport to be aware of the risk factors and warning signs or red flags of DE and EDs (tables 2 and 3). Personnel should also be informed of effective communication channels for concerns. Some warning signs (table 3) can occur early (behavioural changes) whereas others such as weight changes may occur later in the person's trajectory of DE.
## The cmt
The recommended CMT is comprised of the doctor, sports dietitian and psychologist, and together they coordinate the prevention, assessment, management and maintenance care in possible DE cases. As per the Olympic Movement Medical Code, all activities of the CMT should be based on the premise that the health and the welfare of athletes are pre-eminent and prevail over competitive, economic, legal or political considerations.Each member of the CMT provides expertise in a mutually supportive manner (figure 3) to deliver optimal care for the athlete in a safe, supported, individualised and purposeful way, governed by the ethos, 'do no harm'. Doctors, sports dietitians and psychologists working within sport, despite not always self-identifying as Sport-specific risk factors ► Transition periods -Early start of sport-specific training -Making a senior team at a young age -Retirement (forced or voluntary) -Non-selection or de-selection -Injury, illness, surgery, time away from sport and training ► Changes in weight/body shape following injury/illness ► Pressures (perceived or real) to change body shape or composition ► Weight cycling ► Patterns of restriction or disordered behaviours ► Coaching behaviour and accepted 'norms' within sport ► Rules and regulations in sports ► Performance optimisation pressure ► Use of supplements, and nutritional and ergogenic aids ► Body composition testing, weighing and measuring ► Public displays of 'results' in common areas, for example, training environment ► Media and social media pressure (perceived or real) to look a certain way Gender-based factors ► Media-driven gender stereotypes ► Drive for muscularity/leanness/thinness ► Anabolic-androgenic steroid use ► Gender diversity
Other risk factors ► Chronic disease related to caloric utilisation, for example, diabetes, thyroid ► Co-occurring conditions, for example, coeliac disease, other gastrointestinal conditions ► LGBTQI+ ► History of trauma ► History of food insecurity ► Major life transitions, for example, moving away from home, moving between schools, moving overseas experts in this field, need to have an awareness of DE and EDs and regularly seek professional development in this area. The CMT works with the athlete, coach and support staff to investigate and manage health, performance and return to play (RTP) considerations. With the athlete's permission and respecting patient confidentiality, the ideal management model includes regular and collaborative communication between the CMT and coach. Further input may be sought from a range of specialists including an endocrinologist, gynaecologist, psychiatrist, sport scientist, physiotherapist, occupational therapist, social worker, paediatrician and/or specialist ED service (figure 4). The CMT is responsible for ensuring continuity of care. This includes effective collaboration between physical and mental health services, private and public health services, sport and community-based services and between professional disciplines.It is crucial that there are well-defined roles and a clear communication strategy within the CMT and across relevant stakeholders. A designated member of the CMT should ideally coordinate the flow of information across the team and with relevant sports staff.
## Assessment of de in athletes
Clinical judgement and an understanding of the high performance sport context is crucial in distinguishing acceptable from problematic behaviours. Warning signs in the general population may be masked within the sporting environment. For example, a disciplined training diet and preoccupation with body weight and shape may reflect a specific sport culture, changes in, or absolutely low, levels of body fat may be balanced by muscle to present an acceptable body weight, and excessive exercise is easily hidden by demanding training programmes. [bib_ref] The athletes' relationships with training scale (art): a self-report measure of unhealthy..., Chapa [/bib_ref] [bib_ref] Sports psychiatry: mental health and mental disorders in athletes and exercise treatment..., Ströhle [/bib_ref] Although a number of tools have been developed to screen for DE and EDs in the general population, validated and specialised tools Warning signs or red flags for disordered eating and eating disorders in athletes Behavioural changes ► Preoccupation with food, calories, body shape and weight ► Polarised/dichotomous thinking (including but not limited to thoughts about food, body or exercise) ► Avoidance of food-related social activities ► Restrictive eating, for example, cutting down or cutting out food groups, nutrients, reducing overall energy intake, counting, measuring and weighing food ► Bathroom visits after meals ► Evidence of binge eating (large amounts of food purchased/consumed, evidence of food wrappers hidden in the bin or another location) ► Restriction followed by binge eating ► Secretive behaviour regarding food intake and/or exercise behaviour ► Increasing rigidity or inflexibility in situations Physical changes ► Wearing baggy or layered clothing that hides body shape ► Relentless, excessive exercise ► Exercise through injury/illness with inadequate recovery ► Bone stress injury ► Hormone dysfunction (including dysregulated menstrual cycle, libido and erectile function) ► Frequent illness ► Low body fat ► Dehydration ► Bad breath, sore gums or signs of enamel loss on teeth ► Swelling around jaw ► Skin effects, including dry skin, fine hairs growing around the face or signs of calluses on the knuckles ► Unexpected weight gain beyond that expected from growth/development/puberty ► Dramatic or rapid weight loss or gain or fluctuation Psychological changes ► Persistently poor and/or declining mental health ► Increased attention to and/or criticism of one's body ► Feeling out of control with regard to food ► Body image dissatisfaction and distortion for use in sport across varied athlete populations are limited in number and quality. [bib_ref] Retired athletes and the intersection of food and body: a systematic literature..., Buckley [/bib_ref] Current recommendations for DE assessment include using self-report screening tools followed by an interview-based assessment, and sport-specific versus general approaches where available. Whenever feasible, and with the athlete's permission, assessment may involve interviewing others in the athlete's support network, including coaches, teammates, family and friends.
## Screening tools and questionnaires
There are a range of screening tools and questionnaires available to assist the assessment of DE in athletes. The Eating Disorder Examination 17.0 (EDE 17.0) is currently regarded as the gold standard for clinical interview for diagnostic purposes of EDs in the general population. The Eating Disorder Examination Questionnaire 6.0 (EDE-Q 6.0) is a short form screening tool based on the EDE 17.0 and is acceptable for use in practice. The EDE-Q 6.0 should form part of a comprehensive assessment of the athlete. Additional tools including the Athletic Milieu Direct Questionnaire Version 2 and Physiological Screening Test, the Brief Eating Disorder in Athletes Questionnaire Version 2, and the Eating Attitudes Test-26; all provide discrimination between athletes with and without EDs. However, there are several limitations of these tools for EDs, particularly for male athletes, and care should be taken to ensure the tool is appropriate for the athlete. [bib_ref] The leaf questionnaire: a screening tool for the identification of female athletes..., Melin [/bib_ref] The assessment of LEA in athletes is also problematic since a quantitative assessment of EA is time-consuming and marred by errors of reliability and validity in calculating its main components (energy intake and exercise energy expenditure). [bib_ref] Pitfalls of conducting and interpreting estimates of energy availability in free-living athletes, Burke [/bib_ref] The assessment of EA is complicated by errors in the measurement of its component parts and failure to account for other factors such as dietary quality and within-day energy spread. [bib_ref] Pitfalls of conducting and interpreting estimates of energy availability in free-living athletes, Burke [/bib_ref] The Low Energy Availability in Females Questionnaire is a validated screening tool which may indicate the need for more in-depth assessments such as a measurement of resting metabolic rate or hormonal status. [bib_ref] Endocrine effects of relative energy deficiency in sport, Elliott-Sale [/bib_ref] However, it is noted that this questionnaire has been principally developed from endurance-trained populations and is unlikely to be as specific and sensitive in other sporting groups. Further work to increase the validity of existing DE screening tools in broader athletic populations is underway while new screening assessment tools are in the validation phase.
## Nutritional assessment
An athlete identified with possible DE should be referred to a sports dietitian for nutritional assessment of DE, EDs and LEA (table 4). The sports dietitian can: conduct screening questionnaires and interviews; complete a diet history and nutritional assessment; assess for the presence of special diets and restrictions/intolerances/allergies; perform an EA assessment; evaluate risk factors and warning signs of DE or EDs and assess where an athlete is on the spectrum of eating behaviour . An athlete may be stable in weight but deficient in energy. Weight should not be the sole focus of the multimodal assessment of DE. The sports dietitian aims to understand the psychological component to food choices; the athlete's views of their body and how these thoughts may impact on food selection. In some cultures and countries, food security may also overlay food choice and eating behaviours. Tracking where an athlete sits on the spectrum of eating behaviour helps a sports dietitian to better understand the athlete and apply appropriate and targeted nutrition interventions. An athlete's ability or inability to follow nutrition advice/recommendations also provides further information as to where the athlete sits on the spectrum.
## Nutrition for health and performance
Nutrition for athletes needs to encompass considerations of both health and performance. The characteristics of optimised nutrition in an athlete include: ► Their eating practices are meeting their physical and mental health needs.
## Figure 3
Core multidisciplinary team management by a doctor, sports dietitian and psychologist: the core multidisciplinary team drives the assessment for disordered eating of an athlete, which may involve some overlap between disciplines depending on the trigger for recognition of disordered eating and the individual case characteristics. BMD, bone mineral density; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; DXA, dual-energy X-ray absorptiometry ► They are able to adapt their intake to meet the specific and changing demands of their sport. ► They have flexibility around their eating and thoughts about food. ► They are able to eat socially. ► They are free of restrictive behaviours such as the avoidance of whole food groups; excessive counting of calories or macronutrients; or rigidity around foods consumed. ► They have a healthy body image.
A plan for optimised nutrition should be safe, supported, purposeful and individualised. Nutrition practices are considered safe if they support the principle of 'at first do no harm' and in doing so, fundamentally prioritise athlete physical and mental health. The delivery of these optimal practices is supported when guided by the appropriately qualified and experienced members of the CMT with interaction and input from the wider performance team.
## Medical assessment
The medical assessment of an athlete with identified DE should include thorough history (see online supplementary tables S1-S3
in Supplementary data) based on information provided by the athlete and CMT. All athletes with bone stress injury and/or menstrual dysfunction should be screened for LEA/RED-S and screened/assessed for DE and EDs. Care should be taken to select appropriate first-line and second-line investigations for the individual case to complete general and hormonal screenings, bearing in mind the timing of testing as it may relate to diurnal fluctuations, fasting status and menstrual cycle if known. Second-line biomarkers (online , data) of appetite, bone formation/resorption and other potential LEA indicators are an evolving space with some markers, such as ghrelin, currently only used in research settings. Consultation with an endocrinologist for interpretation of results may be required if outside the expertise of the practitioner. Referral to an appropriate specialist should be considered for more complex cases with valuable contributions frequently obtained in the fields of endocrinology, gynaecology and psychiatry.
A summary of the endocrine effects of RED-S by Elliott-Sale et al (2018) provides the latest background on hormonal/physiological profiles in LEA in men and women provided in the supplementary data (online supplementary table S4). [bib_ref] Low energy availability in athletes: a review of prevalence, dietary patterns, physiological..., Logue [/bib_ref] While Disordered eating flow chart: recognition of disordered eating and referral of an athlete for assessment and management, primarily by the core multidisciplinary team within the context of a healthy sport system. A nutrition assessment of the athlete with possible DE includes information on a range of issues Behavioural ► Current eating patterns ► Eating behaviour history ► Special diets followed, particularly if the diet involves avoidance of certain foods and/or if the range of foods to be avoided has increased over time ► Specific food restrictions in place, whether for medical or for personal reasons ► Food rules and beliefs ► Flexibility or rigidity around food or nutrient intake ► Current and past nutritional supplement use ► Social interaction with food and meals (any isolation or withdrawing) ► Compensatory behaviours (eg, vomiting, laxative use, diet pills, etc.)
## Physical
► Pathogenic weight control practices ► Adequacy of current dietary intake including overall energy, macronutrients and micronutrients ► Current and past history of weight and body composition (are these stable or do they fluctuate) ► Active pursuit of changes in body composition, including the time course and methods of achieving these changes ► Training load and phase ► Food security some biomarkers/hormones show significant change in female athletes, menstrual dysfunction may be a more readily detectable clinical sign of LEA.Importantly, menstrual dysfunction should not be accepted as an inevitable consequence of being an athlete and should be investigated. Furthermore, hormonal profiling in a female taking hormonal contraception is not clinically useful. Hormonal profiling may be considered after a trial of 3 months off the combined contraceptive pill (COCP). Changes in biomarkers/hormones in men are different from those in women and may occur at a lower EA cut-off. [bib_ref] A six-year longitudinal study of the relationship of physical activity to bone..., Bailey [/bib_ref] The long-term consequences of impaired hormonal health in male athletes is not well established and requires further research. 37
## Bone health
Optimisation of bone health is important for short-term and long-term health and performance outcomes and involves the attainment of peak bone mass (between 18 years and 22 years of age) and prevention of accelerated BMD loss thereafter. [bib_ref] The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in..., Mountjoy [/bib_ref] A medical workup of an athlete with any combination of DE or ED, bone stress injury, menstrual and/or hormonal dysfunction should take into account various modifiers of bone health including nutrition, environmental, sport-specific mechanical loading, hormonal and iatrogenic factors. Instigation of appropriate pharmacological and bone loading treatment may be required. An athlete involved in a non-weight bearing and/ or endurance sport (eg, swimming or cycling) should consider a programme involving drop jumps to satiate ground reaction force contribution to bone health, a typical programme might involve a two-footed landing from a 30 cm platform, repeated 10 times with 10 second gap between jumps. Athletes with 6 months or more of LEA, DE, ED or amenorrhoea should have BMD measured by dual-energy X-ray absorptiometry (DXA), [bib_ref] The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in..., Mountjoy [/bib_ref] as per the guidelines of the International Society of Clinical Densitometry and the American College of Sports Medicine. Assessments should refer to Z-scores (agematched and sex-matched). In the athletic population, low BMD is defined as a Z-score between −1 SD and −2 SD, together with a history of nutritional deficiencies, hypo-oestrogenism, stress fracture or other secondary clinical risk factors for fracture. [bib_ref] The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in..., Mountjoy [/bib_ref] As athletes in weight-bearing sports should have a BMD that is 5%-15% higher than non-athletes, a BMD Z-score less than −1 SD warrants further attention. 9 DXA assessments should be repeated in at-risk adults every 12 months and in at-risk adolescents at a minimum of every 6 months, preferably using the same DXA machine. [bib_ref] The IOC consensus statement: beyond the Female Athlete Triad--Relative Energy Deficiency in..., Mountjoy [/bib_ref] Calcium supplementation may be required if the recommended daily intake is not met from food sources, but such decisions should be made only after a thorough dietary assessment by a sports dietitian. Guidelines for calcium intake vary slightly between countries with the daily recommended dietary intake of calcium 1000 mg for men and women aged 19-50 years in Australia and the USA, and 1300 mg for children and adolescents, aged 12-18 years in Australia, and 9-18 years, in the USA. While the biochemical cut-off for vitamin D deficiency is controversial, [bib_ref] Screening for vitamin D deficiency: a systematic review for the U.S. preventive..., Leblanc [/bib_ref] blood levels <50 nmol/L in winter months or <75 nmol/L in summer months should be considered for supplementation. [bib_ref] Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D..., Jesudason [/bib_ref] The endocrine society clinical practice guidelines provide current recommendations for vitamin D supplementation across age ranges and subpopulations. [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine Society clinical..., Holick [/bib_ref] Vitamin D deficient adults can be treated with 50 000 IU of vitamin D once a week for 8 weeks, followed by maintenance therapy of 1500-2000 IU daily, with repeat serum vitamin D testing to assess response and prevent toxicity. [bib_ref] Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine Society clinical..., Holick [/bib_ref] Inadequate EA is likely to be the most important dietary cause of poor bone health; there is evidence of suppressed bone formation once EA decreases below 30 kcal/ kg FFM/day in women 28 while impaired bone health is likely to occur below 20-25 kcal/kg FFM/day in men. Serum testosterone within the lowest quartile of the normal clinical range (total testosterone 9-38 nmol/L) is associated with an increased risk of bone injuries in men. [bib_ref] A six-year longitudinal study of the relationship of physical activity to bone..., Bailey [/bib_ref]
## Female athletes
Amenorrhoea may occur in up to 66% of athletes, 49 but its presence for more than 3 months should not be accepted as an inevitable consequence of being an athlete and must be investigated. [bib_ref] National athletic trainers' association position statement: preventing, detecting, and managing disordered eating..., Bonci [/bib_ref] Aetiology of oligo-amenorrhoea may include pregnancy, primary ovarian insufficiency, hyperprolactinaemia, thyroid dysfunction, polycystic ovarian syndrome (PCOS) and functional hypothalamic amenorrhoea (FHA), which is a diagnosis of exclusion. The underlying cause of FHA is LEA rather than exercise volume or body composition, thus optimisation of energy availability (EA) should be the first line treatment of FHA, 37 however it may take more than 6 months for favourable menstrual changes. [bib_ref] Behavioral, psychological, and physical characteristics of female athletes with subclinical eating disorders, Beals [/bib_ref] Assessment of an athlete with menstrual dysfunction by a sports dietitian forms a part of the complete care of the female athlete.
The triad amenorrhoea algorithm as produced by Joy et al (2014) provides a succinct and systematic approach to diagnosis and referral of an athlete with menstrual dysfunction. [bib_ref] female athlete triad coalition consensus statement on treatment and return to play..., Joy [/bib_ref] The clinical signs and symptoms of menstrual dysfunction can be used as a surrogate marker for LEA, but these may be masked by concurrent use of oral contraception. Treatment of menstrual dysfunction via supplementation with exogenous hormones, such as the COCP, does not correct the cause of FHA and does not protect against BMD loss. 9 To protect BMD in these athletes, it is preferable to use transdermal oestrogen, with cyclic oral progestin as an adjunct; this is applied twice weekly as a transdermal 51 β-oestradiol (E2) patch (100 µg), with cyclic micronised progesterone (200 mg) for 12 days each month. [bib_ref] female athlete triad coalition consensus statement on treatment and return to play..., Joy [/bib_ref] The transdermal hormones are not a form of contraception and risk factors which may preclude use of the COCP should be considered. [bib_ref] female athlete triad coalition consensus statement on treatment and return to play..., Joy [/bib_ref] Male athletes LEA may suppress reproductive and metabolic hormones in men at <20-25 kcal/kg/fat free mass (FFM)/day 10 but the clinical signs and symptoms are relatively subtle. [bib_ref] Behavioral, psychological, and physical characteristics of female athletes with subclinical eating disorders, Beals [/bib_ref] Reduction in libido and loss of nocturnal penile tumescence may be a sign of relative reduction in testosterone. A relative reduction in testosterone that may remain at a subclinical threshold may be seen in the LEA state. [bib_ref] A six-year longitudinal study of the relationship of physical activity to bone..., Bailey [/bib_ref] Testosterone is best measured as a fasted, morning sample to avoid wider fluctuations throughout the day. A serial/ longitudinal record for the individual in the clinical context may be more beneficial than a single measurement. 37
## Psychological assessment mental health
A comprehensive mental health evaluation is critical to determining intervention and treatment, and can be provided by a psychologist or doctor within the CMT. The mental health evaluation aims to determine range and severity of DE symptoms, diagnose EDs and other mental illnesses, and identify any immediate medical or psychological risk. EDs have one of the highest mortality rates of all psychiatric illnesses, and those diagnosed with an ED have significantly elevated suicide risk. [bib_ref] Suicide attempts in eating disorder subtypes: a meta-analysis of the literature employing..., Mandelli [/bib_ref] [bib_ref] Mortality rates in patients with anorexia nervosa and other eating disorders. A..., Arcelus [/bib_ref] [bib_ref] Epidemiology, course, and outcome of eating disorders, Smink [/bib_ref] Therefore, a suicide risk assessment should be undertaken to include suicidal ideation, deliberate self-harm, previous suicidal behaviours and self-harm events, agitation and current or past risk of harm to others.
The use of interview protocols is well suited to evaluating eating behaviours and beliefs according to Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria. The EDE 17.0 or EDE-Q 6.0 can be used for these purposes, as can a mental health evaluation such as the Mini International Neuropsychiatric Interview (MINI 7.0.2). [bib_ref] The Mini-International neuropsychiatric interview (M.I.N.I.): the development and validation of a structured..., Sheehan [/bib_ref] The MINI 7.0.2 provides a diagnosis of prior and current comorbid conditions, including EDs as well as suicidality. When a focused ED or thorough mental health evaluation is required, this should be done by an appropriately trained mental health clinician.
## Family and social networks
In addition to mental health, psychologists will also examine the athlete's psychosocial history, social support and perceived stress across relevant life domains (sport, school/work, social). Family history of mental illness is also relevant, particularly the presence of DE or body image disturbances. As part of the social network, assessment and engagement of parental support early in the process is important to facilitate implementation of the recommended intervention, particularly if health deteriorates. [bib_ref] National athletic trainers' association position statement: preventing, detecting, and managing disordered eating..., Bonci [/bib_ref] Where DE symptoms are detected or there is a high risk of developing an ED, additional information regarding the athlete's readiness for early intervention and treatment is important. This includes the athlete's readiness to change, as well as anticipated challenges and strengths or protective factors. The athlete's readiness to change, or motivation for treatment is a consistent predictor of treatment success. [bib_ref] Assessing motivation to change in eating disorders: a systematic review, Hoetzel [/bib_ref] The complexity of DE requires a biopsychosocial approach, and it is important to know the type and nature of support within the athletes' social network. A supportive and well-aligned network is critical to successful treatment. 57
## Treatment and ongoing monitoring of the athlete with de
Once DE is identified in the high performance athlete, the review and maintenance process of care requires information summary position statements and key concepts disordered eating prevalence and consequences on health and performance ► There is a spectrum of eating behaviours in high performance sport that spans from optimised nutrition through disordered eating to clinically diagnosed eating disorders. ► Disordered eating and low energy availability can occur together or in isolation. Identification of one necessitates the investigation of the other. Low energy availability underpins the syndrome of relative energy deficiency in sport, which has many health and performance consequences. ► Disordered eating can occur in any athlete, in any sport, at any time, crossing boundaries of gender, age, body size, culture, socioeconomic background, athletic calibre and ability. ► In addressing the health and performance consequences of disordered eating or eating disorders, health must be the priority. ► Inappropriate eating practices increase the risk of illness and injury. Compromised training in turn impairs performance. ► Personal attributes which underpin successful performance, combined with the sport environment may leave athletes vulnerable to disordered eating.
Early identification of disordered eating ► Everyone in the high performance sports system has a role as early identifiers of disordered eating. Education and literacy are required around risk factors, warning signs and red flags. ► The goals of assessment are to identify disordered eating or eating disorders, investigate the presence of low energy availability/relative energy deficiency in sport and its consequences, and manage acute and chronic complications in the athlete.
The core multidisciplinary team ► The core multidisciplinary team of doctor, sports dietitian and psychologist form the cornerstone of professional assessment and management of athletes on the spectrum of eating behaviour. ► The core multidisciplinary team works with athletes and their support network to investigate and manage the health and performance of athletes taking into account individual case characteristics and sport-specific demands. ► Doctors, sports dietitians and psychologists working within sport need to have an awareness and constantly seek to improve their knowledge and skills regarding disordered eating. ► The core multidisciplinary team is responsible for ensuring continuity of care. ► Athletes with an eating disorder should be referred to a specialised eating disorder service. Where there is a delay in access, the core multidisciplinary team is responsible for the athlete's care. ► It is crucial that there are well-defined roles and a clear communication strategy within the core multidisciplinary team and across relevant stakeholders.
nutritional assessment ► When possible disordered eating or an eating disorder is identified in an athlete, a nutrition assessment is required. ► A sports dietitian will determine where an athlete currently sits on the spectrum of eating behaviours (from optimised nutrition to eating disorders) and track their progression along the spectrum based on specific, targeted nutritional interventions. ► Manipulation of nutrition practices can play a valuable role in athletic performance. Athletes must engage in optimised nutrition that is safe, supported, purposeful and individualised. ► An athlete may be stable in weight but deficient in energy. Weight should not be the sole focus of the multimodal assessment of disordered eating. medical assessment ► All athletes with bone stress injury and/or menstrual dysfunction should be screened for low energy availability/relative energy deficiency in sport and screened/assessed for disordered eating and eating disorders. ► Understanding menstrual function in the individual athlete is essential for providing optimal care. Menstrual dysfunction should be investigated. ► While the clinical signs and symptoms are relatively subtle, impaired hormonal health can also occur in male athletes. ► Eating disorders can be life-threatening; doctors should have the key clinical competency to identify an athlete who is unstable and requires removal from sport, emergency intervention and admission to supportive care.
Psychological assessment ► Athletes being evaluated for disordered eating or eating disorders require a comprehensive mental health evaluation. ► Eating disorders have one of the highest mortality rates of any mental illness. An athlete's medical and psychological safety is paramount and requires ongoing vigilance.
return to play ► The core multidisciplinary team monitors and communicates medical and behavioural objectives to ensure safety and inform athletespecific return to play criteria, with input from established return to play frameworks as required.
Prevention and education ► Education is the best evidence-based method for primary prevention of disordered eating and eating disorders and is included within the well-being and performance health strategy. Education should target the key issues in a sport, and may include elements related to increasing awareness of the problem and its risk factors, improving body image and raising nutrition literacy.
## Continued
## Consensus statement summary position statements and key concepts continued
► Athletes, coaches, support staff members and judges should undergo an initial comprehensive education programme and regular refresher education sessions.
body composition assessments in athletes ► Body composition assessment and weighing strategies must reflect individual needs and emphasise choice, collaboration, trust, safety and empowerment. ► High frequency self-weighing and/or team or service provider weighing should be moderated to reduce risk to athletes. ► Body composition assessment should only be undertaken if it is purposeful and necessary to optimise the performance of the athlete. ► All athletes should attend an education session with a qualified anthropometrist prior to any body composition testing being conducted. This should include provision of information to explain the rationale for testing, method of assessment, storage and use of information, and allow time for questions. ► All athletes should complete a consent process for body composition assessments, with parental consent where appropriate. ► Prior to undertaking body composition assessment and/or weighing strategies, serious consideration must be given regarding the purpose of the assessment. Assessment should not take place without adequate nutrition support or if the assessment is considered likely to be harmful to the athlete with disordered eating or an eating disorder. ► The entire process of body composition assessment and feedback is treated as personal and confidential medical information. It must be made clear where the information is being stored, who the information is being shared with and for what specific purpose(s).
body image ► Positive body image is one of the protective factors against development of eating disorders, and forms a foundation for most effective eating disorder prevention programmes. ► Body image dissatisfaction in male and female athletes is a risk factor for disordered eating or eating disorders irrespective of the perceived weight-related performance pressures of their sport.
Healthy sport systems ► Every sporting organisation should have a guideline on prevention and early identification of disordered eating for their sport that encompasses continuity of care, addresses the specific context of their particular sport, and upholds the core principle of 'first do no harm' with regards to athlete body image, nutrition, performance and related measures. ► Sports have a responsibility to all athletes across the entire high performance pathway to create a healthy sports system, both in the environment and culture of the sport.
sharing and progression of treatment goals between the athlete, CMT, sports coaches and support staff. A designated member of the CMT should ideally coordinate the flow of information within the team to formulate individual athlete treatment and maintenance goals, clearly outlining medical and behavioural objectives to ensure safety and sports-specific RTP criteria. This requires engagement with the athlete and follow-through from sports staff. A large amount of information is typically collected in areas of nutrition, medicine and psychology; a consistent, systematic approach is required to ensure that all avenues have been explored and openly communicated. The CMT can formulate a time line for maintenance and review.
## Modifications, exclusions and rtp decisions
Given the potential for injury and/or illness if an athlete continues to train through DE, there may be times when training modification or full exclusion is required. An ED diagnosis may not be needed to justify the need for modification to training and/or competition to ensure the athlete's safety. It is reasonable that athletes with DE can continue to participate in sports, provided they engage appropriately and consistently with their support team. [bib_ref] National athletic trainers' association position statement: preventing, detecting, and managing disordered eating..., Bonci [/bib_ref] Each sport governing organisation or federation should have guidelines to support difficult decisions with respect to affected athletes and the particular diagnoses (eg, RED-S). [bib_ref] Aspects of disordered eating continuum in elite highintensity sports, Sundgot-Borgen [/bib_ref] Clinical assessment tools which may assist and guide decision making in relation to RTP, include the RED-S Clinical Assessment Tool and the 2014 Female Athlete Triad Coalition Consensus Statement (female athletes with DE, menstrual dysfunction and low BMD). [bib_ref] female athlete triad coalition consensus statement on treatment and return to play..., Joy [/bib_ref] Currently, there are no accepted values for sport-specific minimum or optimal levels of body fat or body weight. [bib_ref] How to minimise the health risks to athletes who compete in weight-sensitive..., Sundgot-Borgen [/bib_ref] As such, these values should not be set by sporting organisations. Within the clinical ED treatment environment, the Safe Exercise at Every Stage guideline may be used to guide clinical reviews and RTP plans.Athletes with an ED should be referred to an appropriate ED service and assisted to transition back into the high performance sporting environment as part of their recovery.
## Prevention prevention and education
Creating and embedding an environment and culture that assists in the prevention of DE is of utmost importance to promoting the health of all athletes and minimising DE risk and incidence. To minimise DE risk and incidence, key points of prevention are identified by Sundgot-Borgen and Torstveit (2010) and include advocating health and well-being, de-emphasising body weight, and making DE a 'health and safety issue' not a 'coaching issue' among others. [bib_ref] Aspects of disordered eating continuum in elite highintensity sports, Sundgot-Borgen [/bib_ref] Prevention of DE can also involve advocacy for changes to unhealthy sport rules and identifying strategies to mitigate existing 'at risk' rules. Education programmes are the best method of primary prevention of DE and EDs. [bib_ref] Prevention of eating disorders in female athletes, Gmdeo [/bib_ref] The main aims of education are to reduce stigma, promote healthy relationships with food and body, encourage open and honest discussion, educate about potential health and performance consequences, and educate about optimal nutritional strategies. [bib_ref] National athletic trainers' association position statement: preventing, detecting, and managing disordered eating..., Bonci [/bib_ref] Best practice in this area would see coaches, sport support staff members and judges undergoing an initial comprehensive education programme and regular refresher education sessions.
Athlete prevention efforts are best directed at modifiable risk factors such as body dissatisfaction and low self-esteem, and seek to minimise potential adverse effects of body manipulation. 61
## Assessment and manipulation of body composition
'Dieting', the deliberate restriction of calories and/or specific nutrients for actions to promote the purpose of loss of body mass and/or body fat, is well documented as one of the major risk factors for developing an ED. [bib_ref] Thin-ideal internalization: mounting evidence for a new risk factor for body-image disturbance..., Thompson [/bib_ref] Yet, physique assessment is a common activity undertaken within athlete monitoring protocols, and manipulation of body composition, including weight or body fat loss, is a common goal within an athlete's sports nutrition plan. Routine assessment of body composition requires careful deliberation of the rationale for the assessment (ie, is it purposeful and necessary), who is undertaking the measurements, the level of training required to take the measurements as well as the level of support available to the athlete to interpret the information and provide recommendations. Examples of body composition assessment techniques include (but are not limited to) body mass weighing, skinfolds and DXA. If manipulation of body composition is indicated, expert nutrition support from a sports dietitian should be provided from end to end: that is, from preassessment through assessment to advice and ongoing monitoring. A sports dietitian can formulate advice as to whether to test athletes or not, based on some of the following factors: history of DE or EDs, age, level of nutrition support in the domestic training environment, and the type of protocols used (weighing, skinfolds and DXA). It should be considered that the coach is not primarily involved in the body composition assessment process. The underpinning philosophies of body composition monitoring are that no harm should be done to the athlete being tested and that the data collected from such protocols should be treated as personal and confidential medical information. [bib_ref] Current status of body composition assessment in sport, Ackland [/bib_ref] Education regarding body composition and testing including procedure, rationale, consent and use of information must be conducted for all athletes prior to commencing any testing.
## Strategies for safe weighing and body composition assessment
Strategies for safely weighing and assessing an athlete's body composition include gaining explicit consent for every measurement (verbal), checking in with the athlete prior to the measurement and offering to 'blind weigh' the athlete so that they do not see the results of the examination. [bib_ref] Clinicians' practices regarding blind versus open weighing among patients with eating disorders, Forbush [/bib_ref] If there is any distress about being weighed or measured, this needs to be taken seriously and the coach and CMT need to discuss the appropriate course of action for this athlete. There are some ED treatment modalities which include viewed weighing as a form of exposure therapy and monitoring (eg, enhanced cognitive therapy),however these should not be undertaken by anyone who has not been appropriately trained or does not have adequate support from the CMT and clinical supervision. One member of the CMT will be responsible for ongoing monitoring of this metric, so that the athlete is not weighed or measured either too frequently, or by different clinicians and can foster trust and appropriate interpretation of results to promote continuity of care.
## Body image
Positive body image is one of the protective factors against development of EDs, and forms a foundation for most effective ED prevention programmes in athletes. [bib_ref] Role of body dissatisfaction in the onset and maintenance of eating pathology:..., Stice [/bib_ref] It is notable to acknowledge that negative and positive body image are two different yet intersecting constructs and both need to be taken into consideration within both the general and athlete populations. [bib_ref] What is and what is not positive body image? conceptual foundations and..., Tylka [/bib_ref] An athlete's perception of their physical self, and the thoughts and feelings that are entailed, can produce perceptual, affective, cognitive and behavioural manifestations. An athlete may frequently have separate body images; an athletic body image and a social body image. [bib_ref] Body image of highly trained female athletes engaged in different types of..., Kantanista [/bib_ref] [bib_ref] Body image concerns in female exercisers and athletes: a feminist cultural studies..., Krane [/bib_ref] [bib_ref] Some contradictions and tensions in elite sportsmen's attitudes towards their bodies, Loland [/bib_ref] [bib_ref] On versus off the pitch: the transiency of body satisfaction among female..., Russell [/bib_ref] There may be tensions between the socially desirable body image and the ideal physique for performance in the athlete's sport. [bib_ref] The relationship between gender, type of sport, body dissatisfaction, self Esteem and..., Milligan [/bib_ref] Both male and female athletes may have a body image that is in conflict with cultural norms and gender stereotypes. Body image dissatisfaction in male and female athletes is a risk factor for DE or ED irrespective of the perceived weight-related performance pressures of their sport. [bib_ref] Body image of highly trained female athletes engaged in different types of..., Kantanista [/bib_ref] Some subpopulations are at additional risk for body image dissatisfaction; for example, para-sport athletes and those with concurrent conditions such as diabetes mellitus or PCOS. [bib_ref] Polycystic ovary syndrome and mental health: a review, Himelein [/bib_ref] The biological changes that occur during puberty and adolescence may contrast with the ideal physique in a sport, making this a higher risk time for the development of DE or an ED. 7
## Creating a healthy sport system
Support systems for healthy participation in sport involving individuals with specific expertise in DE and ED will decrease the likelihood that such problems will occur in athletes. Every sporting organisation should be aware of the increased prevalence of DE in high performance athletes and have established guidelines for early identification and prevention of DE. Guidelines should reflect this position statement, be sport-specific, and promote nutrition practices that are safe, supported, purposeful and individualised. Sporting organisations need communication protocols to refer athletes to a member of the CMT, as part of accepted and routine care to support athlete health and performance optimisation. Some sporting organisations may not currently have access to a member of the CMT. Sports should work to build their healthcare network to ensure that they are able to work with a fully comprised CMT.
The rules and regulations for specific sports can influence prevalence of DE behaviours in athletes. [bib_ref] Weight control strategies of Olympic athletes striving for leanness: what can be..., Mountjoy [/bib_ref] Sporting organisations should be aware of the implications of the specific rules within their sport and their potential impact on the eating practices of their athletes. It may be necessary for organisations to lobby for rule changes to decrease the risk of practices contributing to DE or EDs within their sport.
Lastly, further research is required in the area of DE in high performance athletes, particularly intervention studies, prevention studies, validation of sport-specific and gender/ cultural-specific screening tools, as well as the para-athlete and investigating the prevalence of DE in the variety of athlete subpopulations.
# Conclusion
This AIS-NEDC document reviews the current literature and provides a set of positions and key concepts on the approach to early identification, assessment and prevention of DE in high performance sport. Athlete health and welfare must remain the primary focus of preventing and managing DE in sport at all times. Awareness, recognition and referral of the athlete with DE to a CMT comprising a doctor, sports dietitian and psychologist forms the foundation of support for optimised nutrition. Sporting organisations should develop sport-specific guidelines around DE to best optimise health and performance. This document provides guidance for the high performance system
# Consensus statement
to improve the awareness and management of this complex condition.
Correction notice This article has been corrected since it published Online First. [fig_ref] Figure 2: Eating disorders/disordered eating can occur in the absence or presence of low... [/fig_ref] has been corrected and replaced.
[fig] Figure 2: Eating disorders/disordered eating can occur in the absence or presence of low energy availability (adapted from Mountjoy et al) 10 78 . DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. [/fig]
[table] Table 2: Suggested risk factors for disordered eating and eating disorders in high performance athletes4 10 14 17 18 [/table]
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https://bjsm.bmj.com/content/bjsports/54/21/1247.full.pdf
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Identification, evaluation and management of disordered eating (DE) is complex. DE exists along the spectrum from optimised nutrition through to clinical eating disorders (EDs). Individual athletes can move back and forth along the spectrum of eating behaviour at any point in time over their career and within different stages of a training cycle. Athletes are more likely to present with DE than a clinical ED. Overall, there is a higher prevalence of DE and EDs in athletes compared with non-athletes. Additionally, athletes participating in aesthetic, gravitational and weight-class sports are at higher risk of DE and EDs than those in sports without these characteristics. The evaluation and management of DE requires a cohesive team of professional practitioners consisting of, at minimum, a doctor, a sports dietitian and a psychologist, termed within this statement as the core multidisciplinary team. The Australian Institute of Sport and the National Eating Disorders Collaboration have collaborated to provide this position statement, containing guidelines for athletes, coaches, support staff, clinicians and sporting organisations. The guidelines support the prevention and early identification of DE, and promote timely intervention to optimise nutrition for performance in a safe, supported, purposeful and individualised manner. This position statement is a call to action to all involved in sport to be aware of poor self-image and poor body image among athletes. The practical recommendations should guide the clinical management of DE in high performance sport.
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2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus.
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2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus.
# Introduction
In 1995, the US Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) in persons infected with human immunodeficiency virus (HIV) . These guidelines, written for health-care providers and patients, were revised in 1997 and again in 1999 . They have been published in the MMWR , Clinical Infectious Diseases 2,6,7 , the Annals of Internal Medicine , the American Family Physician 9,10 , and Pediatrics 11 ; accompanying editorials have appeared in JAMA . Response to these guidelines (e.g., the many requests for reprints, numerous web site contacts and observations from health-care providers) suggests they have served as a valuable reference for HIV care providers. Because the 1995, 1997 and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation.
Since AIDS was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life of HIV-infected persons in the industrialized world. During the first decade of the epidemic, this improvement occurred because of better recognition of opportunistic disease processes, better therapy for acute and chronic complications and the introduction of chemoprophylaxis against important opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating individual OIs. HAART has reduced the incidence of OIs and extended life substantially [bib_ref] and the Adult/Adolescent Spectrum of Disease Group. Effects of antiretroviral therapy and..., Mcnaghten [/bib_ref]. HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy [bib_ref] and the Adult/Adolescent Spectrum of Disease Group. Effects of antiretroviral therapy and..., Mcnaghten [/bib_ref]. However, some patients are not ready or able to take HAART and others have tried HAART regimens, but therapy has failed. Such patients will benefit from prophylaxis against OIs [bib_ref] and the Adult/Adolescent Spectrum of Disease Group. Effects of antiretroviral therapy and..., Mcnaghten [/bib_ref]. In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART [bib_ref] and the Adult/Adolescent Spectrum of Disease Group. Effects of antiretroviral therapy and..., Mcnaghten [/bib_ref].
Since HAART was introduced in the United States in 1995, it has become increasingly clear that chemoprophylaxis for OIs need not necessarily be life-long. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by the CD4 + T lymphocyte count for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART seems logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care and potentially facilitate adherence to antiretroviral regimens. In 1999, the USPHS/IDSA guidelines suggested that it may be safe to stop primary or secondary prophylaxis for some (but not all) pathogens if HAART has led to an increase in CD4 + T lymphocyte counts above specified threshold levels. Recommendations were made for only those pathogens for which adequate clinical data were available. Data generated since 1999 continue to support these recommendations and allow additional recommendations to be made concerning the safety of stopping primary or secondary prophylaxis for other pathogens.
For recommendations on discontinuation of chemoprophylaxis, readers will note that criteria vary by such factors as duration of CD4 + T lymphocyte count increase, and, in the case of secondary prophylaxis, duration of treatment of the initial episode of disease. These differences reflect the criteria used in specific studies. Therefore, some inconsistency in the format of these criteria is unavoidable.
Although considerable data are now available concerning discontinuing primary and secondary OI prophylaxis, essentially no data are available regarding restarting prophylaxis when the CD4 + T lymphocyte count decreases again to levels at which the patient is likely to again be at risk for OI. For primary prophylaxis, whether to use the same threshold at which prophylaxis may be stopped (derived from data in studies addressing prophylaxis discontinuation), or to use the threshold below which initial prophylaxis is recommended is unknown. Therefore in this revision of the guidelines, in some cases ranges are provided for restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis carinii pneumonia (PCP), the suggested threshold for restarting both primary and secondary prophylaxis is 200 cells/ml. For all these recommendations, the roman numeral ratings reflect the lack of data available to assist in making these decisions (see description of rating system below).
During the development of these revised guidelines, working group members reviewed published manuscripts as well as abstracts and material presented at professional meetings. A series of teleconferences were held to develop the revisions. In this revision, information and recommendations which are new since the 1999 publication are indicated in bold.
## Major changes in these recommendations
Major changes in the guidelines since 1999 include:
## Higher level ratings have been provided for discontinuing primary prophylaxis for pcp and mac when cd4 + t lymphocytes have increased to > 200 cells/ml and > 100 cells/ml, respectively, for 3 months in response to haart (ai), and a new recommendation to discontinue primary toxoplasma prophylaxis has been provided when the cd4 + t lymphocyte count has increased to > 200 cells/ml for 3 months (ai).
## The importance of screening all hiv-infected individuals for hepatitis c virus (hcv) is emphasized (biii).
## Additional information about transmission of human herpes virus 8 infection (hhv-8) is provided.
7. New information on drug interactions is provided, especially with regard to rifamycins and antiretroviral drugs. . Revised recommendations for immunization of HIV exposed/infected adults and children are provided.
## How to use the information in this report
For each of the 19 diseases covered in this report, specific recommendations are provided that address a) prevention of exposure to the opportunistic pathogen, b) prevention of the first episode of disease and c) prevention of disease recurrence. Recommendations are rated by a revised version of the IDSA rating system 17 . In this system, the letters A-E signify the strength of the recommendation for or against a preventive measure and roman numerals I-III indicate the quality of evidence supporting the recommendation (see [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref]. This report incldes a number of tables that summarize recommendations. They are as follows: dosages for prophylaxis to prevent first episode of opportunistic disease in HIV infected adults and adolescents [fig_ref] Table 2: Prophylaxis to prevent first episode of opportunistic disease in adults and adolescents... [/fig_ref] ; dosages for prophylaxis to prevent recurrence of opportunistic disease in HIV-infected adults and adolescents [fig_ref] Table 3: Prophylaxis to prevent recurrence of opportunistic disease in adults [/fig_ref] ; effects of food on drugs used to treat OIs [fig_ref] Table 4: Effects of Food on Drugs used to prevent opportunistic infections [/fig_ref] ; effects of medications on drugs used to treat OIs [fig_ref] Table 5: Effects of medications on drugs used to prevent opportunistic infections [/fig_ref] ; effects of OI medications on drugs commonly administered to HIV-infected persons ; adverse effects of drugs used to manage HIV infection ; dosages of drugs for prevention of OIs for persons with renal insufficiency; costs of agents recommended for the prevention of OIs in adults with HIV infection ; immunologic categories for HIV-infected
## Iii
Both strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered Moderate evidence for efficacy -or strong evidence for efficacy but only limited clinical benefit -supports recommendation for use. Should generally be offered Evidence for efficacy is insufficient to support a recommendation for or against use. Or evidence for efficacy might not outweigh adverse consequences (e.g.,drug toxicity, drug, interactions) or cost of the chemoprophylaxis or alternative approaches. Optional Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered Quality of evidence supporting the recommendation Evidence from at least one properly randomized, controlled trial Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), or from multiple time-series studies. Or dramatic results from uncontrolled experiments Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] ; immunization schedule for HIV-infected children [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] ; dosages for prophylaxis to prevent first episode of opportunistic disease in HIV-infected infants and children [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] ; dosages for prophylaxis to prevent recurrence of opportunistic disease in HIV-infected infants and children [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] ; and criteria for discontinuing and restarting OI prophylaxis for adult patients with HIV infection Pyrimethamine-sulfadiazine confers protection against PCP as well as toxoplasmosis; clindamycin-pyrimethamine does not offer protection against PCP. Many multiple-drug regimens are poorly tolerated. Drug interactions (e.g., those seen with clarithromycin and rifabutin) can be problematic; rifabutin has been associated with uveitis, especially when administered at daily doses of > 300 mg or concurrently with fluconazole or clarithromycin. See discussion of rifamycin interactions in paragraph 9 in section on Tuberculosis (54). Efficacy for eradication of Salmonella has been demonstrated only for ciprofloxacin. *During pregnancy, azithromycin is recommended instead of clarithromycin because clarithromycin is teratogenic in animals. [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref]. Recommendations advising patients how to prevent exposure to opportunistic pathogens appear in the Appendix at the end of this report. This report is oriented toward the prevention of specific OIs in HIV-infected persons in the United States and other industrialized countries. Recommendations for use of HAART, which is designed to prevent immunologic deterioration, to restore immune function and delay the need for many of the chemoprophylactic strategies described in this report, were originally published elsewhereand are updated regularly (www.hivatis.org).
Pamphlets for patients regarding prevention of OIs can be obtained from the HIV/AIDS Treatment Information Service (ATIS) by calling (800) 448-0440, (301) 519-0459 (international) or (888) 480-3739 (TTY). They also can be accessed on both the CDC and HIVATIS websites (www.cdc.gov/hiv/pubs/brochure.htm and www.hivatis.org).
New data on prevention of OIs in HIV-infected persons are emerging, and randomized controlled trials addressing some unresolved issues in OI prophylaxis are ongoing. The OI Working Group review emerging data routinely and will update these guidelines on a regular basis.
## Pneumocystis carinii pneumonia prevention of exposure
Although some authorities recommend that persons with HIV infection who are at risk for P. carinii pneumonia (PCP) not share a hospital room with a patient who has PCP, data are insufficient to support this recommendation as standard practice (CIII).
## Prevention of disease
## Initiation of primary prophylaxis
Adults and adolescents who have HIV infection (including pregnant women and those on HAART) should receive chemoprophylaxis against PCP if they have a CD4 + T lymphocyte count of less than 200 ml (AI) or a history of oropharyngeal candidiasis (AII) [bib_ref] and the Multicenter AIDS Cohort Study Group. The risk of Pneumocystis carinii..., Phair [/bib_ref] [bib_ref] Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents..., Kaplan [/bib_ref]. Persons who have a CD4 + T lymphocyte percentage of less than 14% or history of an acquired immunodeficiency syndrome (AIDS)-defining illness but do not otherwise qualify should be considered for prophylaxis (BII) [bib_ref] and the Multicenter AIDS Cohort Study Group. The risk of Pneumocystis carinii..., Phair [/bib_ref] [bib_ref] Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents..., Kaplan [/bib_ref]. When monitoring the CD4 + T lymphocyte count at least every 3 months is not possible, initiation of chemoprophylaxis at a CD4 + T lymphocyte count of greater than 200 but less than 250 cells/ml also should be considered (BII) [bib_ref] Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents..., Kaplan [/bib_ref]. Trimethoprim-sulfamethoxazole (TMP-SMZ) is the recommended prophylactic agent (AI) [bib_ref] A randomized trial of three antipneumocystis agents in patients with advanced human..., Bozzette [/bib_ref] [bib_ref] and the Dutch AIDS Treatment Group. A controlled trial of aerosolized pentamidine..., Schneider [/bib_ref] [bib_ref] Efficacy and toxicity of two doses of trimethoprimsulfamethoxazole as primary prophylaxis against..., Schneider [/bib_ref]. One double-strength tablet per day is the preferred regimen (AI) [bib_ref] Efficacy and toxicity of two doses of trimethoprimsulfamethoxazole as primary prophylaxis against..., Schneider [/bib_ref]. However, one single-strength tablet per day is also effective and might be better tolerated than one double strength tablet per day (AI). One double-strength tablet three times per week is also effective (BI) [bib_ref] A randomized trial of daily and thrice weekly trimethoprimsulfamethoxazole for the prevention..., El-Sadr [/bib_ref]. TMP-SMZ at a dose of one double-strength tablet per day confers cross-protection against toxoplasmosis [bib_ref] Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS, Carr [/bib_ref] and some common respiratory bacterial infections [bib_ref] A randomized trial of three antipneumocystis agents in patients with advanced human..., Bozzette [/bib_ref] [bib_ref] for the AIDS Clinical Trials Group. A controlled trial of trimethoprim-sulfamethoxazole or..., Hardy [/bib_ref]. Lower doses of TMP-SMZ also might confer such protection. For patients who have an adverse reaction that is not life-threatening, treatment with TMP-SMZ should be continued Clinical significance unknown; monitor for ddI-related adverse effects *Little data are available for use of rifamycin drugs with ritonavir-boosting protease inhibitor regimens except for ritonavir-saquinavir and ritonavir-lopinavir. Therefore, concomitant use of rifamycins with these regimens must be approached cautiously Effects of opportunistic infection medications on antiinfective drugs commonly administered to persons infected with human immunodeficiency virus* if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstitution of TMP-SMZ should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, especially fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (desensitization) as per published regimens (BI) [bib_ref] A randomized, double-blind trial of TMP/SMX dose escalation vs. direct challenge in..., Leoung [/bib_ref] [bib_ref] for the ACTG 268 Study Team. Reduced toxicity with gradual initiation of..., Para [/bib_ref] or reintroduction of TMP-SMZ at a reduced dose or frequency (CIII); up to 70% of patients can tolerate such reinstitution of therapy [bib_ref] for the AIDS Clinical Trials Group. A controlled trial of trimethoprim-sulfamethoxazole or..., Hardy [/bib_ref].
If TMP-SMZ cannot be tolerated, prophylactic regimens that can be recommended as alternatives include dapsone (BI) [bib_ref] A randomized trial of three antipneumocystis agents in patients with advanced human..., Bozzette [/bib_ref] , dapsone plus pyrimethamine plus leucovorin (BI) [bib_ref] Intermittent trimethoprim sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of..., Podzamczer [/bib_ref] [bib_ref] Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis..., Opravil [/bib_ref] , aerosolized pentamidine administered by the Respirgard II TM nebulizer (Marquest, Englewood, Colorado) (BI) [bib_ref] and the Dutch AIDS Treatment Group. A controlled trial of aerosolized pentamidine..., Schneider [/bib_ref] and atovaquone (BI) [bib_ref] Atovaquone suspension compared with aerosolized pentamidicine for prevention of Pneumocystis carinii pneumonia..., Chan [/bib_ref] [bib_ref] Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in..., El-Sadr [/bib_ref]. Atovaquone appears to be as effective as aerosolized pentamidine 31 or dapsone (BI) 32 but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMZ, recommended alternatives to TMP-SMZ for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine (BI) [bib_ref] Intermittent trimethoprim sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of..., Podzamczer [/bib_ref] [bib_ref] Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis..., Opravil [/bib_ref] or atovaquone with or without pyrimethamine (CIII). The following regimens generally cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient for a firm recommendation: aerosolized pentamidine administered by other nebulization devices, intermittently administered parenteral pentamidine, oral pyrimethamine plus sulfadoxine, oral clindamycin plus primaquine and intravenous trimetrexate. However, clinicians may consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).
## Discontinuation of primary prophylaxis
Primary pneumocystis prophylaxis should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4 + T lymphocyte counts to > 200 cells/ml for at least 3 months (AI). In observational and randomized studies supporting this recommendation, most patients were taking antiretroviral regimens that included a protease inhibitor and most had a CD4 + T lymphocyte count greater than 200 cells/ml for at least 3 months before discontinuation of PCP prophylaxis [bib_ref] Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated..., Furrer [/bib_ref] [bib_ref] Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral..., Weverling [/bib_ref] [bib_ref] Discontinuation of chemoprophylaxis for Pneumocystis Carinii penumonia in patients with HIV infection, Yangco [/bib_ref] [bib_ref] Discontinuation of Pneumocystis carinii pneumonia prophylaxis in HIV-1 infected patients treated with..., Schneider [/bib_ref] [bib_ref] Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy..., Dworkin [/bib_ref] [bib_ref] Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in..., Mussini [/bib_ref] [bib_ref] Podzamczer D, and the GESIDA 04/98 Study Group. A randomized trial of..., Lopez [/bib_ref] [bib_ref] Discontinuation of primary prophylaxis in HIV infected patients at high risk of..., Furrer [/bib_ref] [bib_ref] Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4..., Kirk [/bib_ref]. The median CD4 + lymphocyte count at the time prophylaxis was discontinued was > 300 cells/ml, and many patients had a sustained suppression of HIV plasma RNA levels below detection limits of the assay employed. Median follow-up ranged from 6-16 months.Dosing of drugs for primary prevention or maintenance therapy for opportunistic infections in renal insufficiency *Discontinuation of primary prophylaxis in these patients is recommended not only because prophylaxis appears to add very little to disease prevention (for PCP, toxoplasmosis, or bacterial infections), but also because discontinuation of drug reduces pill burden, the potential for drug toxicity, drug interactions, selection of drug-resistant pathogens and cost.
## Restarting primary prophylaxis
Prophylaxis should be reintroduced if the CD4 + T lymphocyte count decreases to < 200 cells/ml (AIII).
## Prevention of recurrence
Patients who have a history of PCP should be administered chemoprophylaxis (i.e., secondary prophylaxis or chronic maintenance therapy) with the regimens listed in [fig_ref] Table 3: Prophylaxis to prevent recurrence of opportunistic disease in adults [/fig_ref] for life (AI) unless immune reconstitution occurs as a consequence of HAART.
## Discontinuation of secondary prophylaxis (chronic maintenance therapy (cmt))
Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4 + T cell count has increased from < 200 cells ml to > 200 cells/ml for at least 3 months due to HAART (BII). Reports from observational studies 37,41,42 and from a randomized trial 39 , as well as a combined analysis of eight European cohorts being followed prospectively 43 , support this recommendation. In these studies, patients had responded to HAART with an increase in CD4 + T lymphocyte count to > 200 cells/ml for at least 3 months. Most patients were taking protease inhibitor-containing regimens. The median CD4 + T lymphocyte count at the time prophylaxis was discontinued was > 300 cells/ml. Most patients had sustained suppression of HIV plasma HIV RNA levels below the detection limits of the assay employed; the longest follow-up was 13 months. If the episode of PCP occurred at a CD4 + T lymphocyte count > 200 cells/ml, it Wholesale acquisition costs of agents recommended for the prevention of opportunistic infections in adults infected with human immunodeficiency virus is probably prudent to continue PCP prophylaxis for life regardless of how high the CD4+ T lymphocyte count rises as a consequence of HAART (CIII). Discontinuation of secondary prophylaxis for patients is recommended (see above*).
## Restarting secondary prophylaxis
## Prophylaxis should be reintroduced if the cd4 + t lymphocyte count decreases to < 200 cells/ml (aiii), or if pcp recurred at a cd4 + t lymphocyte count > 200 cells/ml (ciii).
## Special considerations
## Children
Children born to HIV-infected mothers should be administered prophylaxis with TMP-SMZ beginning at 4-6 weeks of age [bib_ref] revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with..., Cdc [/bib_ref] (AII). Prophylaxis should be discontinued for children who are subsequently found not to be infected with HIV. HIV-infected children and children whose infection status remains unknown should continue to receive prophylaxis for the first year of life. The need for subsequent prophylaxis should be determined on the basis of age-specific CD4 + T lymphocyte count thresholds [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] (AII). The safety of discontinuing prophylaxis in HIV-infected children receiving HAART has not been studied extensively. Children who have a history of PCP should be administered lifelong chemoprophylaxis to prevent recurrence 44 (AI).
## Pregnant women
Chemoprophylaxis for PCP should be administered to pregnant women as is done for other adults and adolescents (AIII). TMP-SMZ is the recommended prophylactic agent; dapsone is an alternative. Because of theoretical concerns regarding possible teratogenicity associated with drug exposures during the first trimester, providers may choose to withhold prophylaxis during the first trimester. In such cases, aerosolized pentamidine may be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug (CIII).
## Toxoplasmic encephalitis prevention of exposure
HIV-infected persons should be tested for immunoglobulin G (IgG) antibody to Toxoplasma soon after the diagnosis of HIV infection to detect latent infection with T. gondii (BIII). [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] Immunologic categories for human immunodeficiency virus-infected children based on age-specific CD4 + T lymphocyte counts and percentage of total lymphocytes* This schedule indicates the recommended ages for routine administration of currently licensed childhood vaccines as of November 1, 2000, for children through age 18 years. Additional vaccines may be licensed and recommended during the year. Licensed combination vaccines may be used whenever any components of the combination are indicated and the vaccine's other components are not contraindicated. Providers should consult the manufacturer's package inserts for detailed recommendations. 1. Infants born to hepatitis B surface antigen (HBsAg)-negative mothers should receive the first dose of hepatitis B vaccine (Hep B) at birth and no later than age 2 months. The second dose should be administered at least 1 month after the first dose. The third dose should be administered at least 4 months after the first dose and at least 2 months after the second dose, but not before age 6 months. Infants born to HBsAg-positive mothers should receive Hep B and 0.5 ml hepatitis B immune globulin (HBIG) within 12 hours of birth at separate sites. The second dose is recommended at age 1-2 months and the third dose at age 6 months. Infants born to mothers whose HBsAg status is unknown should receive Hep B within 12 hours of birth. Maternal blood should be drawn at delivery to determine the mother's HBsAg status; if the HBsAg test is positive, the infant should receive HIBG as soon as possible (no later than age one week). All children and adolescents (through age 18 years) who have not been immunized against hepatitis B should begin the series during any visit. Providers should make special efforts to immunize children who were born in or whose parents were born in areas of the world where hepatitis B virus infection is moderately or highly endemic. 2. The fourth dose of diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) may be administered as early as age 12 months, provided 6 months have elapsed since the third dose and the child is unlikely to return at age 15-18 months. Tetanus and diphtheria toxoids (Td) is recommended at age 11-12 years if at least 5 years have elapsed since the last dose of diphtheria and tetanus toxoids and pertussis ) is administered at ages 2 and 4 months, a dose at age 6 months is not required. Because clinical studies in infants have demonstrated that using some combination products may induce a lower immune response to the Hib vaccine component, DTaP/Hib combination products should not be used for primary immunization in infants at ages 2, 4 or 6 months unless approved by the Food and Drug Administration for these ages.
4. An all-inactivated poliovirus vaccine (IPV) schedule is recommended for routine childhood polio vaccination in the United States. All children should receive four doses of IPV at age 2 months, age 4 months, between ages 6 and 18 months, and between ages 4 and 6 years. Oral poliovirus vaccine should not be administered to HIV infected persons or their household contacts. 5. Hepatitis A vaccine (Hep A) is recommended for use in selected states and/or regions, and for certain high-risk groups such as those with Hepatitis B or Hepatitis C infection. Information is available from local public health authorities. 6. The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for all children age 2-59 months with HIV. Children 2 years and older should also receive the 23 valent pneumococcal polysaccharide vaccine; a single revaccination with the 23 valent vaccine should be offered to children after 3-5 years. Refer to the Advisory Committee on Immunization Practices recommendations (80) on dosing intervals for children starting the vaccination schedule after 2 months of age. 7. MMR should not be administered to severely immunocompromisd (category 3) children. HIV infected children without severe immunosuppression would routinely receive their first dose of MMR as soon as possible after reaching their first birthday. Consideration should be given to administering the second dose of MMR as soon as 1 month (i.e., a minimum of 28 days) after the first dose rather than waiting until school entry. 8. Varicella zoster virus vaccine, 0.5 ml, is given as a subcutaneous dose between 12 months and 12 years of age; a second dose should be given 3 months later. The vaccine should be given only to asymptomatic, nonimmunosuppressed children. . For children aged 6 months to < 9 years who are receiving influenze vaccine for the first time, two injections given one month apart are recommended. For specific recommendations, see: CDC, Prevention and Control of Influenza: HIV exposure/infection Routine immunizations (see [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref]
## Recommendations of the advisory committee on immunization practices (acip). mmwr 2001;50:rr-4. inactivated split influenza virus vaccine should be administered to all hiv infected children 6 months of age each year
None
## Ii. generally recommended
## Iii. not recommended for most children; indicated for use only in unusual circumstances
Invasive bacterial infections Hypogamma-globulinemia (i.e., IgG < 400 mg/dl) The efficacy of parenteral pentamidine (e.g. 4 mg/kg q 2-4 wks) is controversial. Patients receiving therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected against PCP and do not need TMP-SMZ. Significant drug interactions might occur between rifamycins (rifampin and rifabutin) and protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Consult a specialist. Children routinely being administered intravenous immune globulin (IVIG) should receive VZIG if the last dose of IVIG was administered > 21 days before exposure. HIV-infected and HIV-exposed children should be immunized according to the childhood immunization schedule in this report [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] , which has been adapted from the January-December 2001 schedule recommended for immunocompetent children by the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians. This schedule differs from that for immunocompetent children in that both the conjugate pneumococcal vaccine (PCV-7) and the pneumococcal polysaccharide vaccine (PPV-23) are recommended (BII) and vaccination against influenza (BIII) should be offered. MMR should not be administered to severely immunocompromised children (DIII). Vaccination against varicella is indicated only for asymptomatic nonimmunosuppressed children (BII). Once an HIV-exposed child is determined not to be HIV infected, the schedule for immunocompetent children applies. Protection against toxoplasmosis is provided by the preferred antipneumocystis regimens and possibly by atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides little, if any, protection (for definition of severe immunosuppression, see . Respiratory syncytial virus (RSV) IVIG (750 mg/kg), not monoclonal RSV antibody, may be substituted for IVIG during the RSV season to provide broad antiinfective protection, if this product is available. Oral ganciclovir and perhaps valganciclovir results in reduced CMV shedding in CMV-infected children. Acyclovir is not protective against CMV All HIV-infected persons, but particularly those who lack IgG antibody to Toxoplasma, should be counseled about the various sources of toxoplasmic infection. They should be advised not to eat raw or undercooked meat, particularly undercooked lamb, beef, pork or venison (BIII). Specifically, lamb, beef and pork should be cooked to an internal temperature of 165-170 F 44 ; meat cooked until it is no longer pink inside generally has an internal temperature of 165-170 F and therefore from a more practical perspective, satisfies this requirement. HIV-infected persons should wash their hands after contact with raw meat and after gardening or other contact with soil; in addition, they should wash fruits and vegetables well before eating them raw (BIII). If the patient owns a cat, the litter box should be changed daily, preferably by an HIV-negative, nonpregnant person; alternatively, the patient should wash the hands thoroughly after changing the litter box (BIII). Patients should be encouraged to keep their cats inside and not to adopt or handle stray cats (BIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII). Patients need not be advised to part with their cats or to have their cats tested for toxoplasmosis (EII). Only pyrimethamine plus sulfadiazine confers protection against PCP as well as toxoplasmosis. Although the clindamycin plus pyrimethamine regimen is recommended in adults, it has not been tested in children. However, these drugs are safe and are used for other infections. Significant drug interactions might occur between rifabutin and protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Consult an expert. Drug should be determined by susceptibilities of the organism isolated. Alternatives to TMP-SMZ include ampicillin, chloramphenicol, or ciprofloxacin. However, ciprofloxacin is not approved for use in persons aged < 18 years; therefore, it should be used in children with caution and only if no alternatives exist. Antimicrobial prophylaxis should be chosen based on the microorganism and antibiotic sensitivities. TMP-SMZ, if used, should be administered daily. Providers should be cautious about using antibiotics solely for this purpose because of the potential for development of drug-resistant microorganisms. IVIG might not provide additional benefit to children receiving daily TMP-SMZ but may be considered for children who have recurrent bacterial infections despite TMP-SMZ prophylaxis. Choice of antibiotic prophylaxis vs. IVIG should also involve consideration of adherence, ease of intravenous access, and cost, if IVIG is used, respiratory syncytial virus (RSV) IVIG (750 mg/kg), not monoclonal RSV antibody, may be substituted for IVIG during the RSV season to provide broad anti-infective protection, if this product is available
[formula] IVIG [/formula]
## Initiation of primary prophylaxis
Toxoplasma-seropositive patients who have a CD4 + T lymphocyte count of less than 100/ml should be administered prophylaxis against toxoplasmic encephalitis (TE) (AII) [bib_ref] Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS, Carr [/bib_ref]. The double-strength tablet daily dose of TMP-SMZ recommended as the preferred regimen for PCP prophylaxis appears to be effective against TE as well and is therefore recommended (AII) [bib_ref] Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS, Carr [/bib_ref]. If patients cannot tolerate TMP-SMZ, the recommended alternative is dapsone-pyrimethamine, which is also effective against PCP (BI) [bib_ref] Intermittent trimethoprim sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of..., Podzamczer [/bib_ref] [bib_ref] Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis..., Opravil [/bib_ref]. Atovaquone with or without pyrimethamine also may be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of current data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI) [bib_ref] A randomized trial of three antipneumocystis agents in patients with advanced human..., Bozzette [/bib_ref] [bib_ref] Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS, Carr [/bib_ref].
Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE should be retested for IgG antibody to Toxoplasma when their CD4 + T lymphocyte count declines below 100/ml to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described above (AII).
## Discontinuation of primary prophylaxis
## Prophylaxis against te should be discontinued in adult and adolescent patients who have responded to haart with an increase in cd4 + t lymphocyte counts to > 200 cells/ml for at least 3 months (ai).
Several observational studies 37,41,47 and two randomized trials [bib_ref] Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in..., Mussini [/bib_ref] [bib_ref] Discontinuation of Primary and Secondary Toxoplasma gondii Prophylaxis is Safe in HIV-1..., Miro [/bib_ref] have shown that primary prophylaxis can be discontinued with minimal risk of developing TE in patients who have responded to HAART with an increase in CD4 + T lymphocyte count from < 200 cells/ml to > 200 cells/ml for at least 3 months. In these studies, most patients were taking protease inhibitor-containing regimens and the median CD4 + T lymphocyte count at the time prophylaxis was discontinued was > 300 cells/ml. At the time prophylaxis was discontinued, many patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow up ranged from 7-22 months.
While patients with CD4 + T lymphocyte counts of < 100 cells/ml are at greatest risk for developing TE, the risk of TE occurring when the CD4 + T lymphocyte count has increased to 100-200 cells/ml has not been studied as rigorously as a rise to > 200 cells/ml. Thus, the recommendation specifies discontinuation of prophylaxis after an increase to > 200 cells/ml. Discontinuation of primary TE prophylaxis is recommended not only because prophylaxis appears to add very little to disease prevention for toxoplasmosis, but also because discontinuation of drug reduces pill burden, the potential for drug toxicity, drug interaction and selection of drug resistant pathogens.
## Restarting primary prophylaxis
Prophylaxis should be reintroduced if the CD4 + T lymphocyte count decreases to < 100-200 cells/ml (AIII).
## Prevention of recurrence
Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (secondary prophylaxis or CMT) (AI) 48,49 unless immune reconstitution occurs as a consequence of HAART (see below). The combination of pyrimethamine plus sulfadiazine plus leucovorin is highly effective for this purpose (AI). A commonly used regimen for patients who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin (BI); however, only the combination of pyrimethamine plus sulfadiazine appears to provide protection against PCP as well (AII).
## Discontinuation of secondary prophylaxis (cmt)
Adult and adolescent patients receiving secondary prophylaxis (CMT) for TE appear to be at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with respect to signs and symptoms of TE, and have a sustained increase in their CD4 + T lymphocyte counts to > 200 cells/ml following HAART (e.g., 6 months) 41,42,46 . While the numbers of patients who have been evaluated remain small and occasional recurrences have been seen, based on these observations and on inference from more extensive cumulative data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease, it is reasonable to consider discontinuation of CMT in such patients (CIII). Some experts would obtain a magnetic resonance image of the brain as part of their evaluation to determine whether or not discontinuation of therapy is appropriate.
## Restarting secondary prophylaxis
## Secondary prophylaxis (cmt) should be reintroduced if the cd4 + t lymphocyte count decreases to < 200 cells/ml (aiii).
## Special considerations
Children TMP-SMZ, when administered for PCP prophylaxis, also provides prophylaxis against toxoplasmosis. Atovaquone might also provide protection (CIII). Children aged greater than 12 months who qualify for PCP prophylaxis and who are receiving an agent other than TMP-SMZ or atovaquone should have serologic testing for Toxoplasma antibody (BIII), because alternative drugs for PCP prophylaxis might not be effective against Toxoplasma. Severely immunosuppressed children who are not receiving TMP-SMZ or atovaquone who are found to be seropositive for Toxoplasma should be administered prophylaxis for both PCP and toxoplasmosis (i.e., dapsone plus pyrimethamine) (BIII).
Children with a history of toxoplasmosis should be administered lifelong prophylaxis to prevent recurrence (AI). The safety of discontinuing primary or secondary prophylaxis in HIV-infected children receiving HAART has not been studied extensively.
## Pregnant women
TMP-SMZ can be administered for prophylaxis against TE as described for PCP (AIII). However, because of the low incidence of TE during pregnancy and the possible risk associated with pyrimethamine treatment, chemoprophylaxis with pyrimethamine-containing regimens can reasonably be deferred until after pregnancy (CIII). For prophylaxis against recurrent TE, the health-care provider and clinician should be well informed about the benefit of lifelong therapy and the concerns about teratogenicity of pyrimethamine. The above guidelines should be used when making decisions regarding secondary prophylaxis for TE in pregnancy.
In rare cases, HIV-infected pregnant women who have serologic evidence of remote toxoplasmic infection have transmitted Toxoplasma to the fetus in utero. Pregnant HIV-infected women who have evidence of primary toxoplasmic infection or active toxoplasmosis (including TE) should be evaluated and managed during pregnancy in consultation with appropriate specialists (BIII). Infants born to women who have serologic evidence of infections with HIV and Toxoplasma should be evaluated for congenital toxoplasmosis (BIII).
## Cryptosporidiosis
Prevention of exposure 1. HIV-infected persons should be educated and counseled about the many ways that Cryptosporidium can be transmitted (BIII). Modes of transmission include having direct contact with infected adults, diaper-aged children and infected animals; drinking contaminated water; coming into contact with contaminated water during recreational activities and eating contaminated food. 2. HIV-infected persons should avoid contact with human and animal feces. They should be advised to wash their hands after contact with human feces (e.g., diaper changing), after handling pets and after gardening or other contact with soil. HIV-infected persons should avoid sexual practices that might result in oral exposure to feces (e.g., oral-anal contact) (BIII). 3. HIV-infected persons should be advised that newborn and very young pets might pose a small risk for transmitting cryptosporidial infection, but they should not be advised to destroy or give away healthy pets. Persons contemplating the acquisition of a new pet should avoid bringing any animal that has diarrhea into their households, should avoid purchasing a dog or cat aged less than six months, and should not adopt stray pets. HIV-infected persons who wish to assume the small risk for acquiring a puppy or kitten aged less than six months should request that their veterinarian examine the animal's stool for Cryptosporidium before they have contact with the animal (BIII). 4. HIV-infected persons should avoid exposure to calves and lambs and to premises where these animals are raised (BII). 5. HIV-infected persons should not drink water directly from lakes or rivers (AIII). 6. Waterborne infection also might result from swallowing water during recreational activities. HIV-infected persons should be aware that many lakes, rivers, salt-water beaches, and some swimming pools, recreational water parks, and ornamental water fountains might be contaminated with human or animal waste that contains Cryptosporidium. They should avoid swimming in water that is likely to be contaminated and should avoid swallowing water while swimming or playing in recreational waters (BIII). 7. Several outbreaks of cryptosporidiosis have been linked to municipal water supplies. During outbreaks or in other situations in which a community 'boil-water' advisory is issued, boiling water for 1 minute will eliminate the risk for cryptosporidiosis (AI). Use of submicron personal-use water filters* (home/office types) and/or bottled water** also might reduce the risk (CIII). The magnitude of the risk for acquiring cryptosporidiosis from drinking water in a non-outbreak setting is uncertain, and current data are inadequate to recommend that all HIV-infected persons boil water or avoid drinking tap water in nonoutbreak settings. However, HIV-infected persons who wish to take independent action to reduce the risk for waterborne cryptosporidiosis may choose to take precautions similar to those recommended during outbreaks. Such decisions should be made in conjunction with health-care providers. Persons who opt for a personal-use filter or bottled water should be aware of the complexities involved in selecting appropriate products, the lack of enforceable standards for the destruction or removal of oocysts, the cost of the products, and the logistic difficulty of using these products consistently. 8. Patients who take precautions to avoid acquiring cryptosporidiosis from drinking water should be advised that ice made from contaminated tap water also can be a source of infection (BII). Such persons also should be aware that fountain beverages served in restaurants, bars, theaters and other places also might pose a risk because these beverages, as well as the ice they contain, are made from tap water. Nationally distributed brands of bottled or canned carbonated soft drinks are safe to drink. Commercially packaged non-carbonated soft drinks and fruit juices that do not require refrigeration until after they are opened (i.e., those that can be stored unrefrigerated on grocery shelves) also are safe. Nationally distributed brands of frozen fruit juice concentrate are safe if they are reconstituted by the user with water from a safe source. Fruit juices that must be kept refrigerated from the time they are processed to the time of consumption might be either fresh (unpasteurized) or heat-treated (pasteurized); only those juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasterurized beverages and beers also are considered safe to drink (BII). No data are available concerning survival of Cryptosporidium oocysts in wine. . HIV-infected persons should avoid eating raw oysters because cryptosporidial oocysts can survive in oysters for more than 2 months and have been found in oysters taken from some commercial oyster beds (BIII). Cryptosporidium-infected patients should not work as food handlers, especially if the food to be handled is intended to be eaten without cooking (BII). Because most food-borne outbreaks of cryptosporidiosis are believed to have been caused by infected food handlers, more specific recommendations to avoid exposure to contaminated food cannot be made.. In a hospital, standard precautions (i.e., use of gloves and hand washing after removal of gloves) should be sufficient to prevent transmission of cryptosporidiosis from an infected patient to a susceptible HIV-infected person (BII). However, because of the potential for fomite transmission, some experts recommend that HIV-infected persons, especially those who are severely immunocompromised, should not share a room with a patient with cryptosporidiosis (CIII).
Prevention of disease 11. Rifabutin or clarithromycin, when taken for Mycobacterium avium complex prophylaxis, have been found to protect against cryptosporidiosis 50,51 . However, data are insufficient at this time to warrant a recommendation for using these drugs as chemoprophylaxis for cryptosporidiosis.
Prevention of recurrence 12. No drug regimens are known to be effective in preventing the recurrence of cryptosporidiosis.
## Special considerations
Children . At present, no data indicate that formula-preparation practices for infants should be altered in an effort to prevent cryptosporidiosis (CIII). However, in the event of a 'boil water' advisory, similar precautions for the preparation of infant formula should be taken as for drinking water for adults (AII). Decisions about whether to continue with activities in these settings should be made in conjunction with the health-care provider and should be based on factors such as the patient's specific duties in the workplace, the prevalence of TB in the community and the degree to which precautions are taken to prevent the transmission of TB in the workplace (BIII). Whether the patient continues with such activities might affect the frequency with which screening for TB needs to be conducted. Options include isoniazid daily (AII) or twice weekly (BII) for nine months; four months of therapy daily with either rifampin (BIII) or rifabutin (CIII); or two months of therapy with either rifampin and pyrazinamide (BI) or rifabutin and pyrazinamide (CIII) [bib_ref] Notice to Readers: Updated guidelines for the use of rifabutin or rifampin..., Cdc [/bib_ref]. There have been reports of fatal and severe liver injury associated with the treatment of latent TB infection in HIV-uninfected persons treated with the two-month regimen of daily rifampin and pyrazinamide; therefore it may be prudent to use regimens that do not contain pyrazinamide in HIV-infected persons whose completion of treatment can be assured. Because HIV-infected persons are at risk for peripheral neuropathy, those receiving isoniazid should also receive pyridoxine (BIII). A decision to use a regimen containing either rifampin or rifabutin should be *Only filters capable of removing particles 1 mm in diameter should be considered. Filters that provide the greatest assurance of oocyst removal include those that operate by reverse osmosis, those labeled as absolute 1 mm filters, and those labeled as meeting NSF (National Sanitation Foundation) standard no. 53 for cyst removal. The nominal 1 mm filter rating is not standardized, and many filters in this category might not be capable of removing 99% of oocysts. For a list of filters certified as meeting NSF standards, consult the International Consumer Line at 800-673-8010 or http://www.nsf.org/notice/crypto.html **Sources of bottled water (e.g., wells, springs, municipal tap-water supplies, rivers and lakes) and methods for its disinfection differ; therefore, all brands should not be presumed to be free of cryptosporidial oocysts. Water from wells and springs is much less likely to be contaminated by oocysts than water from rivers or lakes. Treatment of bottled water by distillation or reverse osmosis ensures oocyst removal. Water passed through an absolute 1 mm filter or a filter labeled as meeting NSF standard no. 53 for cyst removal before bottling will provide nearly the same level of protection. Use of nominal 1 mm filters by bottlers as the only barrier to Cryptosporidia might not result in the removal of 99% of oocysts. For more information, the International Bottled Water Association can be contacted at 703-683-5213 or at http://bottled water.org made after careful consideration of potential drug interactions, especially those related to protease inhibitors and nonnucleoside reverse transcriptase inhibitors (see Special Considerations/Drug Interactions). Directly observed therapy should be used with intermittent dosing regimens (AI) and when otherwise operationally feasible (BIII). 5. HIV-infected persons who are close contacts of persons who have infectious TB should be treated for latent TB infection -regardless of their TST results, age or prior courses of treatment -after the diagnosis of active TB has been excluded (AII) [bib_ref] Notice to Readers: Updated guidelines for the use of rifabutin or rifampin..., Cdc [/bib_ref]. In addition to household contacts, such persons might also include contacts in the same drug-treatment or health-care facility, co-workers and other contacts if transmission of TB is demonstrated. 6. For persons exposed to isoniazid-and/or rifampin-resistant TB, the decision to use chemoprophylactic antimycobacterial agents other than isoniazid alone, rifampin or rifabutin alone, rifampin plus pyrazinamide or rifabutin plus pyrazinamide should be based on the relative risk for exposure to resistant organisms and should be made in consultation with public health authorities (AII). 7. TST-negative, HIV-infected persons from risk groups or geographic areas with a high prevalence of Mycobacterium tuberculosis infection might be at increased risk for primary or reactivation tuberculosis. However, the efficacy of treatment in this group has not been demonstrated. Decisions concerning the use of chemoprophylaxis in these situations must be considered individually. 8. Although the reliability of the TST might diminish as the CD4 + T lymphocyte count declines, annual repeat testing should be considered for HIV-infected persons who are TST-negative on initial evaluation and who belong to populations in which there is a substantial risk for exposure to M. tuberculosis (BIII). Clinicians should consider repeating the TST for persons whose initial skin test was negative and whose immune function has improved in response to HAART (i.e., those whose CD4 + T lymphocyte count has increased to greater than 200 cells/ml) (BIII). In addition to confirming TB infection, TST conversion in an HIV-infected person should alert health-care providers to the possibility of recent M. tuberculosis transmission and should prompt notification of public health officials for investigation to identify a possible source case. 9. The administration of bacille Calmette-Guerin (BCG) vaccine to HIV-infected persons is contraindicated because of its potential to cause disseminated disease (EII).
## Microsporidiosis
## Prevention of recurrence
10. Chronic suppressive therapy for a patient who has successfully completed a recommended regimen of treatment for tuberculosis is not necessary (DII).. However, it may be used with ritonavir, ritonavir plus saquinavir, efavirenz and possibly with nevirapine. Rifabutin is an acceptable alternative to rifampin but should not be used with the protease inhibitor hard-gel saquinavir or delavirdine; caution is advised if the drug is coadministered with soft-gel saquinavir, because data are sparse. Rifabutin can be administered at one-half the usual daily dose, i.e., reduce from 300 mg to 150 mg per day, with indinavir, nelfinavir or amprenavir or with one-fourth the usual dose, i.e., 150 mg every other day or three times a week, with ritonavir, ritonavir plus saquinavir, or lopinavir/ritonavir.
## Special considerations
## Drug interactions
## Rifampin can induce metabolism of all the protease inhibitors and nonnucleoside reverse transcriptase inhibitors. this can result in more rapid drug clearance and possibly subtherapeutic drug concentrations of most of these antiretroviral agents. rifampin should not be co-administered with the following protease inhibitors and nonnucleoside reverse transcriptase inhibitors: amprenavir, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir and delavirdine
## When rifabutin is administered with indinavir as the sole protease inhibitor, the dose of indinavir should be increased from 800 mg every 8 h to 1000 mg every 8 h. pharmacokinetic data suggest that rifabutin at an increased dose can be administered with efavirenz; doses of 450-600 mg per day have been suggested 54 . however, little information is available about appropriate dosing if a protease inhibitor is used concurrently with efavirenz and rifabutin; with such a combination the rifabutin dose might need to be reduced. rifabutin can be used without dose adjustment with nevirapine.
Children 12. Infants born to HIV-infected mothers should have a TST (5-TU PPD) at or before the age of 9-12 months and should be retested at least once a year (AIII). HIV-infected children living in households with TST-positive persons should be evaluated for TB (AIII); children exposed to a person who has active TB should be administered preventive therapy after active TB has been excluded, regardless of their TST results (AII).
## Pregnant women
13. Chemoprophylaxis for TB is recommended during pregnancy for HIV-infected patients who have either a positive TST or a history of exposure to active TB, after active TB has been excluded (AIII). A chest radiograph should be obtained before treatment and appropriate abdominal/pelvic lead apron shields should be used to minimize radiation exposure to the embryo/fetus. When an HIV-infected person has not been exposed to drug-resistant TB, isoniazid daily or twice weekly is the prophylactic regimen of choice. Because of concerns regarding possible teratogenicity associated with drug exposures during the first trimester, providers may choose to initiate prophylaxis after the first trimester. Preventive therapy with isoniazid should be accompanied by pyridoxine to reduce the risk for neurotoxicity. Experience with rifampin or rifabutin during pregnancy is more limited, but anecdotal experience with rifampin has not been associated with adverse pregnancy outcomes. Pyrazinamide should generally be avoided, particularly in the first trimester because of lack of information concerning fetal effects.
## Disseminated infection with mycobacterium avium complex
Prevention of exposure 1. Organisms of the M. avium complex (MAC) are common in environmental sources such as food and water. Current information does not support specific recommendations regarding avoidance of exposure.
## Prevention of disease
## Initiation of primary prophylaxis
2. Adults and adolescents who have HIV infection should receive chemoprophylaxis against disseminated MAC disease if they have a CD4 + T lymphocyte count of less than 50 cells/ml (AI). Clarithromycin [bib_ref] CPCRA 009 Study Team. Clarithromycin or Rifabutin alone or in combination for..., Benson [/bib_ref] [bib_ref] A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex..., Pierce [/bib_ref] or azithromycin 59 are the preferred prophylactic agents (AI). The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis and is associated with a higher rate of adverse effects than either drug alone; this combination should not be used (EI) [bib_ref] Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or..., Havlir [/bib_ref]. The combination of azithromycin with rifabutin is more effective than azithromycin alone; however, the additional cost, increased occurrence of adverse effects, potential for drug interactions and absence of a difference in survival when compared with azithromycin alone do not warrant a routine recommendation for this regimen (CI) [bib_ref] Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or..., Havlir [/bib_ref]. In addition to their preventive activity for MAC disease, clarithromycin and azithromycin each confer protection against respiratory bacterial infections (BII). If clarithromycin or azithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease although rifabutin-associated drug interactions make this agent difficult to use (BI) [bib_ref] Notice to Readers: Updated guidelines for the use of rifabutin or rifampin..., Cdc [/bib_ref]. Tolerance, cost and drug interactions are among the issues that should be considered in decisions regarding the choice of prophylactic agents for MAC disease. Particular attention to interactions with antiretroviral protease inhibitors and nonnucleoside reverse transcriptase inhibitors is warranted (see Special Considerations/Drug Interactions). Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC if warranted. Because treatment with rifabutin could result in the development of resistance to rifampin in persons who have active TB, active TB should also be excluded before rifabutin is used for prophylaxis. 3. Although the detection of MAC organisms in the respiratory or gastrointestinal tract might predict the development of disseminated MAC infection, no data are available on the efficacy of prophylaxis with clarithromycin, azithromycin, rifabutin or other drugs in patients with MAC organisms at these sites and a negative blood culture. Therefore, routine screening of respiratory or gastrointestinal specimens for MAC cannot be recommended (DIII).
## Discontinuation of primary prophylaxis
## Primary mac prophylaxis should be discontinued in adult and adolescent patients who have responded to haart with an increase in cd4 + t lymphocyte count to > 100 cells/ml for at least three months (ai). two large randomized, placebo controlled trials and observational data have shown that such patients can discontinue primary prophylaxis with minimal risk of developing mac 37,60-62 . discontinuation of primary prophylaxis in patients meeting the criteria above is recommended not only because prophylaxis appears to add very little to disease prevention for mac or for bacterial infections, but also because discontinuation of drug reduces pill burden, the potential for drug toxicity, drug interactions, selection of drug resistant pathogens and cost.
## Restarting primary prophylaxis
## Primary prophylaxis should be reintroduced if the cd4 + t lymphocyte count decreases to < 50-100 cells/ml (aiii).
Prevention of recurrence [bib_ref] A randomized, placebo-controlled study of rifabutin added to a regimen of clarithromycin..., Gordin [/bib_ref]. Treatment of MAC disease with clarithromycin in a dose of 1000 mg twice a day is associated with a higher mortality rate than has been observed with clarithromycin administered at 500 mg twice a day; thus, the higher dose should not be used (EI) [bib_ref] Clarithromycin therapy for bacteremic Mycobacterium avium complex disease: a randomized, double-blind, dose-ranging..., Chaisson [/bib_ref] [bib_ref] A prospective randomized trial of four three-drug regimens in the treatment of..., Cohn [/bib_ref]. Clofazimine has been associated with adverse clinical outcomes in the treatment of MAC disease and should not be used (DII) [bib_ref] A prospective randomized trial of four three-drug regimens in the treatment of..., Cohn [/bib_ref].
## Adult and adolescent patients with disseminated mac should receive lifelong therapy (i.e., secondary prophylaxis or cmt) (aii), unless immune reconstitution occurs as a consequence of haart (see guideline 7 below). unless good clinical or laboratory evidence of macrolide resistance exists, the use of a macrolide (clarithromycin or, alternatively, azithromycin) is recommended in combination with ethambutol (aii) with or without rifabutin (ci)
## Discontinuation of secondary prophylaxis (cmt)
7. Patients appear to be at low risk for recurrence of MAC when they have completed a course of at least 12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase , e.g., six months, in their CD4 + T lymphocyte counts to > 100 cells/ml following HAART. While the numbers of patients who have been evaluated remain small, and recurrences could occur 41,42,68-70 , based on these observations and on inference from more extensive data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease, it may be reasonable to consider discontinuation of CMT in such patients (CIII). Some experts would obtain a blood culture for MAC, even in asymptomatic patients, prior to discontinuation of therapy, to substantiate that disease is no longer active.
## Restarting secondary prophylaxis
## Secondary prophylaxis should be reintroduced if the cd4 + t lymphocyte count decreases to < 100 cells/ml (aiii).
## Special considerations
## Drug interactions
## Rifabutin should not be administered to patients receiving certain protease inhibitors and nonnucleoside reverse transcriptase inhibitors because the complex interactions have been incompletely studied and the clinical implications of those interactions are unclear 16,54 (see special considerations: drug interactions in the tuberculosis section, above). protease inhibitors may increase clarithromycin levels, but no recommendation to adjust the dose of either clarithromycin or protease inhibitors can be made on the basis of existing data. efavirenz can induce metabolism of clarithromycin. this may result in reduced serum concentration of clarithromycin but increased concentration of 14-oh clarithromycin, an active metabolite of clarithromycin. although the clinical significance of this interaction is not known, the efficacy of clarithromycin in mac prophylaxis could be reduced because of this interaction. azithromycin pharmacokinetics are not affected by the cytochrome p450 system; azithromycin can be used safely in the presence of protease inhibitors and/or nonnucleoside reverse transcriptase inhibitors without concerns of drug interactions.
Children 10. HIV-infected children aged less than 13 years who have advanced immunosuppression also can develop disseminated MAC infections and prophylaxis should be offered to high-risk children according to the following CD4 + T lymphocyte thresholds: children aged greater than or equal to six years, less than 50 cells/ml; children aged 2-6 years, less than 75 cells/ml; children aged 1-2 years, less than 500 cells/ml; and children aged less than 12 months, less than 750 cells/ml (AII). For the same reasons that clarithromycin and azithromycin are the preferred prophylactic agents for adults, they should also be considered for children (AII); oral suspensions of both agents are commercially available in the United States. No liquid formulation of rifabutin suitable for pediatric use is commercially available in the United States. Children with a history of disseminated MAC should be administered lifelong prophylaxis to prevent recurrence (AII). The safety of discontinuing MAC prophylaxis in children whose CD4 + T lymphocyte counts have increased in response to HAART has not been studied. . Chemoprophylaxis for MAC disease should be administered to pregnant women as is done for other adults and adolescents (AIII). However, because of general concerns about administering drugs during the first trimester of pregnancy, some providers may choose to withhold prophylaxis during the first trimester. Animal studies and anecdotal evidence of safety in humans suggest that of the available agents, azithromycin is the drug of choice (BIII) [bib_ref] Chlamydia in pregnancy: a randomized trial of azithromycin and erythromycin, Adair [/bib_ref]. Experience with rifabutin is limited. Clarithromycin has been demonstrated to be a teratogen in animals and should be used with caution during pregnancy. For secondary prophylaxis (CMT), azithromycin plus ethambutol are the preferred drugs (BIII) [bib_ref] Successful Discontinuation of MAC Therapy Following Effective HAART, Shafran [/bib_ref].
## Pregnant women
## Bacterial respiratory infections
Prevention of exposure 1. Because Streptococcus pneumoniae and Haemophilus influenzae are common in the community, no effective way exists to reduce exposure to these bacteria.
## Prevention of disease
## Adults and adolescents who have a cd4 + t lymphocyte count of greater than or equal to 200 cells/ml should be administered a single dose of 23-valent polysaccharide pneumococcal vaccine if they have not received this vaccine during the previous five years (bii) 73-77 . one randomized placebo-controlled trial of pneumococcal vaccine in africa paradoxically found an increase in pneumonia among vaccinated subjects 78 . however, several observational studies in the united states have not identified increased risk associated with vaccination and have identified benefit in this group 73-77 . most experts believe that the potential benefit of pneumococcal vaccination in the united states outweighs the risk. immunization should also be considered for patients with cd4 + t lymphocyte counts < 200 cells/ml, although there is no clinical evidence for efficacy (ciii). revaccination may be considered for patients who were initially immunized when their cd4 + t lymphocyte count was < 200 cells/ml and whose cd4 + count has increased to > 200 cells/ml in response to haart (ciii). the recommendation to vaccinate is increasingly pertinent because of the increasing incidence of invasive infections with drug-resistant (including tmp-smz-, macrolide-and beta-lactam-resistant) strains of s. pneumoniae.
3. The duration of the protective effect of primary pneumococcal vaccination is unknown. Periodic revaccination may be considered; an interval of five years has been recommended for persons not infected with HIV and also might be appropriate for persons infected with HIV (CIII). There is, however, no evidence for clinical benefit from revaccination. 4. The incidence of H. influenzae type B infection in adults is low. Therefore, H. influenzae type B vaccine is not generally recommended for adult use (DIII). 5. TMP-SMZ, when administered daily for PCP prophylaxis, reduces the frequency of bacterial respiratory infections. This should be considered in the selection of an agent for PCP prophylaxis (AII). However, indiscriminate use of this drug (when not indicated for PCP prophylaxis or other specific reasons) might promote the development of TMP-SMZ-resistant organisms. Thus, TMP-SMZ should not be prescribed solely to prevent bacterial respiratory infection (DIII). Similarly, clarithromycin administered daily and azithromycin administered weekly for MAC prophylaxis might be effective in preventing bacterial respiratory infections; this should be considered in the selection of an agent for prophylaxis against MAC disease (BII). However, these drugs should not be prescribed solely for preventing bacterial respiratory infection (DIII).
6. An absolute neutrophil count that is depressed because of HIV disease or drug therapy is associated with an increased risk for bacterial infections, including pneumonia. To reduce the risk for such bacterial infections, providers may consider taking steps to reverse neutropenia, either by stopping myelosuppressive drugs (CII) or by administering granulocyte-colony-stimulating factor (G-CSF) (CII).
Prevention of recurrence 7. Some clinicians may administer antibiotic chemoprophylaxis to HIV-infected patients who have very frequent recurrences of serious bacterial respiratory infections (CIII). TMP-SMZ, administered for PCP prophylaxis and clarithromycin or azithromycin, administered for MAC prophylaxis, are appropriate for drug-sensitive organisms. However, providers should be cautious about using antibiotics solely for preventing the recurrence of serious bacterial respiratory infections because of the potential development of drug-resistant microorganisms and drug toxicity.
## Special considerations
## Children
## Hiv infected children, less than five years old should be administered h. influenzae type b vaccine (aii) and pneumococcal conjugate vaccine 77-81 (bii) in accordance with the guidelines of the advisory committee on immunization practices 74,76,79 and the american academy of pediatrics 80 . children aged greater than two years should also receive the 23-valent polysaccharide pneumococcal vaccine (bii). revaccination with a second dose of the 23 valent polysaccharide pneumococcal vaccine should generally be offered after 3-5 years to children aged less than or equal to ten years and after five years to children aged greater than ten years (biii).
9. To prevent serious bacterial infections in HIV-infected children who have hypogammaglobulinemia (IgG less than 400 mg/dl), clinicians should use intravenous (i.v.) immunoglobulin (IVIG) (AI). Respiratory syncytial virus (RSV) IVIG (750 mg/kg), not monoclonal RSV antibody, may be substituted for IVIG during the RSV season to provide broad anti-infective protection, if RSV IVIG is available.. To prevent recurrence of serious bacterial respiratory infections, antibiotic chemoprophylaxis may be considered (BI). However, providers should be cautious about using antibiotics solely for this purpose because of the potential development of drug-resistant microorganisms and drug toxicity. The administration of IVIG should also be considered for HIV-infected children who have recurrent serious bacterial infections, although such treatment might not provide additional benefit to children who are being administered daily TMP-SMZ. However, IVIG may be considered for children who have recurrent serious bacterial infections despite receiving TMP-SMZ or other antimicrobials (CIII) [bib_ref] A controlled trial of intrevenous immune globulin for the prevention of serious..., Spector [/bib_ref]. . Pneumococcal vaccination is recommended during pregnancy for HIV-infected patients who have not been vaccinated during the previous five years (BIII). Among nonpregnant adults, vaccination has been associated with a transient burst of HIV replication. Whether the transient viremia can increase the risk for perinatal HIV transmission is unknown. Because of this concern, when feasible, vaccination may be deferred until after HAART has been initiated to prevent perinatal HIV transmission (CIII).
## Pregnant women
## Bacterial enteric infections
Prevention of exposure Food 1. Health-care providers should advise HIV-infected persons not to eat raw or undercooked eggs (including foods that might contain raw eggs [e.g., some preparations of hollandaise sauce, Caesar and certain other salad dressings, some mayonnaises, uncooked cookie and cake batter, egg nog]); raw or undercooked poultry, meat, seafood (especially raw shellfish); unpasteurized dairy products; unpasteurized fruit juices; and raw seed sprouts (e.g., alfalfa sprouts, mung bean sprouts). Poultry and meat are safest when adequate cooking is confirmed with a thermometer (internal tempera-
## Ture of 180°f for poultry and 165°f for red meats). if a thermometer is not used, the risk of illness is decreased by consuming poultry and meat that have no trace of pink color. color change of the meat (e.g., absence of pink) does not always correlate with internal temperature. (biii). produce should be washed thoroughly before being eaten (biii).
2. Health-care providers should advise HIV-infected persons to avoid cross-contamination of foods. Uncooked meats, (including hot dogs) and their juices should not come into contact with other foods. Hands, cutting boards, counters, knives, and other utensils should be washed thoroughly after contact with uncooked foods (BIII). 3. Health-care providers should advise HIV-infected persons that, although the incidence of listeriosis is low, it is a serious disease that occurs with unusually high frequency among severely immunosuppressed HIV-infected persons. An immunosuppressed, HIV-infected person who wishes to reduce the risk of acquiring listeriosis as much as possible may choose to do the following (CIII): a) avoid soft cheeses (e.g., feta, Brie, Camembert, blue-veined and Mexican-style cheese such as queso fresco).
Hard, processed and cream cheese (including slices and spreads), cottage cheese or yogurt need not be avoided; b) cook leftover foods or ready-to-eat foods (e.g., hot dogs) until steaming hot before eating; c) avoid foods from delicatessen counters (e.g., prepared salads, meats, cheeses) or heat/reheat these foods until steaming before eating; d) avoid refrigerated pates and other meat spreads, or heat/reheat these foods until steaming. Canned or shelf-stable pate and meat spreads need not be avoided and e) avoid raw or unpasteurized milk (including goat's milk) or milk-products, or foods which contain unpasteurized milk or milk-products. (CIII).
## Pets
4. When obtaining a new pet, HIV-infected persons should avoid animals aged less than six months, especially those that have diarrhea (BIII). 5. HIV-infected persons should avoid contact with animals that have diarrhea (BIII). HIV-infected pet owners should seek veterinary care for animals with diarrheal illness, and a fecal sample from such animals should be examined for Cryptosporidium, Salmonella, and Campylobacter. 6. HIV-infected persons should wash their hands after handling pets (especially before eating) and should avoid contact with pets' feces (BIII). 7. HIV-infected persons should avoid contact with reptiles (e.g., snakes, lizards, iguanas and turtles) as well as chicks and ducklings because of the risk for salmonellosis (BIII). Travel 8. The risk for food-borne and waterborne infections among immunosuppressed, HIV-infected persons is magnified during travel to developing countries. Persons who travel to such countries should avoid foods and beverages that might be contaminated, particularly raw fruits and vegetables, raw or undercooked seafood or meat, tap water, ice made with tap water, unpasteurized milk and dairy products, and items sold by street vendors (AII). Foods and beverages that are generally safe include steaming-hot foods, fruits that are peeled by the traveler, bottled (especially carbonated) beverages, hot coffee and tea, beer, wine, and water brought to a rolling boil for 1 minute (AII). Treatment of water with iodine or chlorine might not be as effective as boiling but can be used when boiling is not practical (BIII).
Prevention of disease 9. Prophylactic antimicrobial agents are not generally recommended for travelers (DIII). The effectiveness of these agents depends on local antimicrobial-resistance patterns of gastrointestinal pathogens, which are seldom known. Moreover, these agents can elicit adverse reactions and can promote the emergence of resistant organisms. However, for HIV-infected travelers, antimicrobial prophylaxis may be considered, depending on the level of immunosuppression and the region and duration of travel (CIII). The use of fluoroquinolones such as ciprofloxacin (500 mg per day) can be considered when prophylaxis is deemed necessary (CIII). As an alternative (e.g., for children, pregnant women, and persons already taking TMP-SMZ for PCP prophylaxis), TMP-SMZ might offer some protection against traveler's diarrhea (BIII). The risk of toxicity should be considered before treatment with TMP-SMZ is initiated solely because of travel.. Antimicrobial agents such as fluoroquinolones should be given to patients before their departure, to be taken empirically (e.g., 500 mg of ciprofloxacin twice a day for 3-7 days) should significant traveler's diarrhea develop (BIII). Fluoroquinolones should be avoided for children aged less than 18 years and pregnant women, and alternative antibiotics should be considered (BIII). Travelers should consult a physician if their diarrhea is severe and does not respond to empirical therapy, if their stools contain blood, if fever is accompanied by shaking chills, or if dehydration develops. Antiperistaltic agents (e.g., loperamide) can be used to treat mild diarrhea. However, the use of these drugs should be discontinued if symptoms persist beyond 48 h. Moreover, these agents should not be administered to patients who have a high fever or who have blood in the stool (AII). 11. Some experts recommend that HIV-infected persons who have Salmonella gastroenteritis be administered antimicrobial therapy to prevent extraintestinal spread of the pathogen. However, no controlled study has demonstrated a beneficial effect of such treatment, and some studies of immunocompetent persons have suggested that antimicrobial therapy can lengthen the shedding period. The fluoroquinolones -primarily ciprofloxacin (750 mg twice a day for 14 days) -can be used when antimicrobial therapy is chosen (CIII).
## Prevention of recurrence
12. HIV-infected persons who have Salmonella septicemia require long-term therapy (i.e., secondary prophylaxis or CMT) to prevent recurrence. Fluoroquinolones, primarily ciprofloxacin, are usually the drugs of choice for susceptible organisms (BII). 13. Household contacts of HIV-infected persons who have salmonellosis or shigellosis should be evaluated for persistent asymptomatic carriage of Salmonella or Shigella so that strict hygienic measures and/or antimicrobial therapy can be instituted and recurrent transmission to the HIV-infected person can be prevented (CIII).
## Special considerations
Children. Like HIV-infected adults, HIV-infected children should wash their hands after handling pets (especially before eating) and should avoid contact with pets' feces. Hand washing should be supervised (BIII). 15. HIV-exposed infants aged less than three months and all HIV-infected children who have severe immunosuppression should be administered treatment for Salmonella gastroenteritis to prevent extraintestinal spread of the pathogen (CIII). Choices of antibiotics include TMP-SMZ, ampicillin, cefotaxime, ceftriaxone or chloramphenicol; fluoroquinolones should be used with caution and only if no alternatives exist.. HIV-infected children who have Salmonella septicemia should be offered long-term therapy to prevent recurrence (CIII). TMP-SMZ is the drug of choice; ampicillin or chloramphenicol can be used if the organism is susceptible. Fluoroquinolones should be used with caution and only if no alternative exists. 17. Antiperistaltic drugs are not recommended for children (DIII).
## Pregnant women
18. Because both pregnancy and HIV infection confer a risk for listeriosis, pregnant HIV-infected women should heed recommendations regarding listeriosis (BII). [bib_ref] Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents..., Kaplan [/bib_ref]. Because extraintestinal spread of Salmonella during pregnancy might lead to infection of the placenta and amniotic fluid and result in pregnancy loss similar to that seen with Listeria monocytogenes, pregnant women with Salmonella gastroenteritis should receive treatment (BIII). Choices for treatment include ampicillin, cefotaxime, ceftriaxone, or TMP-SMZ. Fluoroquinolones should be avoided. 20. Fluoroquinolones should not be used during pregnancy. TMP-SMZ might offer some protection against traveler's diarrhea.
## Bartonellosis
Prevention of exposure 1. HIV-infected persons, particularly those who are severely immunosuppressed, are at unusually high risk for developing relatively severe disease due to infection with Bartonella, which can be transmitted from cats. These persons should consider the potential risks of cat ownership (CIII). Persons who acquire a cat should adopt or purchase an animal aged greater than one year that is in good health (BII). Prevention of recurrence 6. Relapse or reinfection with Bartonella has sometimes followed a course of primary treatment. Although no firm recommendation can be made regarding prophylaxis in this situation, long-term suppression of infection with erythromycin or doxycycline should be considered (CIII).
Special considerations Children 7. The risks of cat ownership for HIV-infected children who are severely immunocompromised should be discussed with parents and caretakers (CIII).
## Pregnant women
8. If long-term suppression of Bartonella infection is required, erythromycin should be used. Tetracycline should not be used during pregnancy.
## Candidiasis
Prevention of exposure 1. Candida organisms are common on mucosal surfaces and skin. No measures are available to reduce exposure to these fungi.
Prevention of disease 2. Data from prospective controlled trials indicate that fluconazole can reduce the risk for mucosal (oropharyngeal, esophageal and vaginal) candidiasis and cryptococcosis as well in patients with advanced HIV disease [bib_ref] Evaluation of effectiveness of 23-valent pneumococcal capsular polysaccharide vaccine for HIV-infected patients, Breiman [/bib_ref] [bib_ref] 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised, and placebo-controlled..., French [/bib_ref]. However, routine primary prophylaxis is not recommended because of the effectiveness of therapy for acute disease, the low mortality associated with mucosal candidiasis, the potential for resistant Candida organisms to develop, the possibility of drug interactions, and the cost of prophylaxis (DIII).
## Prevention of recurrence
3. Many experts do not recommend chronic prophylaxis of recurrent oropharyngeal or vulvovaginal candidiasis for the same reasons that they do not recommend primary prophylaxis. However, if recurrences are frequent or severe, providers may consider administering an oral azole (fluconazole [CI] [bib_ref] A randomized trial comparing fluconazole with clotrimazole troches for the prevention of..., Powderly [/bib_ref] [bib_ref] Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV..., Schuman [/bib_ref] [bib_ref] Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with..., Havlir [/bib_ref] or itraconazole solution [CI]). Other factors that influence choices about such therapy include the impact of the recurrences on the patient's well-being and quality of life, the need for prophylaxis for other fungal infections, cost, toxicities, drug interactions, and the potential to induce drug resistance among Candida and other fungi. Prolonged use of systemically absorbed azoles, particularly in patients with low CD4 + T lymphocyte counts (i.e., less than 100 cells/ml), increases the risk for the development of azole resistance. 4. Adults or adolescents who have a history of documented esophageal candidiasis, particularly multiple episodes, should be considered candidates for chronic suppressive therapy. Fluconazole at a dose of 100-200 mg daily is appropriate (BI). However, the potential development of azole resistance should be taken into account when long-term azoles are considered.
## Special considerations
Children 5. Primary prophylaxis of candidiasis in HIV-infected infants is not indicated (DIII). 6. Suppressive therapy with systemic azoles should be considered for infants who have severe recurrent mucocutaneous candidiasis (CIII) and particularly for those who have esophageal candidiasis (BIII).
## Pregnant women
7. Experience is limited with the use of systemic antifungal drugs during human pregnancy. Four cases of infants born with craniofacial and skeletal abnormalities following prolonged in utero exposure to fluconazole have been reported [bib_ref] Fluconazole-induced congenital anomalies in three infants, Pursley [/bib_ref] [bib_ref] Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional..., Aleck [/bib_ref]. In addition, itraconazole is embryotoxic and teratogenic in animal systems [bib_ref] Product information: Sporanox (itraconazole) oral solution, Janssen Pharmaceutical [/bib_ref]. These same potential risks of teratogenicity are presumed to apply to other systemically absorbed azole antifungals, such as ketoconazole. Therefore, chemoprophylaxis against oropharyngeal, esophageal, or vaginal candidiasis using systemically absorbed azoles should not be initiated during pregnancy (DIII), and azoles should be discontinued for HIV-infected women who become pregnant (DIII). Effective birth control measures should be recommended to all HIV-infected women on azole therapy for candidiasis (AIII).
## Cryptococcosis
Prevention of exposure 1. HIV-infected persons cannot completely avoid exposure to Cryptococcus neoformans. No evidence exists that exposure to pigeon droppings is associated with an increased risk for acquiring cryptococcosis.
Prevention of disease 2. Routine testing of asymptomatic persons for serum cryptococcal antigen is not recommended because of the low probability that the results will affect clinical decisions (DIII). 3. Prospective controlled trials indicate that fluconazole and itraconazole can reduce the frequency of cryptococcal disease among patients who have advanced HIV disease. However, most experts recommend that antifungal prophylaxis not be used routinely to prevent cryptococcosis because of the relative infrequency of cryptococcal disease, the lack of survival benefits associated with prophylaxis, the possibility of drug interactions, the potential development of antifungal drug resistance, and cost. The need for prophylaxis or suppressive therapy for other fungal infections (e.g., candidiasis, histoplasmosis, or coccidioidomycosis) should be considered in making decisions about prophylaxis for cryptococcosis. If used, fluconazole at doses of 100-200 mg daily is reasonable for patients whose CD4 + T lymphocyte counts are less than 50 cells/ml (CI) [bib_ref] A randomized trial comparing fluconazole with clotrimazole troches for the prevention of..., Powderly [/bib_ref].
Prevention of recurrence 4. Patients who have completed initial therapy for cryptococcosis should be administered lifelong suppressive treatment, (i.e., secondary prophylaxis or CMT) (AI) unless immune reconstitution occurs as a consequence of HAART (see recommendation 5 below). Fluconazole is superior to itraconazole in preventing relapse of cryptococcal disease and is the preferred drug (AI) [bib_ref] A controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal..., Bozzette [/bib_ref] [bib_ref] A controlled trial of fluconazole or amphotericin B to prevent relapse of..., Powderly [/bib_ref] [bib_ref] Comparison of fluconazole versus itraconazole as maintenance therapy of AIDS-associated cryptococcal meningitis, Saag [/bib_ref].
## Discontinuation of secondary prophylaxis (cmt)
5. Adult and adolescent patients appear to be at low risk for recurrence of cryptococcosis when they have successfully completed a course of initial therapy for cryptococcosis, remain asymptomatic with respect to signs and symptoms of cryptococcosis, and have a sustained increase (e.g., six months) in their CD4 + T lymphocyte counts to > 100-200 cells/ml following HAART. The numbers of patients who have been evaluated remain small [bib_ref] Discontinuation of antifungal therapy for cryptococcosis after immunologic response to antiretroviral therapy, Aberg [/bib_ref] [bib_ref] Discontinuation or continuation of maintenance therapy for cryptococcal meningitis in patients with..., Mussini [/bib_ref]. Based on these observations and on inference from more extensive data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease and while recurrences could occur it may be reasonable to consider discontinuation of CMT in such patients (CIII). Some experts would perform a lumbar puncture to determine if the CSF is culture negative before stopping therapy even if patients have been asymptomatic; other experts do not believe this is necessary.
## Restarting secondary prophylaxis
## Maintenance therapy should be reinitiated if the cd4 + t lymphocyte count decreases to 100-200 cells/ml (aiii).
Special considerations Children 7. No data exist on which to base specific recommendations for children, but lifelong suppressive therapy with fluconazole after an episode of cryptococcosis is appropriate (AIII).
## Pregnant women
8. Prophylaxis with fluconazole or itraconazole should not be initiated during pregnancy because of the low incidence of cryptococcal disease, the lack of a recommendation for primary prophylaxis against cryptococcosis in nonpregnant adults, and potential teratogenic effects of these drugs during pregnancy (DIII) [bib_ref] Fluconazole-induced congenital anomalies in three infants, Pursley [/bib_ref] [bib_ref] Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional..., Aleck [/bib_ref]. For patients who conceive while being administered primary prophylaxis and who elect to continue their pregnancy, prophylaxis should be discontinued. The occurrence of craniofacial and skeletal abnormalities in infants following prolonged in utero exposure to fluconazole should be considered when assessing the therapeutic options for HIV-infected women who become pregnant and are receiving secondary prophylaxis (CMT) for cryptococcosis [bib_ref] Fluconazole-induced congenital anomalies in three infants, Pursley [/bib_ref] [bib_ref] Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional..., Aleck [/bib_ref]. If a woman meets the criteria for discontinuation of secondary prophylaxis as discussed above, strong consideration should be given to discontinuing therapy during pregnancy as long as the CD4 + T lymphocyte could remains above 100-200 cells/ml. For patients requiring therapy, amphotericin B may be preferred, especially during the first trimester. Effective birth control measures should be recommended to all HIV-infected women on azole therapy for cryptococcosis (AIII).
## Histoplasmosis
Prevention of exposure 1. Although HIV-infected persons living in or visiting histoplasmosis-endemic areas cannot completely avoid exposure to Histoplasma capsulatum, those whose CD4 + T lymphocyte counts are less than 200 cells/ml should avoid activities known to be associated with increased risk (e.g., creating dust when working with surface soil; cleaning chicken coops that are heavily contaminated with droppings; disturbing soil beneath bird-roosting sites; cleaning, remodeling or demolishing old buildings; and exploring caves) (CIII).
Prevention of disease 2. Routine skin testing with histoplasmin and serologic testing for antibody or antigen in histoplasmosis-endemic areas are not predictive of disease and should not be performed (DII). 3. Data from a prospective randomized controlled trial indicate that itraconazole can reduce the frequency of histoplasmosis among patients who have advanced HIV infection and who live in H. capsulatumendemic areas [bib_ref] Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus..., Mckinsey [/bib_ref]. However, no survival benefit was observed among persons receiving itraconazole. Prophylaxis with itraconazole may be considered in patients with CD4 + T lymphocyte counts less than 100 cells/ml who are at especially high risk because of occupational exposure or who live in a community with a hyperendemic rate of histoplasmosis (greater than or equal to ten cases per 100 patient-years) (CI).
Prevention of recurrence 4. Patients who complete initial therapy for histoplasmosis should be administered lifelong suppressive treatment (i.e., secondary prophylaxis or CMT) with itraconazole (200 mg twice a day) (AI) [bib_ref] Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus..., Mckinsey [/bib_ref]. . Although patients receiving secondary prophylaxis (CMT) might be at low risk for recurrence of systemic mycosis when their CD4 + T lymphocyte counts increase to greater than 100 cells/ml, in response to HAART, the numbers of patients who have been evaluated are insufficient to warrant a recommendation to discontinue prophylaxis.
## Discontinuation of secondary prophylaxis (cmt)
Special considerations Children 6. Because primary histoplasmosis can lead to disseminated infection in children, a reasonable option is to administer lifelong suppressive therapy after an acute episode of the disease (AIII).
## Pregnant women
7. Because of the embryotoxicity and teratogenicity of itraconazole in animal systems, primary prophylaxis against histoplasmosis should not be offered during pregnancy (DIII). These data as well as the observation of craniofacial and skeletal abnormalities in infants following prolonged in utero exposure to fluconazole [bib_ref] Fluconazole-induced congenital anomalies in three infants, Pursley [/bib_ref] [bib_ref] Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional..., Aleck [/bib_ref] should be considered when assessing the need for CMT in HIV-infected pregnant women with histoplasmosis. For such patients, therapy with amphotericin B may be preferred, especially during the first trimester. For women receiving HAART with a sustained rise in CD4 + T lymphocyte counts above 100 cells/ml, discontinuation of azole prophylaxis, especially during the first trimester, should be considered. Effective birth control measures should be recommended to all HIV-infected women on azole therapy for histoplasmosis (AIII).
## Coccidioidomycosis
Prevention of exposure 1. Although HIV-infected persons living in or visiting areas in which coccidioidomycosis is endemic cannot completely avoid exposure to Coccidioides immitis, they should, when possible, avoid activities associated with increased risk (e.g., those involving extensive exposure to disturbed native soil, for example, at building excavation sites or during dust storms) (CIII).
Prevention of disease 2. Routine skin testing with coccidioidin (spherulin) in coccidioidomycosis-endemic areas is not predictive of disease and should not be performed (DII). Within the endemic area, a positive serologic test might indicate an increased risk for active infection; however, routine testing does not appear to be useful and should not be performed (DIII). 3. Primary prophylaxis for HIV-infected persons who live in coccidioidomycosis-endemic areas is not routinely recommended.
Prevention of recurrence 4. Patients who complete initial therapy for coccidioidomycosis should be administered lifelong suppressive therapy (i.e., secondary prophylaxis or CMT) (AII) using either 400 mg of fluconazole by mouth each day or 200 mg of itraconazole twice a day [bib_ref] Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized,..., Galgiani [/bib_ref]. Patients with meningeal disease require consultation with an expert.
Discontinuation of secondary prophylaxis (CMT) . Although patients receiving secondary prophylaxis (CMT) might be at low risk for recurrence of systemic mycosis when their CD4 + T lymphocyte counts increase to greater than 100 cells/ml, in response to HAART, the numbers of patients who have been evaluated are insufficient to warrant a recommendation to discontinue prophylaxis.
Special considerations Children 6. Although no specific data are available regarding coccidioidomycosis in HIV-infected children, a reasonable option is to administer lifelong suppressive therapy after an acute episode of the disease (AIII).
## Pregnant women
7. The potential teratogenicity of fluconazole [bib_ref] Fluconazole-induced congenital anomalies in three infants, Pursley [/bib_ref] [bib_ref] Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional..., Aleck [/bib_ref] and itraconazole 81 should be considered when assessing the therapeutic options for HIV-infected women who become pregnant while receiving CMT for coccidioidomycosis. For such patients, therapy with amphotericin B may be preferred, especially during the first trimester. For women receiving HAART with a sustained rise in CD4 + T lymphocyte counts above 100 cells/ml, discontinuation of azole prophylaxis, especially during the first trimester, should be considered. Effective birth control measures should be recommended for all HIV-infected women on azole therapy for coccidioidomycosis (AIII).
## Cytomegalovirus disease
Prevention of exposure 1. HIV-infected persons who belong to risk groups with relatively low rates of seropositivity for cytomegalovirus (CMV) and who therefore cannot be presumed to be seropositive should be tested for antibody to CMV (BIII). These groups include patients who have not had male homosexual contact or used injection drugs. 2. HIV-infected adolescents and adults should be advised that CMV is shed in semen, cervical secretions and saliva and that latex condoms must always be used during sexual contact to reduce the risk for exposure to CMV and to other sexually transmitted pathogens (AII). 3. HIV-infected adults and adolescents who are child-care providers or parents of children in child-care facilities should be informed that they are at increased risk for acquiring CMV infection (BI). Similarly, parents and other caretakers of HIV-infected children should be advised of the increased risk to children at these centers (BIII). The risk for acquiring CMV infection can be diminished by good hygienic practices such as hand washing (AII). 4. HIV-exposed infants and HIV-infected children, adolescents, and adults who are seronegative for CMV and require blood transfusion should be administered only CMV antibody-negative or leukocyte-reduced cellular blood products in nonemergency situations (BIII).
Prevention of disease 5. Prophylaxis with oral ganciclovir may be considered for HIV-infected adults and adolescents who are CMV seropositive and who have a CD4 + T lymphocyte count of less than 50 cells/ml (CI) [bib_ref] Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS, Spector [/bib_ref] [bib_ref] A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir..., Brosgart [/bib_ref]. Ganciclovir-induced neutropenia, anemia, conflicting reports of efficacy, lack of proven survival benefit, the risk for developing ganciclovir-resistant CMV and cost are among the issues that should be considered when deciding whether to institute prophylaxis in individual patients. Acyclovir is not effective in preventing CMV disease, and valacyclovir is not recommended because of an unexplained trend toward increased deaths among persons with AIDS who were administered valacyclovir for CMV prophylaxis [bib_ref] A randomized, double-blind trial of valacyclovir prophylaxis for cytomegalovirus disease in patients..., Feinberg [/bib_ref]. Therefore, neither acyclovir nor valacyclovir should be used for this purpose (EI). The most important method for preventing severe CMV disease is recognition of the early manifestations of the disease. Early recognition of CMV retinitis is most likely when the patient has been educated on this topic. Patients should be made aware of the significance of increased floaters in the eye and should be advised to assess their visual acuity regularly by using simple techniques such as reading newsprint (BIII). Regular funduscopic examinations performed by an ophthalmologist are recommended by some experts for patients with low (e.g., less than 50 cells/ml) CD4 + T lymphocyte counts (CIII).
## Prevention of recurrence
6. CMV disease is not cured with courses of the currently available antiviral agents (e.g., ganciclovir, foscarnet, cidofovir or fomivirsen). Following induction therapy, secondary prophylaxis (CMT) is recommended for life (AI), unless there is immune reconstitution as a consequence of HAART (see recommendation 7 below). Regimens demonstrated to be effective for chronic suppression in randomized, controlled clinical trials include parenteral or oral ganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration via intraocular implant or repetitive intravitreous injections of fomivirsen (AI) 100-108 . Oral valganciclovir has been approved by the FDA for both acute induction therapy and for maintenance therapy although much of the data have not been published. Repetitive intravitreous injections of ganciclovir, foscarnet and cidofovir have been reported to be effective for secondary prophylaxis of CMV retinitis in uncontrolled case series [bib_ref] Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with AIDS, Kirsch [/bib_ref] [bib_ref] High-dose (2000-microgram) intravitreous ganciclovir in the treatment of cytomegalovirus retinitis, Young [/bib_ref]. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically is combined with oral ganciclovir [bib_ref] Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant, Martin [/bib_ref]. The choice of a CMT for patients treated for CMV disease should be made in consultation with an expert. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should take into consideration the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to HAART (BIII).
## Discontinuation of secondary prophylaxis (cmt)
7. Several case series have reported that maintenance therapy can be discontinued safely in adult and adolescent patients with CMV retinitis whose CD4 + T lymphocyte counts have shown a sustained (e.g., six months) increase to > 100-150 cells/ml in response to HAART 112-116 . These patients have remained disease-free for greater than 30-95 weeks, whereas in the pre-HAART era, retinitis typically reactivated within 6-8 weeks after stopping CMV therapy. Plasma HIV RNA levels were variable in these patients, suggesting that the CD4 + T lymphocyte count is the primary determinant of immune recovery to CMV. Discontinuation of prophylaxis should be considered in patients with a sustained, (e.g., 6 months) increase in CD4 + T lymphocyte count to > 100-150 cells/ml in response to HAART (BII). Such decisions should be made in consultation with an ophthalmologist and should take into account such factors as magnitude and duration of CD4 + T lymphocyte increase, anatomic location of the retinal lesion, vision in the contralateral eye and the feasibility of regular ophthalmologic monitoring (BII). All patients who have had anti-CMV maintenance therapy discontinued should continue to undergo regular ophthalmologic monitoring for early detection of CMV relapse (as well as for immune reconstitution uveitis) (AIII). CMV viral load or other markers of CMV infection, e.g., antigenemia or viral DNA tests are not well standardized; their role in predicting relapse remains to be defined [bib_ref] Plasma cytomegalovirus (CMV) DNA load predicts CMV disease and survival in AIDS..., Spector [/bib_ref] [bib_ref] Plasma cytomegalovirus DNA, PP65 antigenaemia and a low CD4 cell count remain..., Salmon-Cerm [/bib_ref]. Relapses have been reported rarely in patients with CD4 + T lymphocyte count > 100-150 cells/ml 119 .
Restarting secondary prophylaxis 8. Relapse of CMV retinitis occurs in patients whose anti-CMV maintenance therapy has been discontinued and whose CD4 + T lymphocyte count has decreased to 50 cells/ml 109 . Therefore, reinstitution of secondary prophylaxis should be reinstituted when the CD4 + T-lymphocyte count has decreased to 100-150 cells/ml (AIII). Relapse has been reported in patients whose CD4 + T lymphocyte counts are higher then 100 cells/ml, but such reports are rare to date 119 .
## Special considerations
Children 9. Some experts recommend obtaining a CMV urine culture on all HIV-infected (or exposed) infants at birth or at an early postnatal visit to identify those infants with congenital CMV infection (CIII). In addition, beginning at one year of age, CMV antibody testing on an annual basis may be considered for CMV-seronegative (and culture-negative) HIV-infected infants and children who are severely immunosuppressed [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] (CIII). Annual testing will allow identification of children who have acquired CMV infection and might benefit from screening for retinitis. 10. HIV-infected children who are CMV-infected and severely immunosuppressed might benefit from a dilated retinal examination performed by an ophthalmologist every 4-6 months (CIII). In addition, older children should be counseled to be aware of floaters in the eye, similar to the recommendation for adults (BIII). 11. Oral ganciclovir results in reduced CMV shedding in CMV-infected children and may be considered for primary prophylaxis against CMV disease in CMV-infected children who are severely immunosuppressed (e.g., CD4 + T lymphocyte count less than 50 cells/ml) (CII). 12. Patients with a history of CMV disease should be administered lifelong prophlyaxis to prevent recurrence (AII). For children with CMV disease, no data are available to guide decisions concerning discontinuation of secondary prophylaxis (CMT) when the CD4+ T lymphocyte count has increased in response to HAART. . Indications for prophylaxis are the same for pregnant women as for non-pregnant women. The choice of agents to be used in pregnancy should be individualized after consultation with experts.
## Pregnant women
## Herpes simplex virus disease
Prevention of exposure 1. HIV-infected persons should use latex condoms during every act of sexual intercourse to reduce the risk for exposure to herpes simplex virus (HSV) and to other sexually transmitted pathogens (AII). They should specifically avoid sexual contact when herpetic lesions (genital or orolabial) are evident (AII).
2. Antiviral prophylaxis after exposure to HSV, or to prevent initial episodes of HSV disease in individuals with latent infection is not recommended (DIII).
## Prevention of recurrence
3. Because episodes of HSV disease can be treated successfully, chronic therapy with acyclovir is not required after lesions resolve. However, persons who have frequent or severe recurrences can be administered daily suppressive therapy with oral acyclovir or oral famciclovir (AI) [bib_ref] Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among..., Schacker [/bib_ref] [bib_ref] Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation..., Schacker [/bib_ref]. Valacyclovir also is an option (CIII). Foscarnet or cidofovir i.v. can be used to treat infection due to acyclovir-resistant isolates of HSV, which are routinely resistant to ganciclovir as well (AII).
Special considerations Children 4. The recommendations for preventing initial disease and recurrence among adults and adolescents apply to children as well.
## Pregnant women
5. Oral acyclovir prophylaxis during late pregnancy is a controversial strategy recommended by some experts to prevent neonatal herpes transmission. However, such prophylaxis is not routinely recommended. For patients who have frequent, severe recurrences of genital HSV disease, acyclovir prophylaxis might be indicated (BIII). No pattern of adverse pregnancy outcomes has been reported after acyclovir exposures 122 .
## Varicella-zoster virus disease
Prevention of exposure 1. HIV-infected children and adults who are susceptible to varicella-zoster virus (VZV) (i.e., those who have no history of chickenpox or shingles or are seronegative for VZV) should avoid exposure to persons with chickenpox or shingles (AII). Household contacts (especially children) of susceptible HIV-infected persons should be vaccinated against VZV if they have no history of chickenpox and are seronegative for HIV, so that they will not transmit VZV to their susceptible HIV-infected contacts (BIII).
Prevention of disease 2. Very little data regarding the safety and efficacy of varicella vaccine in HIV-infected adults are available, and no recommendation for its use can be made for this population. (See Special Considerations/Children, below). 3. For the prophylaxis of chickenpox, HIV-infected children and adults who are susceptible to VZV (i.e., those who have no history of chickenpox or shingles or who have no detectable antibody against VZV) should be administered varicella zoster immune globulin (VZIG) as soon as possible but within 96 h after close contact with a patient who has chickenpox or shingles (AIII). Data are lacking on the effectiveness of acyclovir for preventing chickenpox in susceptible HIV-infected children or adults. 4. No preventive measures are currently available for shingles.
Prevention of recurrence 5. No drug has been proven to prevent the recurrence of shingles in HIV-infected persons.
Special considerations Children 6. HIV-infected children who are asymptomatic and not immunosuppressed (i.e., in immunologic category 1, [fig_ref] Table 1: System used to rate the strength and quality of evidence supporting recommendations... [/fig_ref] should receive live attenuated varicella vaccine at 12-15 months of age or later (BII). Varicella vaccine should not be administered to other HIV-infected children because of the potential for disseminated viral infection (EIII).
## Pregnant women
7. VZIG is recommended for VZV-susceptible, HIV-infected pregnant women within 96 h after exposure to VZV (AIII). If oral acyclovir is used, VZV serology should be performed so that the drug can be discontinued if the patient is seropositive for VZV (BIII).
## Human herpesvirus 8 infection (kaposi's sarcoma-associated herpes virus)
Prevention of exposure 4. For patients whose Pap smears are interpreted as atypical squamous cells of undetermined significance (ASCUS), several management options are available; the choice depends in part on whether the interpretation of ASCUS is qualified by a statement indicating that a neoplastic process is suspected. Follow-up by Pap tests without colposcopy is acceptable, particularly when the diagnosis of ASCUS is not qualified further or the cytopathologist suspects a reactive process. In such situations, Pap tests should be repeated every 4-6 months for 2 years until three consecutive smears have been negative. If a second report of ASCUS occurs in the 2-year follow-up period, the patient should be considered for colposcopic evaluation (BIII). 5. Women who have a diagnosis of unqualified ASCUS associated with severe inflammation should be evaluated for an infectious process. If specific infections are identified, reevaluation should be performed after appropriate treatment, preferably after 2-3 months (BIII). 6. If the diagnosis of ASCUS is qualified by a statement indicating that a neoplastic process is suspected, the patient should be managed as if a low-grade squamous intraepithelial lesion (LSIL) were present (see recommendation 7) (BIII). If a patient who has a diagnosis of ASCUS is at high risk (i.e., previous positive Pap tests or poor adherence to follow-up), the option of colposcopy should be considered (BIII). 7. Several management options are available for patients who have LSIL. Follow up with Pap tests every 4-6 months is used by many clinicians and is currently used in countries outside the United States as an established method of management. Patients managed in this way must be carefully selected and considered reliable for follow-up. If repeat smears show persistent abnormalities, colposcopy and directed biopsy are indicated (BIII). Colposcopy and directed biopsy of any abnormal area on the ectocervix constitute another appropriate option (BIII). 8. Women who have cytologic diagnosis of high-grade squamous intraepithelial lesions (HSILs) or squamous cell carcinoma should undergo colposcopy and directed biopsy (AII). . No data are available to suggest that these guidelines to prevent cervical disease should be modified for women on HAART. HPV-associated anal intraepithelial neoplasia and anal cancer in HIV-infected homosexuals and in women. Evidence from several studies shows that HPV-positive homosexuals and HPV infected women are at increased risk for anal HSILs and might be at increased risk for anal cancer. In view of this evidence, coupled with a recent cost-effectiveness analysis projecting that screening and treatment for anal HSILs provide clinical benefits comparable to other measures to prevent OIs in HIV-infected persons [bib_ref] Seroprevalence of human herpesvirus 8 among Zambian women of childbearing age without..., He [/bib_ref] , anal cytology screening of HIV-infected homosexuals and women might become a useful preventive measure in the near future. However, further studies of screening and treatment programs for anal HSILs need to be carried out before recommendations for routine anal cytology screening can be made.
## Persons co-infected with hiv and hhv-8 are at risk for developing kaposi's sarcoma (ks) and, there is evidence that progression to ks may be accelerated in individuals who seroconvert to hhv-8 after being infected with hiv. thus it is important to prevent acquisition of hhv-8 infections in those already infected with hiv 123-125 . the three major routes of hhv-8 transmission appear to be oral (the virus infects oral epithelial cells, and infection has been associated
Prevention of recurrence 11. The risks for recurrence of squamous intraepithelial lesions and cervical cancer after conventional therapy are increased among HIV-infected women. The prevention of illness associated with recurrence depends on careful follow-up of patients after treatment. Patients should be monitored with frequent cytologic screening and, when indicated, with colposcopic examination for recurrent lesions (AI) [bib_ref] Interim guidelines for management of abnormal cervical cytology, Kurman [/bib_ref] [bib_ref] Hepatitis B or Hepatitis C virus infection is a risk factor for..., Saves [/bib_ref]. 12. In one recent study of HIV-infected women treated for HSILs using standard therapy, low-dose intravaginal 5-fluorouracil (2 g twice a week for six months) reduced the short-term risk for recurrence and possibly the grade of recurrence [bib_ref] Vaginal 5-fluorouracil for high grade cervical dysplasia in HIVinfection: A randomized trial, Maiman [/bib_ref]. However, clinical experience with this therapy is too limited to provide a recommendation for routine use.
## Special considerations
Pregnant women . Use of intravaginal 5-fluorouracil to prevent recurrent dysplasia is not recommended during pregnancy.
## Hepatitis c virus infection
Prevention of exposure 1. The chief route of hepatitis C virus (HCV) transmission in the United States is injection drug use. Because injection drug use is a complex behavior, clinicians should assess the individual's readiness to change this practice and encourage efforts to provide patient education and support directed at recovery.
Patients who inject drugs should be advised [bib_ref] Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus..., Sulkowski [/bib_ref] [bib_ref] Mortality from liver cancer and liver disease in haemophilic men and boys..., Darby [/bib_ref] (a) to stop using injection drugs (AIII); to enter and complete a substance-abuse treatment program, including a relapse prevention program (AIII).
## If they are continuing to inject drugs (biii)
to never reuse or share syringes, needles, rinse water or drug preparation equipment; if, nonetheless, injection equipment that has been used by other persons is shared, to first clean the equipment with bleach and water as is recommended for prevention of HIV; to use only sterile syringes obtained from a reliable source (e.g., pharmacies or syringe exchange programs); to use sterile (e.g., boiled) water to prepare drugs; if not possible, to use clean water from a reliable source (e.g., fresh tap water); to use a new or disinfected container (cooker) and a new filter (cotton) to prepare drugs; to clean the injection site with a new alcohol swab before injection; and to safely dispose of syringes after one use. 2. Persons considering tattooing or body piercing should be informed of potential risks of acquiring bloodborne infections, which could be transmitted if equipment is not sterile or if proper infection control procedures are not followed (e.g., washing hands, using latex gloves and cleaning and disinfecting surfaces) 139 (BIII). 3. To reduce risks for acquiring bloodborne infections, patients should be advised not to share dental appliances, razors or other personal care articles (BIII). 4. Although the efficiency of sexual transmission of HCV is low, safe-sexual practices should be encouraged for all HIV infected persons and barrier precautions (e.g., latex condoms) are recommended to reduce the risk for exposure to sexually transmitted pathogens (AII).
## Prevention of disease
## All patients with hiv infection should be screened for hcv infection (biii).
Screening is recommended because some HIV-infected patients (e.g., injection drug users, and patients with hemophilia) are at increased risk for HCV infection and HCV related disease, and because knowledge of HCV status is important for management of all HIV-infected patients (e.g., to interpret and manage elevated liver related tests). Screening should be performed by using enzyme immunoassays (EIAs) licensed for detection of antibody to HCV (anti-HCV) in blood (BIII). Positive anti-HCV results should be verified with additional testing (i.e., recombinant immunoblot assay or reverse transcriptase polymerase chain reaction (RT-PCR) for HCV RNA). The presence of HCV RNA in blood might also be assessed in HIV-infected persons with undetectable antibody but other evidence of chronic liver disease (e.g., unexplained elevated liver-specific enzymes) or when acute HCV infection is suspected (CIII). 6. Persons coinfected with HIV and HCV should be advised not to drink excessive amounts of alcohol (AII). Avoiding alcohol altogether might be prudent because it is unclear whether even occasional alcohol use (e.g., less than 12 ounces of beer or less than 10 grams of alcohol per day) increases the incidence of cirrhosis among HCV-infected persons (CIII). 7. Patients with chronic hepatitis C should be vaccinated against hepatitis A because a) the risk for fulminant hepatitis associated with hepatitis A appears increased in such patients; b) hepatitis A vaccine is safe for HIV-infected persons; and c) although immunogenicity is reduced in patients with advanced HIV infection, more than two thirds of patients develop protective antibody responses (BIII). Prevaccination screening for total (IgG and IgM) antibody to hepatitis A virus is cost-effective and therefore recommended when greater than 30% prevalence of hepatitis A virus antibody is expected in the population being screened (e.g., persons greater than 40 years of age) [bib_ref] Natural history of hepatitis C virus infection in multitransfused hemophiliacs: effect of..., Eyster [/bib_ref]. Patients should also be immunized for HBV if they are susceptible (BIII). 8. HIV-HCV-coinfected patients may develop HCV associated liver disease over a shorter time course than patients infected with HCV alone [bib_ref] Mortality from liver cancer and liver disease in haemophilic men and boys..., Darby [/bib_ref] [bib_ref] Effect of HIV infection on hepatitis C virus infection among injection drug..., Thomas [/bib_ref] [bib_ref] Hepatotoxicity after introduction of highly active antiretroviral therapy, Rodriguez-Rosado [/bib_ref] [bib_ref] Hepatitis B or Hepatitis C virus infection is a risk factor for..., Saves [/bib_ref] and should be evaluated for chronic liver disease and for the possible need for treatment. Limited data suggest that HCV treatment can be safely provided to patients coinfected with HIV and HCV. Because the optimal means of treating coinfected patients has not been established and many HIV-infected patients have conditions that complicate therapy (e.g., depression), this care should occur in a clinical trial or be coordinated by providers with experience treating both HIV and HCV infections (BIII). . In some studies, the incidence of antiretroviral-associated liver enzyme elevations has been increased in patients coinfected with HIV and HCV 142 ; such increases might not require treatment modifications. Thus, although liver enzymes should be carefully monitored, HAART should not be routinely withheld from patients coinfected with HIV and HCV (DIII). However, coinfected patients initiating HAART might have an inflammatory reaction that mimics an exacerbation of underlying liver disease. In this situation, careful monitoring of liver function is required.
## Prevention of recurrence
10. If the serum HCV RNA level becomes undetectable during HCV therapy and remains undetectable for 6 months after HCV therapy is stopped (sustained virologic response), greater than 90% of HIVuninfected patients with hepatitis C will remain HCV RNA negative for greater than five years and have improved liver histology [bib_ref] Persistent hepatitis C viremia predicts late relapse after sustained response to interferon..., Chemello [/bib_ref]. For HIV-HCV-coinfected patients, the durability of treatment response and requirement for maintenance therapy are unknown.
## Special considerations
Children . Transmission of HCV from mother to child appears to be more frequent for mothers co-infected with HIV and HCV than for those infected with HCV alone. Therefore, children born to women coinfected with HIV and HCV should be tested for HCV infection 137 (BI). Because maternal HCV antibody can persist for up to 18 months, testing should be performed at or after two years of age. If earlier diagnosis is desired, RT-PCR for HCV RNA may be performed after one month of age and should be repeated at a subsequent time. The average rate of HCV infection among infants born to coinfected women is approximately 15% (range, 5-36%) [bib_ref] Condom use also will, theoretically, reduce the risk for acquiring human herpesvirus..., Mast [/bib_ref]. Data are limited on the natural history of HCV infection and treatment of chronic hepatitis C in children. In addition, anmtiviral treatment for chronic hepatitis C is not approved for patients < 18 years of age.
## Hepatitis a immunization is recommended for all susceptible men who have sex with men, as well as others with indications for hav vaccine (biii).
persons boil or otherwise avoid drinking tap water in nonoutbreak settings. However, persons who wish to take independent action to reduce their risk for waterborne cryptosporidiosis may choose to take precautions similar to those recommended during outbreaks. Such decisions are best made in conjunction with a health-care provider. Persons who opt for a personal-use filter or bottled water should be aware of the complexities involved in selecting the appropriate products, the lack of enforceable standards for destruction or removal of oocysts, the cost of the products, and the difficulty of using these products consistently. Patients taking precautions to avoid acquiring cryptosporidiosis from drinking water should be advised that ice made from contaminated tap water also can be a source of infection (BII). Such persons should be aware that fountain beverages served in restaurants, bars, theaters, and other public places might also pose a risk, because these bever-ages, as well as the ice they might contain, are made from tap water. Nationally distributed brands of bottled or canned carbonated soft drinks are safe to drink. Commercially packaged noncarbonated soft drinks and fruit juices that do not require refrigeration until after they are opened (i.e., those that can be stored unrefrigerated on grocery shelves) also are safe. Nationally distributed brands of frozen fruit juice concentrate are safe if they are reconstituted by the user with water from a safe source. Fruit juices that must be kept refrigerated from the time they are processed to the time of consumption might be either fresh (unpasteurized) or heat-treated (pasteurized); only juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasteurized beverages and beers are also considered safe to drink (BII). No data are available concerning survival of Cryptosporidium oocystsin wine.
# Travel-related exposures
[fig] 2: Although declawing is not generally advised, HIV-infected persons should avoid rough play with cats and situations in which scratches are likely (BII). Any cat-associated wound should be washed promptly (CIII). Cats should not be allowed to lick open wounds or cuts of HIV-infected persons (BIII). 3. Care of cats should include flea control (CIII). 4. No evidence indicates any benefits to cats or their owners from routine culture or serologic testing of the pet for Bartonella infection (DII). Prevention of disease 5. No data support chemoprophylaxis for Bartonella-associated disease (CIII). [/fig]
[table] Table 1: System used to rate the strength and quality of evidence supporting recommendations for prevention of opportunistic infections in persons infected with HIV [/table]
[table] Table 3: Prophylaxis to prevent recurrence of opportunistic disease in adults (after chemotherapy for acute disease) in adults and adolescents infected with human immunodeficiency virus [/table]
[table] Table 4: Effects of Food on Drugs used to prevent opportunistic infections [/table]
[table] Table 5: Effects of medications on drugs used to prevent opportunistic infections [/table]
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https://downloads.hindawi.com/journals/idog/2002/282894.pdf
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In 1995, the US Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) in persons infected with human immunodeficiency virus (HIV)1–3. These guidelines, written for health-care providers and patients, were revised in 19974 and again in 19995. They have been published in the MMWR1,4,5, Clinical Infectious Diseases2,6,7, the Annals of Internal Medicine3,8, the American Family Physician9,10, and Pediatrics11; accompanying editorials have appeared in JAMA12,13. Response to these guidelines (e.g., the many requests for reprints, numerous web site contacts and observations from health-care providers) suggests they have served as a valuable reference for HIV care providers. Because the 1995, 1997 and 1999 guidelines included ratings indicating the strength of each recommendation and the quality of supporting evidence, readers have been able to assess the relative importance of each recommendation. Since AIDS was first recognized 20 years ago, remarkable progress has been made in improving the quality and duration of life of HIV-infected persons in the industrialized world. During the first decade of the epidemic, this improvement occurred because of better recognition of opportunistic disease processes, better therapy for acute and chronic complications and the introduction of chemoprophylaxis against important opportunistic pathogens. The second decade of the epidemic has witnessed extraordinary progress in developing highly active antiretroviral therapies (HAART) as well as continuing progress in preventing and treating individual OIs. HAART has reduced the incidence of OIs and extended life substantially14–16. HAART is the most effective approach to preventing OIs and should be considered for all HIV-infected persons who qualify for such therapy14–16. However, some patients are not ready or able to take HAART and others have tried HAART regimens, but therapy has failed. Such patients will benefit from prophylaxis against OIs15. In addition, prophylaxis against specific OIs continues to provide survival benefits even among persons who are receiving HAART15. Since HAART was introduced in the United States in 1995, it has become increasingly clear that chemoprophylaxis for OIs need not necessarily be life-long. Antiretroviral therapy can restore immune function. The period of susceptibility to opportunistic processes continues to be accurately indicated by the CD4+ T lymphocyte count for patients who are receiving HAART. Thus, a strategy of stopping primary or secondary prophylaxis for certain patients whose immunity has improved as a consequence of HAART seems logical. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower cost of care and potentially facilitate adherence to antiretroviral regimens. Infect Dis Obstet Gynecol 2002;10:3–64
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pubmed
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A practical guide for probiotics applied to the case of antibiotic-associated diarrhea in The Netherlands
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A practical guide for probiotics applied to the case of antibiotic-associated diarrhea in The Netherlands
Background: Antibiotic-associated diarrhea (AAD) is a side-effect frequently associated with the use of broad spectrum antibiotics. Although a number of clinical studies show that co-administration of specific probiotics reduces the risk for AAD, there is still unclarity among healthcare professionals on the recommendation of probiotic products. This paper aims at a practical guide to inform healthcare professionals, patients and consumers about the exact product characteristics of available probiotics with a proven efficacy to prevent AAD. Methods: The workflow in this paper includes three consecutive steps: 1) systematic review of relevant clinical studies for effective probiotics by a meta-analysis, 2) compilation of a list of available probiotic products, and 3) recommendation of probiotic products that match effective formulations. Our systematic review on the efficacy of probiotics for the prevention of AAD included only studies with randomized, double blind placebo-controlled trials, a clear definition of antibiotic associated diarrhea, and a probiotic administration regime for at least the duration of the antibiotic therapy. Results: Using our inclusion criteria, we selected 32 out of 128 identified trials and pooled the results of these studies for each specific dairy product and food supplement. The results indicate a total of seven single or multiple-strain formulations favoring the probiotic treatment group, with the strain Lactobacillus rhamnosus GG being the most effective [relative risk ratio of probiotic versus placebo 0.30 (95% CI 0.16-0.5) ]. We selected products for recommendation from a compiled list of all probiotic dairy products and food supplements available in The Netherlands and categorized them into groups of products showing effects against the incidence of AAD in at least one, two or three independent clinical studies. We excluded all products which did not unambiguously declare on the label the specific probiotic strain(s) and the number of colony forming units. Conclusion: Here we present a practical guide that informs healthcare professionals and patients on the availability of probiotic products with a proven efficacy for the prevention of AAD.
# Background
Antibiotic associated diarrhea (AAD)
The use of antibiotics is associated with a variety of side-effects. The most common side effects are gastro-intestinal, such as nausea and diarrhea (Additional file 1). Antibiotic-associated diarrhea (AAD) arises when the antibiotic disrupts the ecology of the intestinal microbiota, by altering the diversity and numbers of bacteria in the gut. These changes can affect the capacity of the resident microbiota to resist the invasion of pathogenic microorganisms [bib_ref] Effects of antibiotics on human microbiota and subsequent disease, Keeney [/bib_ref] or the overgrowth of opportunistic pathogens species that are endogenously present in the microbiota [bib_ref] Antibiotics and the human gut microbiome: Dysbioses and accumulation of resistances, Francino [/bib_ref] [bib_ref] Ciprofloxacin affects host cells by suppressing expression of the endogenous antimicrobial peptides..., Sarker [/bib_ref]. Even after the recovery of total bacterial counts, there can be long-lasting effects on the balance of the intestinal microbiota and consequently on the patient's susceptibility to infection and other diseases [bib_ref] Prolonged impact of antibiotics on intestinal microbial ecology and susceptibility to enteric..., Croswell [/bib_ref] [bib_ref] Long-term ecological impacts of antibiotic administration on the human intestinal microbiota, Jernberg [/bib_ref]. Therefore, AAD may result in prolonged hospitalization, increased health care costs and other complications. Diarrhea is most frequently associated with the use of broad spectrum antibiotics [bib_ref] Incidence and risk factors of oral antibiotic-associated diarrhea in an outpatient pediatric..., Turck [/bib_ref] [bib_ref] Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study, Wiström [/bib_ref] [bib_ref] Antibiotic-associated gastrointestinal symptoms in general pediatric outpatients, Kramer [/bib_ref] , and a tendency to an increase in the prescriptions of broad-spectrum antibiotics has been observed even in a low-prescribing country like the Netherlands [bib_ref] Outpatient antibiotic prescriptions from 1992 to 2001 in The Netherlands, Kuyvenhoven [/bib_ref]. For example, the broad-spectrum antibiotic amoxicillin is one of the top 25 drugs that have increased in the numbers of prescriptions in 2015. Therefore, it is important to consider the methods currently used to contrast the incidence of AAD and to evaluate their efficacy.
## Probiotics as prophylaxis
Probiotics are "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host". The core benefit of probiotics is exercised by contributing to the maintenance of a balanced microbiota and therefore by creating a favorable gut environment [bib_ref] Expert consensus document: The international scientific association for probiotics and prebiotics consensus..., Hill [/bib_ref]. Furthermore, probiotics support the health of the digestive tract and the immune system [bib_ref] Expert consensus document: The international scientific association for probiotics and prebiotics consensus..., Hill [/bib_ref]. The positive effect of probiotics on gut health in a variety of conditions (antibiotic-associated and infectious diarrhea, irritable bowel syndrome, necrotizing enterocolitis, etc.) has been evaluated by a number of randomized controlled clinical trials [bib_ref] A meta-analysis of probiotic efficacy for gastrointestinal diseases, Ritchie [/bib_ref]. Probiotics can antagonize pathogenic microorganisms in a variety of ways. They can compete with pathogens for nutrients and adhesion sites on the gastrointestinal mucosa [bib_ref] Displacement of bacterial pathogens from mucus and Caco-2 cell surface by lactobacilli, Lee [/bib_ref] [bib_ref] Mucosal adhesion properties of the probiotic Lactobacillus rhamnosus GG SpaCBA and SpaFED..., Ossowski [/bib_ref] in the process of competitive exclusion [bib_ref] Antimicrobial peptides are among the antagonistic metabolites produced by Bifidobacterium against Helicobacter..., Collado [/bib_ref]. They can also prevent pathogenicity by interfering with signaling between pathogens by degrading quorum sensing molecules [bib_ref] Isolation and characterization of new potential probiotic bacteria based on quorum-sensing system, Chu [/bib_ref]. In addition, direct antagonism can occur through the production of bacteriocins or metabolites with antimicrobial activity against pathogenic microorganisms [bib_ref] Bacteriocins RPR. developing innate immunity for food, Cotter [/bib_ref] [bib_ref] Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens, Servin [/bib_ref]. Finally, probiotics are able to modulate and stimulate local and systemic immune responses in the patient [bib_ref] Immune system stimulation by probiotic microorganisms, Ashraf [/bib_ref].
According to the Agency for Healthcare Research and Quality (AHRQ) there is not enough information to confidently judge the safety of probiotic-based interventions [bib_ref] Safety of probiotics used to reduce risk and prevent or treat disease, Hempel [/bib_ref]. This is because many clinical trials do not adequately document adverse events, and also because rare adverse events are difficult to assess. Still, probiotic products are generally regarded as safe, and they are used both by healthy and ill people globally. Possible safety concerns include diseases such as bacteremia and fungemia [bib_ref] The safety of probiotics, Snydman [/bib_ref] , and are especially concerning for patients with a weakened or compromised immune system (critically ill infants, post-surgery and hospitalized patients, immuno-compromised patients are at high risk [bib_ref] Immunosuppression and probiotics: Are they effective and safe?, Stadlbauer [/bib_ref] [bib_ref] A systematic review of the safety of probiotics, Didari [/bib_ref]. Additionally, probiotics can constitute a source of antibiotic resistance genes. Although commercial probiotic strain are tested for the presence of such genes, reports have documented the presence of antibiotic resistance in probiotic bacteria from dietary supplements [bib_ref] Antibiotic resistance among commercially available probiotics, Sharma [/bib_ref] [bib_ref] Detection of antibiotic resistance in probiotics of dietary supplements, Wong [/bib_ref].
## Scope of the paper
In this paper we present a practical guide to the use of probiotics for the prevention of antibiotic-associated diarrhea. The guide is based on available scientific evidence and developed by following a workflow in three steps: 1) evaluation of the efficacy of probiotics in the context of AAD and identification of effective strains/ formulations by a systematic review of relevant clinical trials and meta-analysis of their results; 2) identification of probiotic products available to the target population; 3) recommendation of specific probiotic products matching effective formulations. The scope of this guide is to inform healthcare professionals and patients on the availability of probiotic products with a proven efficacy for the prevention of AAD.
# Methods
## Search strategy and inclusion criteria
Included in this review are studies that assessed the efficacy of probiotics in reducing the incidence of antibiotic-associated diarrhea (AAD) in patients treated with antibiotics, regardless of their age, of the intervention setting (hospital or outpatients) and of the indication for which they were prescribed. In order to identify these studies we first screened the references listed by previously published systematic reviews and meta-analyses, and then we directly searched clinical trials in public databases. Database searches were conducted on the 16th of January 2017.
We searched reviews and meta-analyses on the following databases for the period 1960-2016: the Database of Abstracts of Reviews of Effects (DARE), the Cochrane Database of Systematic Reviews (CDSR) and PubMed. For the DARE and the CDSR databases we searched combinations of the following terms: "probiotic", "antibiotic", "diarrhea" and "antibiotic-associated diarrhea". The search yielded 25 results from the DARE and 50 from the CDSR. In PubMed, we searched for meta-analyses using the following search texts: " ", which yielded 34 results. After screening of titles and abstracts and exclusion of duplicates and reviews not relevant to our purpose, we identified 28 relevant reviews and meta-analyses [bib_ref] A meta-analysis of probiotic efficacy for gastrointestinal diseases, Ritchie [/bib_ref] , containing a total of 102 relevant studies.
To confirm and update the information obtained from previously published reviews, we also directly searched clinical trials on the Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED and Excerpta Medica Database (EMBASE) for the period 2010-2017. We used the following search texts: "probiotic AND antibiotic associated diarrhea OR antibiotic associated diarrhoea" and "probiotic AND antibiotic AND diarrhea". These searches yielded 26 studies.
Among the studies resulting from our searches, we defined the relevant ones on the basis of specific inclusion criteria: (i) randomized trial, with a double-blind setup and including a placebo control, (ii) clear definition of AAD, and incidence of AAD measured as one of the outcomes, and (iii) probiotic administered for at least the duration of antibiotic therapy. Studies that did not meet the above inclusion criteria were excluded. Furthermore, we excluded studies when diarrhea was already present at the start of the intervention and when the probiotics were tested in combination with other products. We also excluded studies not written in English, studies that were not published or not available, and duplicates (studies reporting results already included in another publication). One author screened the abstract and the body of the papers and extracted information relevant to establish eligibility and conduct the meta-analysis. When the full text of a publication was not accessible, relevant information was obtained from previous reviews. The study was only included when the information available from the other sources met the inclusion criteria.
# Data analysis
For each of the included trials, we calculated the relative risk (RR) and the 95% confidence interval (CI) for the incidence of diarrhea in the probiotic versus placebo treatment. In addition, we conducted a subgroup analysis by pooling studies based on the composition of the probiotic Microsoft Excel (2016); the Meta-Essentials tool was used to measure heterogeneity and risk of bias [bib_ref] Introduction, comparison, and validation of Meta-Essentials: A free and simple tool for..., Suurmond [/bib_ref].
## Available probiotic products in the netherlands
A complete list of probiotic products available in The Netherlands was obtained in December 2016 by screening online websites of pharmacies, vitamin stores, health stores, and shops selling probiotics online. The Dutch association Natuur-en Gezondheidsproducten Nederland (NPN, Amersfoort, The Netherlands) evaluated and completed our list. We also included dairy products routinely sold in food stores.
## Recommendations
Based on the effectiveness of probiotic strains included in this review in preventing AAD and on the number of studies supporting it, we defined three categories of recommendations. The categories include (i) a three-star recommendation for significant effects for the reduction of AAD shown in at least three of our selected studies, (ii) a two-star recommendation for effects shown in at least two of our selected studies, and (iii) a one-star recommendation for an effect shown in only one study, a trend supported by two or more studies, or the presence of a strain that satisfies one of the above criteria (showing an effect in one study or a trend in at least 2 studies) in sufficient amounts in food supplement or dairy product with a mixed formulation. We screened the list of products available in the Netherlands and selected products that satisfied the criteria above and that contained the relevant strain(s) at a daily dose at least equal to the lowest dose showing an effect in the included studies. For dairy products, we only recommended those that had been specifically included in a clinical trial.
# Results
## Search strategy and study selection
The flow of the meta-analysis, from search to study selection, is depicted in [fig_ref] Figure 2: Flow diagram of study selection the probiotic strain [/fig_ref]. The literature search identified 128 relevant studies. An overview of these studies, including the reasons for their exclusion, is presented in Additional file 2. A total of 32 trials satisfied our inclusion criteria and were included in the meta-analysis: 26 were obtained from previous reviews and six from direct database searches [bib_ref] Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile..., Allen [/bib_ref] [bib_ref] Randomized placebo-controlled double blind multicentric trial on efficacy and safety of Lactobacillus..., Chatterjee [/bib_ref] [bib_ref] Effectiveness of Lactobacillus helveticus and Lactobacillus rhamnosus for the management of antibiotic-associated..., Evans [/bib_ref] [bib_ref] Probiotics reduce symptoms of antibiotic use in a hospital setting: A randomized..., Ouwehand [/bib_ref] [bib_ref] Randomized study of probiotics in primary care, Patel [/bib_ref] [bib_ref] Probiotic VSL#3 prevents antibiotic-associated diarrhoea in a double-blind, randomized, placebo-controlled clinical trial, Selinger [/bib_ref]. The specific characteristics of all included studies are summarized in Additional file 3.
Most of the studies that were identified through our search, but were excluded from the meta-analysis, did not include a placebo (31%). The second largest fraction of excluded studies consisted of studies without a clear definition of AAD (20%). Among other reasons for exclusion were the lack of a precise measurement of diarrhea, and an unclear duration of the probiotic treatment.
From the total of 32 included studies, five (15.6%) did not specify the antibiotic used in the trial. Six studies (9%) used only one antibiotic or combination of antibiotics: two studies used amoxicillin, one used amoxicillin with clavulanic acid, one used a non-specified beta-lactam antibiotic, and two used a combination of three different antibiotics to eradicate Helicobacter pylori infection. The remaining 21 studies (60%) enrolled patients that were taking different antibiotics. All of these studies included antibiotics associated with a high risk of AAD, including amoxicillin, beta-lactams, broad-spectrum penicillins, cephalosporins and clindamycin. Ten studies focused on children up to 17 years old (of which one focused on infants 6-36 months), and 22 on adults (three of which focused on elderly over 65 years old).
# Data analysis
The results of the meta-analysis have been summarized in . In this forest plot, studies are pooled based on probiotic formulation and sub-grouped in two categories: dairy products (7 studies) and food supplements (i.e. non-dairy products, 25 studies). Results are also reported for each individual trial in chronological order of publication date in Additional file 4. Overall, probiotics were associated with lower incidence of antibiotic-associated diarrhea (467/3720 [13%]) compared to the control (648/3640 [18%]) (RR 0.66, 95% CI 0.64-0.67). For trials using probiotic dairy products, the incidence of AAD in the probiotic group was 15.2% compared to 27.5% in the control group (RR 1.01, 95% CI 0.95-1.07). For trials including food supplements (i.e. non-dairy products) the incidence of diarrhea in the probiotic group was 12.2% Prescriptions of antibiotics in The Netherlands including those for high risk of AAD. The data have been extracted from the Genees-en hulpmiddelen Informatie Project (GIP; https://www.gipdatabank.nl/databank) from the Zorginstituut Nederland, that collects trends on use of medication in the Netherlands as reported by health insurance companies. Grey bars indicate the antibiotics that are associated with a higher risk of AAD [bib_ref] Displacement of bacterial pathogens from mucus and Caco-2 cell surface by lactobacilli, Lee [/bib_ref] [bib_ref] Mucosal adhesion properties of the probiotic Lactobacillus rhamnosus GG SpaCBA and SpaFED..., Ossowski [/bib_ref] [bib_ref] Antimicrobial peptides are among the antagonistic metabolites produced by Bifidobacterium against Helicobacter..., Collado [/bib_ref] compared to 16.3% in the control group (RR 0.64, 95% CI 0.63-0.65).
## Recommendations
A compiled list of probiotics available in The Netherlands in December 2016 is presented in Additional file 5. We identified the following strains satisfying the recommendation criteria: Lactobacillus rhamnosus GG with a minimal daily dose of 2 × 10 9 CFU, to which we assigned a three-star recommendation, as it is associated with a significant reduction in the incidence of AAD in at least three of our selected studies [bib_ref] double-blind, placebo-controlled trial: Effect of Lactobacillus GG supplementation on Helicobacter pylori eradication..., Szajewska [/bib_ref] [bib_ref] Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children, Vanderhoof [/bib_ref]. In addition, the multi-strain formulation of Lactobacillus rhamnosus GG, Lactobacillus acidophilus LA-5, Bifidobacterium lactis BB-12 shows a significant effect in the reduction of AAD in two of our selected studies, but we did not identify an available probiotic product containing this formulation (see further below) [bib_ref] Can probiotic yogurt prevent diarrhoea in children on antibiotics? A double-blind, randomised,..., Fox [/bib_ref] [bib_ref] Prevention of antibiotic-associated diarrhoea by a fermented probiotic milk drink, Wenus [/bib_ref]. A number of multi-strain formulations led to a one-star recommendation, including those significantly reducing the incidence of AAD in only one selected study: Streptococcus thermophilus and Bifidobacterium lactis (minimal daily dose: 5 billion CFU) [bib_ref] A randomized formula controlled trial of Bifidobacterium lactis and Streptococcus thermophilus for..., Correa [/bib_ref] , Lactobacillus rhamnosus strains Pen, E/N, Oxy (min daily dose: 4 billion CFU) [bib_ref] Clinical trial: Effectiveness of Lactobacillus rhamnosus (strains E/N, Oxy and Pen) in..., Ruszczyński [/bib_ref] and Lactobacillus acidophilus CL1285, Lactobacillus casei (minimal daily dose: 50 billion CFU) [bib_ref] Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and..., Gao [/bib_ref]. Furthermore, we assigned a one-star recommendation to formulations that showed a trend supported by two or more studies, including Saccharomyces boulardii (minimal daily dose: 10 billion CFU) [bib_ref] Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: A randomized..., Kotowska [/bib_ref] [bib_ref] The lack of therapeutic effect of Saccharomyces boulardii in the prevention of..., Lewis [/bib_ref] [bib_ref] Prevention of lactam associated diarrhoea by Saccharomyces boulardii compared with placebo, Mcfarland [/bib_ref] [bib_ref] Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients:..., Pozzoni [/bib_ref] and Bifidobacterium bifidum, Bifidobacterium lactis, Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus salivarium (minimal daily dose: 10 billion CFU) [bib_ref] The effect of a multispecies probiotic on the composition of the faecal..., Koning [/bib_ref] [bib_ref] The effect of a multispecies probiotic on the intestinal microbiota and bowel..., Koning [/bib_ref].
We then identified probiotic products (both food supplements and dairy products) to recommend based on the categories above. We recommend food supplements and dairy products that showed a significant effect favoring the probiotic in at least three independent clinical trials in our meta-analysis. No dairy product showed a significant effect for the reduction of the incidence of AAD in at least three clinical studies, and the only food supplement that shows such an effect in at least three clinical studies is Lactobacillus rhamnosus LGG (minimal daily dose: 2 billion CFU) [bib_ref] Systematic review with meta-analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic-associated..., Szajewska [/bib_ref] [bib_ref] Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children, Vanderhoof [/bib_ref]. If we consider the products available in the Netherlands, the recommended products are the food supplements Microbiol Platinum (Vitals) and Culturelle (Allergy Research Group) containing Lactobacillus rhamnosus GG at a daily dose of 33 and 10 billion CFU, respectively [fig_ref] Table 1: List of recommended probiotic products [/fig_ref]. We did not identify any dairy products of food supplements products in our two-star category. For the one star category we identified one dairy product and five food supplements containing either the exact (combination of ) probiotic(s) that showed a significant effect against AAD in one clinical trial or a trend in at least two clinical trials, or combinations of different probiotic bacteria, for some of which this effect or trend was proven. We only list and recommend products for which [fig_ref] Table 1: List of recommended probiotic products [/fig_ref].
# Discussion
## Study selection and inclusion criteria
In this review we chose to only include studies that had a clear definition of antibiotic-associated diarrhea, to be able to compare their results in a systematic way. However, studies lacking a precise definition of diarrhea may still provide valuable information, and it could be a subject for future discussions how to interpret them and whether to take them into account when formulating recommendations. Furthermore, the strict definition of diarrhea used in some studies means that the protective effect of probiotics against AAD may have been underestimated [bib_ref] Intake of Lactobacillus plantarum reduces certain gastrointestinal symptoms during treatment with antibiotics, Lönnermark [/bib_ref]. Given the scope of the review, we searched for clinical trials involving the use of antibiotics, but we didn't apply strict inclusion criteria regarding the kind of antibiotic used. We didn't look for studies using specific treatments, nor did we exclude studies that did not indicate which antibiotics they used, since diarrhea can be a side-effect of many. Five of the studies that we included did not specify which antibiotic was administered to the patients during the clinical trial. Of the remaining 27 studies, 21 enrolled patients taking different antibiotics, including antibiotic such as broad-spectrum penicillins and cephalosporins associated with a high-risk of AAD.
Only some studies reported which antibiotics were used among the characteristic of patients following treatment [bib_ref] A randomized formula controlled trial of Bifidobacterium lactis and Streptococcus thermophilus for..., Correa [/bib_ref] [bib_ref] Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: A randomized..., Kotowska [/bib_ref] [bib_ref] Clinical trial: Effectiveness of Lactobacillus rhamnosus (strains E/N, Oxy and Pen) in..., Ruszczyński [/bib_ref]. Kotowska et al. [bib_ref] Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: A randomized..., Kotowska [/bib_ref] suggested that the probiotic they tested (Saccharomyces boulardii) may be effective in preventing diarrhea caused by amoxicillin with clavulanate and by intravenous ceforuxime, but they also mentioned that they could not make definitive conclusions regarding differences in the probiotic's efficacy against different classes of antibiotics. Similarly, other studies could not detect significant differences in this regard, either because of a small sample size (relative to the number of antibiotics tested) or because of the low incidence of diarrhea in the study, or both [bib_ref] Randomized placebo-controlled double blind multicentric trial on efficacy and safety of Lactobacillus..., Chatterjee [/bib_ref]. Twenty-two of the studies included in this review included a power analysis. Of these, 11 detected a significant difference between treatment and placebo, including two studies that were underpowered according to their power analysis [bib_ref] Effect of a fermented milk combining Lactobacillus acidophilus CL1285 and Lactobacillus casei..., Beausoleil [/bib_ref] [bib_ref] Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: A randomized..., Kotowska [/bib_ref]. Of the 11 studies that did not detect a significant difference between the treatment and the placebo, four were underpowered [bib_ref] Feasibility and tolerability of probiotics for prevention of antibiotic-associated diarrhoea in hospitalized..., Safdar [/bib_ref] [bib_ref] Efficacy of BIO K+ CL1285 in the reduction of antibiotic-associated diarrhea -A..., Sampalis [/bib_ref] [bib_ref] Effect of probiotic Lactobacillus (Lacidofil® cap) for the prevention of antibioticassociated diarrhea:..., Song [/bib_ref] [bib_ref] Randomized study of probiotics in primary care, Patel [/bib_ref]. By ensuring that clinical trials have enough power it would be possible to identify which probiotics Forest plots of the subgroup meta-analysis of probiotics for AAD (food supplements vs dairy products). Studies are pooled based on composition. Note that we pool all the studies on Saccharomyces boulardii as we consider this to be one strain of Saccharomyces cerevisiae [bib_ref] Genotypic and physiological characterization of Saccharomyces boulardii, the probiotic strain of Saccharomyces..., Edwards-Ingram [/bib_ref] are most effective in preventing diarrhea caused by specific antibiotics, and clinicians would be able to recommend different probiotic products based on the antibiotic therapy prescribed to their patients.
An important aspect in the design of clinical trials is the inclusion of a placebo control group. This kind of control allows clinicians to account for the placebo effect, which is a well-recognized phenomenon in clinical practice. In clinical trials with dairy products the placebo would ideally consist of a specifically developed product with organoleptic properties very similar to the dairy product containing the probiotics. However, in case of the clinical trials testing probiotic dairy drinks included in this review, the placebo is often a different product. Since we are not aware to which extent these product differences affect the placebo response in individual patients, it may be opportune for producers of probiotic dairy drinks to develop products that can be administered as more appropriate placebos in clinical trials.
## Criteria for recommendations
In this review, we adopted strict criteria to derive recommendations from the results of our meta-analysis. Specifically, we decided to limit strong recommendations for commercial products for which the specific probiotic combination was tested, and not the single species separately, and for which the efficacy of the composition is supported by at least three clinical trials. This approach, although necessary to ensure evidence-based decision making, is limiting, since there are likely other products on the market whose exact composition has not been tested but that may be effective in preventing AAD. In fact, many of the works that we reviewed that assessed the efficacy of multi-strain probiotics (more than three strains) in reducing the risk of AAD, concluded that these products had a significant effect on risk reduction [bib_ref] The effect of a multispecies probiotic on the composition of the faecal..., Koning [/bib_ref] [bib_ref] The effect of a multispecies probiotic on the intestinal microbiota and bowel..., Koning [/bib_ref] [bib_ref] Probiotic VSL#3 prevents antibiotic-associated diarrhoea in a double-blind, randomized, placebo-controlled clinical trial, Selinger [/bib_ref].
For dairy products, we recommended those that were shown to have a positive effect in a clinical trial, but it is possible that products from other brands, with a similar Enterococcus faecium W54 1.1 × 10 9
Lactobacillus acidophilus W37 1.1 × 10 9
Lactobacillus acidophilus W55 1.1 × 10 9
Lactobacillus paracasei W20 1.1 × 10 9
Lactobacillus plantarum W62 1.1 × 10 9
Lactobacillus rhamnosus W71 1.1 × 10 9
Lactobacillus salivarius W24 1.1 × 10 9
One-star Probactiol Duo Metagenics Saccharomyces boulardii 6.0 × 10 9 1-2 capsules
Lactobacillus acidophilus NCFM 2.1 × 10 9
Lactobacillus paracasei Lpc-37 2.1 × 10 9
Bifidobacterium lactis Bi-04 2.1 × 10 9
Bifidobacterium lactis Bi-07 2.1 × 10 9
One-star Imutis Trenker Saccharomyces boulardii 6.0 × 10 9 1-4 capsules Lactobacillus acidophilus 2.0 × 10 9
Lactobacillus rhamnosus 3.0 × 10 9
Bifidobacterium longum 2.0 × 10 9
One-star Advanced Multi-Billion Dophilus Solgar Lactobacillus acidophilus LA-5 1.3 × 10 9 1 capsule
Lactobacillus paracasei L CASEI 431 1.3 × 10 9
Lactobacillus rhamnosus GG 1.3 × 10 9
Bifidobacterium lactis BB-12 1.3 × 10 9
formulation, may be as effective as those tested. For example, we reviewed here a study showing a positive effect of the probiotic dairy drink Actimel (Danone) in preventing diarrhea caused by antibiotics [bib_ref] Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised..., Hickson [/bib_ref] , and we subsequently included this product in the list of one-star recommendations. The brand Yakult produces a dairy drink containing a strain of Lactobacillus casei that has been shown to be virtually identical to the strain used by the brand Actimel [bib_ref] Comparative genome analysis of Lactobacillus casei strains isolated from Actimel and Yakult..., Douillard [/bib_ref] , providing an argument for a one-star recommendation to the Yakult dairy drink without the need to conduct additional clinical trials. Although our recommendations are based on different criteria and are not limited to children, they are in line with those of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) working group [bib_ref] Probiotics for the prevention of antibiotic-associated diarrhea in children, Szajewska [/bib_ref]. The strain L. rhamnosus GG, for which we make a three-star recommendation, was also strongly recommended for the prevention of AAD in children by the ESPGHAN working group, on the basis of a moderate quality of evidence. The working group also gave a strong recommendation to S. boulardii. However, we could not do the same on the basis of our analysis, because we pooled results of patients of different ages. In the forest plot in Additional file 4, S. boulardii shows a positive effect in the prevention of AAD in children [bib_ref] Saccharomyces boulardii in the prevention of antibiotic-associated diarrhoea in children: A randomized..., Kotowska [/bib_ref] , a positive trend in adults [bib_ref] Prevention of lactam associated diarrhoea by Saccharomyces boulardii compared with placebo, Mcfarland [/bib_ref] , but no positive effect in elderly [bib_ref] The lack of therapeutic effect of Saccharomyces boulardii in the prevention of..., Lewis [/bib_ref] [bib_ref] Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients:..., Pozzoni [/bib_ref]. Age is one of the factors that should be taken into account when evaluating health benefits of probiotics. In general, differences in the inclusion criteria, in the methods used to conduct the meta-analysis and in the criteria used to formulate recommendations will result in different evidence-based advice.
## Factors affecting the efficacy of probiotics
Multiple factors can determine the efficacy of probiotic products in specific therapeutic contexts. Firstly, the efficacy of a product can be influenced by its strain composition. One of the most studied probiotic strains is Lactobacillus rhamnosus GG, which has been repeatedly proven effective in reducing in the incidence of diarrhea in antibiotic-treated patients and in treating other gastrointestinal disorders [bib_ref] Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood, Horvath [/bib_ref]. Different strains of L. rhamnosus may not be equally effective in preventing the incidence of side effects of antibiotics [bib_ref] A meta-analysis of probiotic efficacy for gastrointestinal diseases, Ritchie [/bib_ref] , and the same is true for other probiotic species. Clinical trials should always specify which probiotic strain they tested, however this is not always the case, making it difficult to evaluate and compare their results. Furthermore, genetic variability has been observed among "identical" strains of LGG [bib_ref] Genome instability in Lactobacillus rhamnosus GG, Sybesma [/bib_ref] , so even when studies indicate precisely which strain they used it is not possible to exclude the possibility of within-strain differences affecting the results of the trial. Apart from strain composition, the formulation of a probiotic product (specific combination of strains) may affect its efficacy. This effect may be particularly significant in dairy products, since the quality of the product will vary depending on the specific strains used during the fermentation, and whether they are included during the process or added as ingredients to the final product. In this review we have analyzed dairy products and food supplements separately, and we have only combined probiotic products with the exact same strain composition and formulation, in order to minimize the effect of these factors on the results of the meta-analysis.
Apart from strain composition and probiotic product formulation, specific individual differences (age, specific health condition, genetic factors and differences in the composition of the gut microbiome) might play a role in the efficacy of probiotics, as is evident in some of the trials we reviewed.
The largest study included in this review contained almost 3000 subjects, as reported by Allen [bib_ref] Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile..., Allen [/bib_ref]. This study showed no significant effect of probiotic versus placebo. However, it included elderly participants (over 65) who may be more susceptible to adverse effects of antibiotics.. The efficacy of probiotics varies across different age groups, and is influenced by the type of antibiotic administered and the duration of the therapy. In fact, higher incidence rates of AAD were previously observed in older patients also subjected to prolonged antibiotic exposure [bib_ref] Probiotics reduce symptoms of antibiotic use in a hospital setting: A randomized..., Ouwehand [/bib_ref] , so the same factors may partly explain the observation of the study by Allen. Furthermore, in the study by Allen antibiotic therapy could last up to 7 days before starting the probiotic treatment, and probiotics may be more effective when administered during the entire period of susceptibility. In fact, a meta-regression analysis conducted by Shen et al. [bib_ref] Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a..., Shen [/bib_ref] showed that probiotics were significantly more effective in reducing the risk of Clostridium difficile infection when administered closer to the first antibiotic dose, and similar considerations could be applied to the use of probiotics to prevent AAD.
The efficacy of probiotics in preventing AAD also depends on the dose. A daily intake of at least 5 × 10 9 CFU is associated with significant efficacy for AAD [bib_ref] Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the..., Mcfarland [/bib_ref] [bib_ref] Probiotics for the prevention of pediatric antibioticassociated diarrhea, Hayes [/bib_ref] , and it has been shown that higher probiotic dose is linked to greater efficacy [bib_ref] Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and..., Gao [/bib_ref] [bib_ref] Probiotics reduce symptoms of antibiotic use in a hospital setting: A randomized..., Ouwehand [/bib_ref]. Although only few dose-effect studies have been performed, they observe a positive correlation between dose and AAD risk [bib_ref] A review of dose-responses of probiotics in human studies, Ouwehand [/bib_ref].
Since so many factors can affect the efficacy of probiotics in prophylaxis, researchers should be rigorous in setting up clinical trials and in providing as much information as possible about them. Studies should report characteristics of the probiotic (strain, dose and duration of therapy), of the antibiotic (type of antibiotic, duration of the therapy) of the patients (age group, diagnosis) and accurate definitions of measured outcomes and adverse effects. In this way, results from different trials can be assessed, compared and used as a basis to formulate recommendations. Individual factors, that are not routinely monitored in clinical trials, may influence the incidence and gravity of side effects and the efficacy of probiotics. For example, each individual has their own unique microbiota, and the impact of a given antibiotic on the composition and stability of different microbial ecosystems can be different; therefore, a specific probiotic strain or combination of strains may not have the same efficacy for every person. Especially for some patients, for example those who are frequently treated with antibiotics such as elderly in care facilities, it is certainly worth being flexible and trying different probiotics until the most effective one has been found. Future research can guide the formulation of personalized therapies.
# Conclusion
We present here a workflow for the assessment of the efficacy of probiotics for the prevention of antibiotic-associated diarrhea. The workflow consists of a series of steps (systematic review of available literature and meta-analysis of relevant clinical trials, inventory of available products and formulation of evidence-based recommendations) that can be applied to other cases, upon adaptation of methodological details such as the inclusion criteria. In order to make strong, evidence-based recommendations it is important that research of high-quality is available, in which adequate methods are followed to perform the trials and to report the results. We conclude that there is sufficient evidence to make a recommendation for the use of specific probiotic products for the prevention of antibiotic associated diarrhea. In particular, we provide a three-star recommendation for preparations with a minimal daily dose of 2 × 10 9 CFU of the probiotic strain Lactobacillus rhamnosus GG.
# Funding
The study was funded by the Netherlands Organization for Applied Scientific Research (TNO, Zeist, The Netherlands) and ARTIS-Micropia, the microbe museum in Amsterdam, The Netherlands. VA and RK are employed by TNO. RK holds a position as the ARTIS-Micropia professor at the VU University Amsterdam.
## Availability of data and materials
All the data supporting the conclusions of this article are included within the published article and its Additional files.
Authors' contributions VA carried out the meta-analysis, wrote the paper and made the figs. CK, GK and RK contributed to the text of the manuscript. All authors contributed to stimulating discussions with healthcare professionals (including those at the launch of the guide at ARTIS-Micropia, Amsterdam), which fueled the content of the manuscript. RK initiated and coordinated the study. All authors critically read, corrected and approved the final manuscript.
Ethics approval and consent to participate Not applicable.
## Consent for publication not applicable.
Competing interests RK is co-founder of the Yoba for Life foundation (2009), a non-profit organization, accredited by the Dutch Tax Authorities as a Public Benevolent Institution (PBI), which aims to promote local production and consumption of fermented products in Africa. African fermented products made with the Yoba starter culture, are not marketed by the foundation as such, but the Yoba for Life foundation stimulates local production and ownership, allowing income-generating activities for African small-scale entrepreneurs in the food sector. The Yoba for Life foundation distributes and sells ready-to-use sachets with dried bacterial starter cultures through a network of partners and volunteers to facilitate the local production of dairy and cereal-based products by controlled bacterial fermentation. The Yoba starter culture contains Lactobacillus rhamnosus yoba 2012, which is a generic variant of Lactobacillus rhamnosus GG. VA, CK and GR declare no competing interests.
## Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
[fig] Figure 2: Flow diagram of study selection the probiotic strain(s) and CFU-counts are specified and correspond to the strain and dose showing an effect or trend favoring the treatment in the included studies. The one-star dairy products is Actimel (Danone) (daily dose of 20 billion CFU) [62] and the food supplements include Probioticum (Wapiti), Winbiotic Pro-AD (Winclove), Probactiol Duo (Metagenics), Advanced Multi-Billion Dophilus (Solgar), and Imutis (Trenker), as listed in [/fig]
[table] Table 1: List of recommended probiotic products [/table]
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ESR/ERS white paper on lung cancer screening
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ESR/ERS white paper on lung cancer screening
Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low-dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low-dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and costeffectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computerassisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and a quality assurance plan. The establishment of a central registry, including a biobank and an image bank, and preferably on a European level, is strongly encouraged.Key points- Lung cancer screening using low dose computed tomography reduces mortality. - Leading US medical societies recommend large scale screening for high-risk individuals. - There are no lung cancer screening recommendations or reimbursed screening programmes in Europe as of yet.
# Introduction
Lung cancer causes 1.37 million deaths per year worldwide, which represents 18 % of all cancer deaths. Within the European Union, lung cancer is the most frequently fatal cancer, leading to over 266,000 deaths yearly and accounting for 20.8 % of all cancer deaths. Definitive surgery in the early stages is the most effective treatment for lung cancer. However, most patients are diagnosed at an advanced, and thus non-curable, disease stage. Survival time decreases significantly with progression of disease, with a 5-year survival time declining from 50 % for clinical stage IA to 43 %, 36 %, 25 %, 19 %, 7 % and 2 % for stages IB, IIA, IIB, IIIA, IIIB and IV, respectively [bib_ref] The IASLC Lung Cancer Staging Project: proposals for the revision of the..., Goldstraw [/bib_ref]. Moreover, Shi et al. [bib_ref] A clinicopathological study of resected non-small cell lung cancers 2 cm or..., Shi [/bib_ref] reported a 5-year survival rate of more than 80 % in 185 surgically treated patients with peripheral small-sized lung cancers (2 cm or less) after lobectomy and lymph node dissection. In particular, the 5-year survival rate increased with smaller tumour size: 80 % in tumours 1.6-2.0 cm in diameter, 85 % in tumours 1.0-1.5 cm in diameter and 100 % in tumours < 1.0 cm in diameter, respectively. It is therefore crucial to detect lung cancer early, before symptoms occur and while curable therapy is still achievable.
During the past decade, several studies focused on the yield of low dose computed tomography (LDCT)-based screening for lung cancer. In total, roughly 100,000 high-risk individuals were screened for lung cancer by LDCT. The largest randomised trial, the US-based National Lung Screening Trial (NLST), has shown a survival benefit for annual LDCT, with a 20 % reduction of the lung cancer related mortality, whereas the all-cause mortality decreased by 6 %. However, there is still some debate associated with the appropriate algorithm with which to select the screening cohort, as well as with how exactly the images should be read. The second largest study, the European NEderlands-Leuvens Screening ONderzoek (NELSON) trial, will be finalised by the end of 2015 and will add insight, probably with a more accurate screening algorithm and lower rate of false positivity, as discussed by Shlomi et al. [bib_ref] Screening for lung cancer: time for large-scale screening by chest computed tomography, Shlomi [/bib_ref].
As the results of this large European study are pending and the screening algorithms used in published studies have not been universal, there are numerous issues that should be taken into consideration before starting an LDCT screening programme in Europe. This paper will review the current status of lung cancer screening, and provide recommendations for the standards and additional evidence required.
## Status quo
## Results of the current trials
The NLST is the first randomised, controlled lung cancer screening trial in current and former smokers (> 30 packyears) aged between 55 and 74 years to show a significant reduction in lung-cancer-specific mortality [bib_ref] Reduced lung-cancer mortality with low-dose computed tomographic screening, Aberle [/bib_ref]. The computed tomography (CT) screening arm of the trial involved 26,722 participants who received three yearly screening rounds of LDCT. The control arm involved 26,732 participants who received three yearly screening rounds using chest radiographs. After a follow-up period of approximately 6.5 years, participants in the CT screening arm were 20 % less likely to die from lung cancer than those in the control arm. A 6 % reduction in overall mortality was also observed within the 6.5-year period. In the CT screening arm, 356 participants died from lung cancer, whereas the number in the corresponding radiography arm was 443 [bib_ref] Reduced lung-cancer mortality with low-dose computed tomographic screening, Aberle [/bib_ref]. In an additional evaluation 1 year later, these numbers had increased to 469 in the CT arm and 552 in the radiography arm, which corresponds to a 15 % reduction [bib_ref] The National Lung Screening Trial: results stratified by demographics, smoking history, and..., Pinsky [/bib_ref]. These results suggest that LDCT finds more cancers, most of them being in stage IA (>50 %) and approximately 10 % in stage IB [bib_ref] Results of the two incidence screenings in the National Lung Screening Trial, Aberle [/bib_ref]. Still, 43 % (469 out of 1089) of those patients who developed lung cancer died of lung cancer. The overall screening effort meant that 320 participants had to be screened to prevent one lung cancer death within the 6.5year follow-up period [bib_ref] Reduced lung-cancer mortality with low-dose computed tomographic screening, Aberle [/bib_ref].
The Dutch−Belgian NELSON trial is the largest European randomised controlled trial with at-risk participants based on age and smoking history randomly selected from population registries. The first outcome data are expected in 2016. The trial involves 7577 participants in the CT screening arm and compares them to 7871 participants in the control arm [bib_ref] Risk-based selection from the general population in a screening trial: selection criteria,..., Van Iersel [/bib_ref]. Apart from a smoking cessation programme, no intervention was offered in the control arm. Published results are available from smaller randomised controlled trials from Denmark (DLST) and Italy (Italung, DANTE and MILD). These trials involved approximately 1000-2000 patients in each arm [bib_ref] Benefits and harms of CT screening for lung cancer: a systematic review, Bach [/bib_ref]. Published results suggest no advantage for lung cancer screening. In fact, DLST and MILD even found a trend towards higher mortality in the yearly CT screening arms [bib_ref] CT screening for lung cancer brings forward early disease. The randomised Danish..., Saghir [/bib_ref] [bib_ref] Annual or biennial CT screening versus observation in heavy smokers: 5-year results..., Pastorino [/bib_ref]. Other current randomised controlled trials are the German Lung Screening and Intervention (LUSI) trial and the UK Lung Screening (UKLS) trial [bib_ref] UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen..., Baldwin [/bib_ref] [bib_ref] Randomized study on early detection of lung cancer with MSCT in Germany:..., Becker [/bib_ref].
## Current recommendations
There is a wide range of acceptance of the general lung cancer screening algorithm using LDCT across the globe; however, different degrees of modification from the NLST algorithm seem to be required [fig_ref] Table 1: Eligibility criteria for early detection of lung cancer by low dose computed... [/fig_ref] [bib_ref] Screening for lung cancer: time for large-scale screening by chest computed tomography, Shlomi [/bib_ref].
From February 2012, the Lung Cancer Screening Panel of the National Comprehensive Cancer Network (NCCN) in the USA recommended annual LDCT screening of all high-risk individuals between the age of 55 and 74 years, as defined in the NLST [bib_ref] Lung cancer screening, Wood [/bib_ref]. However, the NCCN guidelines expanded the NLST criteria based on non-randomised studies and observational data. Individuals 50 years of age or older with a tobacco smoking history of 20 or more pack-years and one additional risk factor should be screened annually. The suggested additional risk factors were history of cancer, history of lung disease [chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis], family history of lung cancer, radon exposure and occupational exposure. The NCCN currently does not advise screening of individuals at moderate and low risk for lung cancer, or for individuals with exposure to secondhand smoke [bib_ref] Lung cancer screening, version 1, Wood [/bib_ref].
A collaborative initiative of the American Cancer Society [bib_ref] Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal,..., Oken [/bib_ref] , the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology, and the NCCN published a review of LDCT screening for lung cancer, together with clinical practice guidelines, in May 2012 [bib_ref] Benefits and harms of CT screening for lung cancer: a systematic review, Bach [/bib_ref]. They adopt the NLST eligibility criteria, but note that the duration and frequency of screening remain undetermined. In June 2012, guidelines for lung cancer screening were issued by the American Association for Thoracic Surgery (AATS) [bib_ref] The American Association for Thoracic Surgery guidelines for lung cancer screening using..., Jaklitsch [/bib_ref] , expanding the criteria beyond the NLST. The AATS guidelines consider the amount of tobacco exposure and age to be the most important risk factors, and therefore do not restrict screening to patients who quit smoking in the previous 15 years. Since the risk of lung cancer does not decrease after 3 years of screening, the AATS recommends annual LDCT screening for high-risk patients from age 55 to 79 years. They consider that level 2 evidence is enough to advise screening for smokers 50-79 years of age with a 20 pack-year smoking history or other factors that produce a cumulative ≥ 5 % risk of developing lung cancer over the following 5 years. Based on AATS consensus opinion (level 3 evidence), patients treated for primary bronchogenic carcinoma who have completed 4 years of radiographic surveillance without evidence for recurrence should also be screened. In January 2013, the American Cancer Society published guidelines that recommend annual lung screening by LDCT based on the NLST eligibility criteria until the age of 74 years [bib_ref] American Cancer Society lung cancer screening guidelines, Wender [/bib_ref]. In May 2013, the ACCP published its third edition guidelines of diagnosis and management of lung cancer, including a recommendation concerning lung cancer screening [bib_ref] Screening for lung cancer: diagnosis and management of lung cancer, Detterbeck [/bib_ref] [bib_ref] Executive summary: diagnosis and management of lung cancer, Detterbeck [/bib_ref]. Annual screening with LDCT for individuals who meet the NLST eligibility criteria is recommended (grade 2B; weak recommendation, moderate level of evidence).
In December 2013, the United States Preventive Services Task Force (USPSTF) developed their recommendation statement, which was published in March 2014 [bib_ref] Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement, Moyer [/bib_ref] , supporting LDCT lung cancer screening for healthy adults between 55 and 80 years of age with a smoking history of 30 pack-years or more and who have smoked within the previous 15 years. The number of years needed for screening is not specified, but screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits the life expectancy or the ability or willingness to have curative lung surgery (grade B recommendation). Under the Affordable Care Act, any procedure that receives a grade B recommendation from the US Preventive Services Task Force (USPSTF) has to be covered by private insurers without co-payment. Most insurers in the USA follow the recommendations of the task force, and pay for those services. In April 2014, the US federal agency For example, COPD with forced expiratory volume in 1 s of 70 % or less than predicted, environmental or occupational exposures, any prior cancer or thoracic radiation, genetic or family history Center for Medicare and Medicaid services (CMS) advisory panel voted against covering lung cancer screening. Key concerns were the high false-positive rate of CT screening, indication creep outside of the intended screening population, inability to assure quality scans with low radiation dose, and consistent interpretation and diagnostic work-up in routine practice. In February 2015, in contrast to the recommendations of the agency's advisory board, Medicare announced its decision to start covering annual lung cancer screening once per year for long-time smokers at high risk for the disease [bib_ref] Decision Memo for Screening for Lung Cancer with Low Dose Computed Tomography..., Centers For Medicare [/bib_ref]. CMS experts require that screening candidates are between ages 55 and 77 years, have no signs or symptoms of lung disease, have tobacco smoking history of at least 30 pack-years and are current smokers or ex-smokers who have quit smoking within the previous 15 years. For the initial screen, the beneficiary must receive a written order for LDCT lung cancer screening obtained during a "lung cancer screening counselling and shared decision-making visit" from a physician, physician assistant, nurse practitioner or clinical nurse specialist. CMS also gives details for that visit, radiologist eligibility criteria and imaging centre eligibility criteria [bib_ref] Decision Memo for Screening for Lung Cancer with Low Dose Computed Tomography..., Centers For Medicare [/bib_ref]. In Europe, there are no lung cancer screening recommendations or reimbursed screening programmes so far.
## Challenges
## Pre-test probability
Tobacco smoking is a major risk factor for lung cancer, as shown by many epidemiological studies. Other less important risk factors are passive (second-hand) smoking, occupational exposure, environmental exposure, residential radon exposure, presence of COPD and family history of lung, head and neck cancer. A meta-analysis of ten case−control studies including 7609 cases and 10,431 controls shows an increase of the relative risk of lung cancer in the European population with active smoking (versus ex-smokers), with duration and amount of smoking and the cumulative dose of pack-years [bib_ref] Lung cancer and cigarette smoking in Europe: an update of risk estimates..., Simonato [/bib_ref]. The recommendations for the NELSON trial are based on data from the Cancer Prevention Study II (CPS II) [bib_ref] Health and Human Services. From the Centers for Disease Control. Health benefits..., Department [/bib_ref]. According to this data, a smoking history of 30 years or more in individuals older than 55 years and a consumption of at least one pack of cigarettes a day correspond to a lung cancer incidence of at least 300 per 100,000. The rate of lung cancer diagnosed for those selected populations in recent randomised trials by LDCT are summarised in [fig_ref] Table 2: Selection criteria, number of enrolled individuals and the rate of diagnosed lung... [/fig_ref].
More data from other cohorts are described in the systematic review published by Bach et al. [bib_ref] Benefits and harms of CT screening for lung cancer: a systematic review, Bach [/bib_ref]. The rate of lung cancer diagnosed ranges between 0.8 and 2.2 % initially and between 2.4 % and 4.7 % in 34−78 months of follow-up. Those figures can be taken as the pre-test probability.
## Overdiagnosis
The detection of small lesions confirmed to be malignant, but which do not grow, spread, or cause death is referred to as overdiagnosis. This includes patients who are destined to die from another cause, e.g., comorbidity or an unexpected event, in addition to slow growing/non-spreading cancers [bib_ref] Benefits and harms of CT screening for lung cancer: a systematic review, Bach [/bib_ref]. Overdiagnosis represents an important potential harm of screening, since it incurs additional cost, anxiety and morbidity associated with the cancer treatment. During earlier screening trials using chest radiographs in the Mayo and the Czechoslovakian randomised trials, substantially more cancers (20 %) were detected in the screened than in the unscreened group [bib_ref] Lung cancer mortality in the Mayo Lung Project: impact of extended followup, Marcus [/bib_ref] [bib_ref] Czech Study on Lung Cancer Screening: post-trial follow-up of lung cancer deaths..., Kubik [/bib_ref]. Nearly all of the excess cancers detected in the screened group in the Mayo clinical trial were early stage cancers. However, the failure to detect early stage cancers in the control group was without apparent ill effect: the control group experienced no excess number of lung cancer deaths [bib_ref] Lung cancer mortality in the Mayo Lung Project: impact of extended followup, Marcus [/bib_ref]. The results were generally confirmed by the Czechoslovakian study. Both studies suggest that screening is detecting "excess" lesions, which probably would not progress to advanced/lethal disease [bib_ref] Lung cancer mortality in the Mayo Lung Project: impact of extended followup, Marcus [/bib_ref] [bib_ref] Czech Study on Lung Cancer Screening: post-trial follow-up of lung cancer deaths..., Kubik [/bib_ref]. The PLCO trial [bib_ref] Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal,..., Oken [/bib_ref] examined 155,000 subjects in the general population and found 18 excess lung cancers in the chest radiography group (compared with no chest radiography group) after 6 years of follow-up (2 years after screening ended) and 76 lung cancers after 13 years of follow-up. Data from the same trial, evaluating overdiagnosis among a high-risk population only, showed a cumulative incidence of lung cancer of 606 per 100,000 person-years in the chest radiography group and 608 per 100,000 person-years in the usual care group after 6 years of follow-up.
The overdiagnosis rate for LDCT screening cannot yet be estimated [bib_ref] Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement, Moyer [/bib_ref]. The NLST data shows a persistent gap of about 120 excess lung cancers in the LDCT versus the chest radiography arm, but further follow-up is needed [bib_ref] Results of initial low-dose computed tomographic screening for lung cancer, Church [/bib_ref]. In both groups, the percentage of stage IA and stage IB lung cancers was high. Relative to the issue of overdiagnosis, fewer stage IV cancers were detected in the LDCT group than in the chest radiography group at the second and third screening rounds in the DANTE trial, where 2472 subjects were screened with chest radiography and sputum cytology at baseline and randomised afterwards to yearly LDCT or clinical follow-up. Lung cancer prevalence in the control chest radiography arm was 0.67 % (n = 8) and 50 % of these patients had stage I cancer, while the prevalence in the CT group was 2.19 % (n = 28) with 57 % stage I cancer, respectively. It has to be noted that 13 of the 28 LDCT lung cancer cases already had abnormal chest radiography findings at baseline [bib_ref] A randomized study of lung cancer screening with spiral computed tomography: threeyear..., Infante [/bib_ref].
Still, while most lung cancer prevention experts think lung cancer screening leads to overdiagnosis, many clinicians believe it does not [bib_ref] Overdiagnosis in lung cancer: different perspectives, definitions, implications, Bach [/bib_ref]. Death rates from lung cancer imply that essentially all histological foci of lung cancer pose a threat to health, irrespective of their CT phenotype or how they are discovered. In the NLST, the size of the nodule and whether it is solid or sub-solid mattered. However, whether this appearance is linked to higher overdiagnosis probability remains to be concluded. Based on the Pan-Canadian early Detection of Lung Cancer Study (PanCan), McWilliams et al. [bib_ref] Probability of cancer in pulmonary nodules detected on first screening CT, Mcwilliams [/bib_ref] presented a model to predict a cancerous pulmonary nodule (versus benign). Predictors for cancer were older age, female sex, family history of lung cancer, emphysema and larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count and spiculation. Adopting such a model may direct the clinicians in their follow-up management.
## Risk models
Risk models help to increase pre-test probability and reduce overdiagnosis. They improve the patient selection in order to define populations with higher pre-test probabilities: the Liverpool Lung Project (LLP) risk prediction model is used in the UKLS screening trial; the PLCO2012 (Prostate, Lung, Colorectal, and Ovarian) randomised trial and the NLST trial. The former two studies predict lung cancer detection, while the latter predicts death by lung cancer [fig_ref] Table 3: Risk prediction models used in different lung cancer screening trials [/fig_ref].
Recently, de Koning et al. [bib_ref] Benefits and harms of computed tomography lung cancer screening strategies: a comparative..., De Koning [/bib_ref] published a study estimating the harms and benefits of lung cancer screening for efficient lung cancer screening policies. They used five separately developed micro-simulation models calibrated to the two largest randomised, controlled trials on lung cancer screening [bib_ref] Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal,..., Oken [/bib_ref] [bib_ref] Benefits and harms of computed tomography lung cancer screening strategies: a comparative..., De Koning [/bib_ref]. Those models were independently developed at five institutions: Erasmus Medical Center (Rotterdam), Fred Hutchinson Cancer Research Center (Seattle), Massachusetts General Hospital (Boston), Stanford University (Stanford), and University of Michigan (Ann Arbor). All account for the individual's age-specific, smoking-related risk for lung cancer, date and stage of lung cancer diagnosis, the corresponding lung cancer mortality and the individual's life expectancy in the presence and absence of screening. The most advantageous strategy identified is the annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. That approach would lead to 50 % of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14 % reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100,000member cohort. Harms would include 67,550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7 % of all cases of lung cancer).
Thus far, there are no good risk predictors for nonsmokers and no convincing data to recommend screening. Lung cancer in never smokers is the seventh leading cause of cancer mortality, and therefore is a significant cause of death worldwide. The main risk factors include age, environmental tobacco exposure, cooking fumes, inherited genetic susceptibility, occupational and environmental exposure to carcinogens, hormonal factors, pre-existing lung disease and oncogenic viruses [bib_ref] Chapter 6: lung cancer in never smokers: epidemiology and risk prediction models, Mccarthy [/bib_ref]. Nonsmall cell lung cancer (NSCLC) in never smokers is clinically characterised by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and nonresectable advanced stage patients [bib_ref] Non-small cell lung cancer in never smokers as a representative 'non-smoking-associated lung..., Yano [/bib_ref]. Even though those factors are known, there is no beneficial screening programme for lung cancer among this population.
## False positives and complications during work-up
With modern multidetector CT, pulmonary nodules are detectable at a size of less than 2 mm. Small nodules are extremely common, but the vast majority of these nodules are benign. Given this fact, the definition of a positive screening result determines the number of false-positive results. On average, about 25 % of the thoracic surgical procedures performed during the various randomised controlled lung cancer screening trials were done for benign nodules [bib_ref] Screening for lung cancer: diagnosis and management of lung cancer, Detterbeck [/bib_ref]. If there are fewer false-positive nodules, there is less need for further workup and lower risk of complications, especially from invasive diagnostic examinations including surgery. The definition of a positive screening result differed substantially between the NLST and most European trials. The NLST defined any non-calcified nodule with a maximum diameter ≥ 4 mm as a positive screening result [bib_ref] Reduced lung-cancer mortality with low-dose computed tomographic screening, Aberle [/bib_ref]. As a consequence, the number of false-positive scans was high: 27 % of scans in the first two screening rounds, of which 96 % were false-positive. According to the NLST nodule management algorithm, these suspicious nodules needed further work-up: either a follow-up LDCT for nodules of 4-10 mm, or a referral to a pulmonologist for nodules > 10 mm in maximum diameter [bib_ref] Reduced lung-cancer mortality with low-dose computed tomographic screening, Aberle [/bib_ref].
The NELSON and some other European trials used a threshold of approximately 10 mm diameter (50 mm 3 volume) for a positive screening result, but also established an indeterminate group of nodules measuring 5-10 mm in diameter (50-500 mm 3 volume) that required earlier follow-up than the yearly screening interval [bib_ref] Nodule management protocol of the NELSON randomised lung cancer screening trial, Xu [/bib_ref]. Only if significant growth (> 25 % volume change) was found, were these nodules considered a positive screening result. By using this approach, the number of scans with positive screening results was reduced from 27 % in the NLST to 2.7 % in the NELSON, and the false-positives could be reduced substantially from > 95 % in the NLST to approximately 50 % in the NELSON [bib_ref] Results of the two incidence screenings in the National Lung Screening Trial, Aberle [/bib_ref] [bib_ref] Management of lung nodules detected by volume CT scanning, Van Klaveren [/bib_ref].
Recently, new criteria for the follow-up of pulmonary nodules, such as LungRADS and LU-RADS, have been presented in order to increase the positive predictive value in CT screening with minimum effect on sensitivity for the detection of malignancy [bib_ref] Performance of ACR Lung-RADS in a Clinical CT Lung Screening Program, Mckee [/bib_ref] [bib_ref] The Lung Reporting and Data System (LU-RADS): a proposal for computed tomography..., Manos [/bib_ref].
The size of a nodule was measured in most screening trials, like the NLST, as the largest diameter of a pulmonary nodule [bib_ref] Reduced lung-cancer mortality with low-dose computed tomographic screening, Aberle [/bib_ref]. This approach suffers from a substantial inter-reader and intra-reader variability, which can be reduced by applying volumetric techniques, as used in the NELSON and other more recent trials. Non-actionable nodules were defined as those with benign morphology (e.g., calcification), small size (< 50 mm 3 ), and lack of or very slow growth of the solid First-degree relative with lung cancer component of a nodule with a volume doubling time (VDT) > 600 days. Indeterminate nodules were defined as nodules with a volume of the solid component between 50 and 500 mm 3 , sub-solid nodules with a diameter of the ground glass component > 10 mm, or solid nodules with a VDT between 400 and 600 days. Actionable nodules were defined as solid components > 500 mm 3 , more than 20 % growth in diameter of a ground glass component, or VDT < 400 days of a solid component [bib_ref] Nodule management protocol of the NELSON randomised lung cancer screening trial, Xu [/bib_ref]. Non-actionable, reportable nodules were kept on regular (yearly) follow-up, indeterminate nodules were put on a more rapid follow-up of 3-6 months, while actionable nodules led to direct medical workup.
Increasing knowledge about the CT phenotypes of screendetected pulmonary nodules with different biologic behaviours will lead to a better estimation of their probability of malignancy, and help to decrease the amount of additional follow-up scans and workup examinations [bib_ref] CT screening for lung cancer: countdown to implementation, Field [/bib_ref] , e.g., perifissural nodules were demonstrated to have a high likelihood of being benign [bib_ref] Smooth or attached solid indeterminate nodules detected at baseline CT screening in..., Xu [/bib_ref] [bib_ref] The role of conventional bronchoscopy in the workup of suspicious CT scan..., Ahn [/bib_ref].
For the invasive diagnostic work-up of small nodules, the value of white light fibrebronchoscopy is very limited [49], but newer diagnostic endoscopic techniques, such as endobronchial ultrasound-guided biopsy with mini probe or electromagnetic navigation bronchoscopy, might be more promising. For some peripheral nodules (> 1 cm), transthoracic CT-guided biopsy or primary resection by video-assisted thoracoscopic surgery for diagnostic and therapeutic reasons may be recommended [bib_ref] Lung cancer screening: the radiologist's perspective, Prokop [/bib_ref]. The risk of serious complications (pneumothorax requiring drainage, cardiorespiratory complications during anaesthesia, infection or haemorrhage) not only relates to the invasiveness of the diagnostic procedure itself, but also to the patient's functional status [bib_ref] Complications following lung surgery in the Dutch-Belgian randomized lung cancer screening trial, Van't Westeinde [/bib_ref]. Subjects eligible for LDCT screening will present themselves mostly with a high comorbidity risk, due to COPD or chronic cardiovascular disease [bib_ref] CT screening for lung cancer: countdown to implementation, Field [/bib_ref] [bib_ref] Screening for lung cancer with low-dose computed tomography: a review of current..., Marshall [/bib_ref].
Adhering to a certified high quality radiology plan for LDCT screening will minimise radiation exposure for screening participants. Further, the adherence to a pulmonary nodule management plan based on nodule diameter, volume and growth rate will help to increase safety for lung cancer screening participants, mostly by decreasing the total amount of diagnostic investigations they will need to undergo in order to determine the nature of their screen-detected lung nodules. Moreover, a lower amount of false-positive lesions with a decreased number of additional diagnostic investigations may finally help to decrease participant's anxiety and psychological stress during lung cancer screening [bib_ref] Issues with implementing a high-quality lung cancer screening program, Mulshine [/bib_ref].
## Radiation exposure
The vast majority of lung cancer screening trials were designed more than a decade ago. The LDCT protocols were simply achieved by reducing the fixed tube load of diagnostic CT from typically 100-300 mAs to 10-40 mAs. A CT dose index (CTDI vol ) of 2-3 mGy was used as a target for NLST [bib_ref] The National Lung Screening Trial: overview and study design, Aberle [/bib_ref] [bib_ref] Description and implementation of a quality control program in an imagingbased clinical..., Cagnon [/bib_ref]. Similar values were used in the NELSON and the various other European trials. The resulting effective dose is roughly 40 % of these values for males and 50 % for females, resulting in 1-1.3 mSv for a CTDI vol of 2.5 mGy. The organ dose (mSv) to the lung or to the breast can be roughly estimated using 1.5×CTDI vol . Precise numbers vary depending on scanner type, and in particular on the pre-filtering of the Xray spectrum.
With recent improvements in detector technology, automated exposure control techniques and iterative image reconstruction, a further substantial decrease in radiation exposure of 80 % to a level around 0.2 mSv is possible without impairing image quality [bib_ref] Model-based iterative reconstruction technique for ultralow-dose chest CT: comparison of pulmonary nodule..., Katsura [/bib_ref]. However, radiation exposure will always have to be higher in obese individuals than in normal weight individuals because of the difference in X-ray absorption. Excessive reduction of radiation dose will lead to image quality degradation with either high image noise or loss of image details, which will especially affect sub-solid lesions. These are the limiting factors for further dose reduction.
Radiation risk in the age range of 40 to 60 years is mainly determined by the organ dose to the lungs. Apart from the breast in premenopausal women, other organs have a much lower contribution to excess cancer risk. Radiation exposure and smoking appear to have an additive effect on cancer risk [bib_ref] Joint effects of radiation and smoking on lung cancer risk among atomic..., Pierce [/bib_ref]. This means that the excess risk for developing radiation-induced lung cancer may be twice as high in smokers as in never-smokers [bib_ref] Radiation and smoking effects on lung cancer incidence among atomic bomb survivors, Furukawa [/bib_ref].
Given an effective dose of 1.3 mSv for women and 1.0 mSv for men, the excess lifetime cancer risk was estimated to be 0.02 % in male smokers and 0.05 % in female smokers if three yearly screening rounds were performed [bib_ref] Low-dose lung computed tomography screening before age 55: estimates of the mortality..., Berrington De Gonzalez [/bib_ref]. Risks did not change whether the starting age for screening was 30, 40 or 50 years. This implies that radiation risk becomes important only if the pre-test risk for lung cancer is small. Given a baseline cancer risk of 0.8-2.2 % in the various screening trials, the risk−benefit ratio is very favourable. Even if the number of screening examinations increases from three to 24, the excess lifetime cancer risk induced by radiation remains below the baseline cancer risk, but it increases with age [bib_ref] Targeting of low-dose CT screening according to the risk of lung-cancer death, Kovalchik [/bib_ref].
Radiation risk grows strongly if follow-up scans are performed using standard clinical protocols (old equipment 4-18 mSv, new equipment 2-4 mSv [bib_ref] Effective doses in radiology and diagnostic nuclear medicine: a catalog, Mettler [/bib_ref] instead of screening with LDCT settings (new equipment 0.2 mSv [bib_ref] Model-based iterative reconstruction technique for ultralow-dose chest CT: comparison of pulmonary nodule..., Katsura [/bib_ref]. For this reason, the work-ups of screen-detected nodules should remain within the screening programme as long as possible [bib_ref] Radiation risks in lung cancer screening programs: a comparison with nuclear industry..., Mccunney [/bib_ref].
## Cost effectiveness
The cost-effectiveness of the screening intervention is one of the major considerations for those who are responsible for screening guidelines, practice measures and insurance coverage [bib_ref] Better evidence about screening for lung cancer, Sox [/bib_ref]. Varying results on the cost-effectiveness of lung cancer screening have been reported [bib_ref] Potential costeffectiveness of one-time screening for lung cancer (LC) in a high..., Marshall [/bib_ref] [bib_ref] The costeffectiveness of low-dose CT screening for lung cancer: preliminary results of..., Wisnivesky [/bib_ref] [bib_ref] Lung cancer screening with helical computed tomography in older adult smokers: a..., Mahadevia [/bib_ref] [bib_ref] Cost-effectiveness analysis of screening for lung cancer with low dose spiral CT..., Manser [/bib_ref]. In their recent publication, the NLST reports reasonable costeffectiveness of LDCT screening of lung cancer [bib_ref] Cost-effectiveness of CT screening in the National Lung Screening Trial, Black [/bib_ref]. LDCT screening as performed in the NLST trial costs $81,000 per quality-adjusted life year (QALY) gained (95 % CI $52,000-186,000). Screening trials that cost less than $100,000 per QALY are considered cost-effective. Incremental cost effectiveness ratio (ICER) is the ratio of the change in costs to incremental benefits of a therapeutic intervention or treatment. The NLST ICER was $52,000 (95 % CI $34,000-106, 000). However, the ICER results of the NLST were highly sensitive to base-case assumptions. For example, if the reduction in mortality from causes other than lung cancer was included in the calculation, the QALY fell to $54,000. QALY increased to more than $100,000 when the cost of future care was increased. Moreover, estimated cost-effectiveness varied in the subgroup analysis. Screening with LDCT was much more cost-effective in women than in men and among the groups with a higher risk of lung cancer. Whether screening performed in different countries in Europe will be costeffective depends on exactly how the screening will become implemented [bib_ref] Cost-effectiveness of CT screening in the National Lung Screening Trial, Black [/bib_ref] , and on which respective cost structures and reimbursement policies will be used.
## Expectation management
Expectation management is crucial for a successful CT screening programme. It is important for three main reasons: 1) giving participants the ability to understand the benefits and potential harms, 2) reducing anxiety in case a nodule is found and 3) reducing litigation and its chances for success. Screening is very likely to reduce a participant's risk of dying from lung cancer. However, a substantial group of participants will still die from lung cancer. Most cancers found will be in a treatable stage (60-80 % stage I)but not all [bib_ref] Results of the two incidence screenings in the National Lung Screening Trial, Aberle [/bib_ref] [bib_ref] Characteristics of lung cancers detected by computer tomography screening in the randomized..., Horeweg [/bib_ref]. Some cancers may grow so slowly that they will not be life-limiting and treating them may be unnecessary (overdiagnosis) [bib_ref] Benefits and harms of computed tomography lung cancer screening strategies: a comparative..., De Koning [/bib_ref]. Screening is known to miss nodules present on LDCT [bib_ref] Missed cancers in lung cancer screening-more than meets the eye, Devaraj [/bib_ref]. The annual screening programme will pick up nodules missed on earlier scans, which reduces the risk of missed nodules developing into untreatable cancer. As small nodules are extremely common, it is very likely that a nodule will be found. LDCT is not optimally suited for the detection and diagnosis of many other chest diseases. However, incidental findings leading to unnecessary workup, costs and complications may occur.
Information given to participants, clinicians not involved in screening and the public should be clearly understandable. Informed consent is important because of the dangers of undetected cancers, overdiagnosis or complications due to workup or treatment of screen-detected lesions. The participants should be aware of the incidental finding policy of the screening programme.
Broaden the scope CT-based screening can provide a more global approach of a smoker's lung and associated comorbidities, which are associated with poor health status and prognosis [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Vestbo [/bib_ref] [bib_ref] Chronic obstructive pulmonary disease (COPD) patients with osteoporotic vertebral compression fractures (OVCFs):..., Masala [/bib_ref]. Regarding smoker's lung features, namely airway disease and emphysema, they can be easily depicted and categorised according to the proposed CT phenotypes [bib_ref] Fleischner Society: glossary of terms for thoracic imaging, Hansell [/bib_ref]. In addition, it is also possible to detect interstitial lung abnormalities in cigarette smokers, as recently observed in 8 % of the COPDGene cohort (194 out of 2416) [bib_ref] Identification of early interstitial lung disease in smokers from the COPDGene Study, Washko [/bib_ref]. While such abnormalities are visually assessed, recent approaches favour automated extraction and quantification of morphological changes in order to refine COPD phenotyping [bib_ref] Distinct quantitative computed tomography emphysema patterns are associated with physiology and function..., Castaldi [/bib_ref] and help predict clinical impairment [bib_ref] Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical..., Estepar [/bib_ref].
Smokers have a highly increased risk for the development of cardiovascular diseases, which also coexist with COPD [bib_ref] Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary..., Vestbo [/bib_ref]. Since lung cancer screening examinations use noncontrast and non-ECG-gated acquisitions, precise analysis of mural changes at the level of coronary arteries, as well as thoracic aorta, remains beyond the scope of such examinations. However, several studies have documented the feasibility of an imaging approach combining lung cancer and quantification of coronary artery calcium in a single chest CT study [bib_ref] Ordinal scoring of coronary artery calcifications on low-dose CT scans of the..., Shemesh [/bib_ref] [bib_ref] Coronary artery and thoracic calcium on noncontrast thoracic CT scans: comparison of..., Budoff [/bib_ref]. Quantification of coronary and aortic calcium volumes in lung cancer screening CT images has recently been shown to help predict cardiovascular risk. Such an approach might prove useful in the reduction of cardiovascular morbidity and mortality, and may enhance the cost-effectiveness of CT-based screening in heavy smokers [bib_ref] Lung cancer screening CT-based prediction of cardiovascular events, Mets [/bib_ref]. Other key targets such as calcifications at the level of heart valves and/or supraaortic arteries could also be included. Osteoporosis is also increasingly recognised as a major comorbidity that can be picked up on LDCT of the chest.
The specificity of a screening programme might also be increased by including non-imaging, non-invasive biomarkers to allow a better discrimination between benign versus malignant conditions. Examination of serum and plasma biomarkers shows some evidence supporting the rationale of using these biomarkers for risk stratification of screendetected lung nodules [bib_ref] Added value of a serum proteomic signature in the diagnostic evaluation of..., Pecot [/bib_ref] [bib_ref] Development and validation of a plasma biomarker panel for discerning clinical significance..., Daly [/bib_ref] [bib_ref] EarlyCDT(R)-lung, in 1600 patients: an evaluation of its performance in routine clinical..., Jett [/bib_ref]. However, there are only few biomarkers that could be implemented immediately. We encourage the community to further investigate in this area and define it as an urgent unmet need in the field of lung cancer.
## Suggestions
The European Society of Radiology and the European Respiratory Society are recommending lung cancer screening in comprehensive, quality-assured programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Based on the results and experience of completed and on-going lung cancer screening activities, we suggest the following minimum requirements for the implementation of lung cancer screening:
& Accredited medical centres with multidisciplinary expertise and access to trained professionals, including, as a minimum, radiologists, pulmonologists, oncologists, pathologists and chest surgeons. & Strong smoking cessation programme and experienced staff providing effective cessation and long-term abstinence advice. & Longitudinal comprehensive screening programme throughout the age interval of eligibility, covering the complete protocol, including work-up, follow-up and potential re-entry, also offering an appropriate expectation management. Single-round screening is discouraged. & Inclusion criteria: age between 55 and 80 years, tobacco smoking history of at least 30 pack-years, and current smoker or ex-smoker who has quit smoking within the last 15 years. & Exclusion criteria: comorbidities precluding curative therapy and lack of consent to undergo curative therapy. & Standardised operating procedures for image acquisition, nodule evaluation, positive screening results and their management, monitoring of false-positive results and rate of iatrogenic complications, and appropriate follow-up. & Computer-assisted nodule evaluation and documentation.
Identical measurement software is required for the followup. Volumetric measurements are preferred over diameter measurements. & Multidetector LDCT with at least 16 detector rows providing isotropic high spatial resolution (slice thickness of about 1 mm with an increment of 0.7 mm) and an effective dose between 1 mSv for normal sized individuals and not more than 3 mSv for obese individuals. & Collection and submission of lung cancer screening data to a lung cancer screening registry. The set-up of a European lung cancer screening registry including biobank and image bank is encouraged.
We also recommend the implementation of the following measures in order to increase quality, outcome and costeffectiveness of lung cancer screening:
& To increase the pre-test probability by using a risk model and considering additional risk factors. & To reduce the effective radiation dose to less than 1 mSv per CT examination for all participants.
& To use volumetric measurements for the assessment of growth rate (tumour doubling time) in order to reduce the rate of false-positives. & To use computer-assisted systems for automated detection, optimised measurements and follow-up, providing structured reports on nodule volume, localisation, phenotype and standard operating procedure-based suggestions for further management plan. & To adapt screening intervals based on refined risk models. & To include additional CT findings such as COPD and vascular calcification. & To include and study biomarkers to better define screening subgroups and refine nodule management.
# Conclusion
Lung cancer is a devastating disease with poor survival once the disease is advanced. As the main risk factor for lung cancer is smoking, there is an urgent need to advocate against smoking and encourage cessation. There are accumulated data supporting the survival benefit for screening of individuals at high risk for early detection of lung cancer using LDCT. Based on the available evidence, we have summarised the key elements necessary for a comprehensive lung cancer screening programme in Europe, including minimum requirements and recommended refinements. These should be adjusted to the national infrastructure and healthcare system in order to exactly define eligibility using a risk model, nodule management and quality assurance plan. The establishment of a central registry, including a biobank and an image bank, preferably on a European level, is strongly encouraged.
[table] Table 1: Eligibility criteria for early detection of lung cancer by low dose computed tomography, according to guidelines issued in 2012-2013 by various organisations[5] [/table]
[table] Table 2: Selection criteria, number of enrolled individuals and the rate of diagnosed lung cancer of major randomised controlled trials Annual computed tomography; † Biannual computed tomography; ‡ NELSON inclusion criteria: number of cigarettes smoked is ≥ 15 per day for 25 years OR ≥10 cigarettes per day for 30 years AND still smoking or having quit < 10 years ago. [/table]
[table] Table 3: Risk prediction models used in different lung cancer screening trials [/table]
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Dutch guideline for clinical foetal-neonatal and paediatric post-mortem radiology, including a review of literature
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Dutch guideline for clinical foetal-neonatal and paediatric post-mortem radiology, including a review of literature
Clinical post-mortem radiology is a relatively new field of expertise and not common practice in most hospitals yet. With the declining numbers of autopsies and increasing demand for quality control of clinical care, post-mortem radiology can offer a solution, or at least be complementary. A working group consisting of radiologists, pathologists and other clinical medical specialists reviewed and evaluated the literature on the diagnostic value of post-mortem conventional radiography (CR), ultrasonography, computed tomography (PMCT), magnetic resonance imaging (PMMRI), and minimally invasive autopsy (MIA). Evidence tables were built and subsequently a Dutch national evidence-based guideline for post-mortem radiology was developed. We present this evaluation of the radiological modalities in a clinical post-mortem setting, including MIA, as well as the recently published Dutch guidelines for post-mortem radiology in foetuses, neonates, and children. In general, for post-mortem radiology modalities, PMMRI is the modality of choice in foetuses, neonates, and infants, whereas PMCT is advised in older children. There is a limited role for post-mortem CR and ultrasonography. In most cases, conventional autopsy will remain the diagnostic method of choice.Conclusion: Based on a literature review and clinical expertise, an evidence-based guideline was developed for post-mortem radiology of foetal, neonatal, and paediatric patients. L. J. P. Sonnemans and M. E. M. Vester shared first authorship and contributed equally to this work. Communicated by Piet Leroy * M. E. M. Vester
# Introduction
Paediatric post-mortem radiology, in addition to autopsy, is becoming widely accepted as an important component of cause of death determination [bib_ref] The rise of forensic and post-mortem radiology-analysis of the literature between the..., Baglivo [/bib_ref] [bib_ref] Times have changed! Forensic radiology-a new challenge for radiology and forensic pathology, Flach [/bib_ref] [bib_ref] Value of the perinatal autopsy: critique, Gordijn [/bib_ref] [bib_ref] million neonatal deaths: when? Where? Why?, Lawn [/bib_ref] [bib_ref] Perinatal death investigations: what is current practice?, Nijkamp [/bib_ref]. The trend in declining clinical autopsy rates in adults [bib_ref] Non-invasive or minimally invasive autopsy compared to conventional autopsy of suspected natural..., Blokker [/bib_ref] [bib_ref] Clinical, educational, and epidemiological value of autopsy, Burton [/bib_ref] [bib_ref] Clinical utility of postmortem microcomputed tomography of the fetal heart: diagnostic imaging..., Hutchinson [/bib_ref] [bib_ref] The value of post-mortem CT in neonaticide in case of severe decomposition:..., Sieswerda-Hoogendoorn [/bib_ref] is also evident in the foetal and paediatric population, though higher autopsy rates of approximately 50% remain [bib_ref] Value of the perinatal autopsy: critique, Gordijn [/bib_ref] [bib_ref] Perinatal and infant autopsy, Adappa [/bib_ref] [bib_ref] Ten years of neonatal autopsies in tertiary referral centre: retrospective study, Brodlie [/bib_ref] [bib_ref] The value of neonatal autopsy, Hickey [/bib_ref] [bib_ref] Diagnostic errors in the pediatric and neonatal ICU: a systematic review, Khong [/bib_ref]. This decline is in spite of evidence that clinical error rates persist: approximately 25% discrepancy between clinical ante-mortem diagnosis and autopsy cause of death diagnosis [bib_ref] Value of the perinatal autopsy: critique, Gordijn [/bib_ref] [bib_ref] Ten years of neonatal autopsies in tertiary referral centre: retrospective study, Brodlie [/bib_ref] [bib_ref] Changes in rates of autopsy-detected diagnostic errors over time: a systematic review, Shojania [/bib_ref].
If an alternative, less-or non-invasive diagnostic method could adequately determine the cause of death, current objections to conventional autopsy (e.g. its invasiveness) could be met. Consequently, this might increase quality control and subsequently improve clinical care. Post-mortem radiology might be such an alternative diagnostic method. It can be helpful for diagnosing anatomic abnormalities, identification of syndromes, or to narrow down the differential diagnosis of genetic disorders. Consequently, it can also be useful for identifying potential siblings at risk, counselling for future pregnancies, and helping the parents in their process of grief [bib_ref] Clinical, educational, and epidemiological value of autopsy, Burton [/bib_ref] [bib_ref] Cross sectional survey of parents' experience and views of the postmortem examination, Rankin [/bib_ref].
Post-mortem radiology is evolving into a subspecialty, reflected by the large increase of publications and the broad spectrum of used techniques [bib_ref] The rise of forensic and post-mortem radiology-analysis of the literature between the..., Baglivo [/bib_ref]. Nevertheless, a guideline on the indications and contraindications for the use of postmortem conventional radiography (CR), ultrasonography, computed tomography (PMCT), magnetic resonance imaging (PMMRI), and minimally invasive autopsy (MIA), was not yet available. This article provides the literature review that is the basis for the evidence-based Dutch guideline for clinical foetal, neonatal, and paediatric post-mortem radiology.
# Materials and methods
The guideline was developed under the guidance of the Dutch knowledge institute of medical specialists. An important objective of the Dutch knowledge institute is to preserve and pool knowledge and expertise about the design and execution of quality assurance projects in the realm of specialist medical care. Medline and Embase were searched for studies comparing clinical post-mortem radiology to autopsy in foetal, neonatal, and paediatric patients from January 2000 up to January 2016, when the guideline committee started her work (Appendix 1, a further detailed search strategy is available upon request). Language selection was restricted to studies published in Dutch and English. The study selection and analysis was performed separately for the group of foetal and neonatal cases (deceased within 28 days post-partum) and for the group of paediatric cases (aged 1 month to 18 years). Studies were initially screened on title and abstract (JE, RR), and hereafter analysed on full text (EK, JE, RR). Case reports and forensic articles were excluded. Outcomes in sensitivity and specificity were mandatory. Reference lists of included studies were screened for additional relevant studies.
Methodological quality assessment of included studies was performed (EK) according to the AMSTAR checklist, PRISMA checklist, or QUADAS II, depending on the type of article [bib_ref] Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, Moher [/bib_ref] [bib_ref] Development of AMSTAR: a measurement tool to assess the methodological quality of..., Shea [/bib_ref] [bib_ref] QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies, Whiting [/bib_ref]. The joint evidence of included articles was scored (EK) according to the Grading Recommendations Assessment, Development and Evaluation (GRADE) tool [bib_ref] Systems for grading the quality of evidence and the strength of recommendations..., Atkins [/bib_ref]. GRADE divides the quality (or certainty) of evidence and conclusions into four categories: high, medium, low or very low. A high GRADE level of evidence means that the conclusion is unlikely to change with future research, whereas in a very low GRADE level of evidence the conclusion is very precarious. In addition to the level of evidence in literature, expertise from the Dutch post-mortem imaging guideline group members was taken into account, along with preferences of bereaved relatives, costs, availability of devices, and organisational issues when formulating the guideline recommendations.
# Results
## Study identification
The literature search resulted in 268 eligible articles for foetuses and neonates and 415 articles for paediatric studies. After title, abstract, and full-text selection 14 foetal-neonatal articles and 9 paediatric studies remained [fig_ref] Figure 1: Foetal-neonatal study selection [/fig_ref]. Studies on CR, PMCT, PMMRI, and MIA were included, other post-mortem imaging methods (e.g. post-mortem ultrasound) did not meet the inclusion criteria.
## Study quality
Both in foetal and neonatal patients, as well as in paediatric patients, the GRADE evidence for post-mortem CR, PMCT, and MIA was graded as low because few studies, with few patients included, have been performed. More studies were published on PMMRI, yet the evidence for PMMRI was also graded as low in both groups, because almost all results were based on the Magnetic Resonance Imaging Autopsy Study (MaRIAS). This study was performed in a specialised setting with welltrained specialists and a relatively low number of patients.
## Post-mortem conventional radiography (cr)
One article was included from the literature review on postmortem CR in foetal and neonatal patients. No articles on post-mortem CR of paediatric patients met the inclusion criteria.
## Foetal-neonatal
A clinical, foetal post-mortem skeletal survey consists mainly of a whole-body radiograph; a 'babygram' [fig_ref] Figure 3: Example of a diagnostic babygram [/fig_ref]. A study of 377 foetal post-mortem skeletal surveys showed a 100% sensitivity and 97% specificity for Example of a diagnostic babygram. This pregnancy was terminated at 22 weeks of gestation because of micromelia on prenatal 2nd trimester ultrasound, suspected to be a skeletal dysplasia. The babygram showed skeletal abnormalities with shortened ribs, metaphyseal flaring (1) and shortened and bowed long bones [bib_ref] Times have changed! Forensic radiology-a new challenge for radiology and forensic pathology, Flach [/bib_ref]. Histology revealed abnormalities in the liver, kidneys, lungs, bone and cartilage compatible with ciliopathy with major skeletal involvement. Jeune syndrome is the most likely diagnosis detection of skeletal abnormalities compared to diagnosis based on autopsy, genetics, and prenatal investigations [bib_ref] When is a post-mortem skeletal survey of the fetus indicated, and when..., Kamphuis-Van Ulzen [/bib_ref]. However, the number of diagnostic abnormalities in this population was limited. The authors concluded that there is no indication for a foetal post-mortem skeletal survey in cases without previous suspicion of skeletal abnormalities on prenatal ultrasound or during post-mortem external inspection. If a foetal 'babygram' is obtained, it should preferably be done using a high resolution 'cabinet radiography' system. If this is not available, the use of a mammography system is advised.
## Post-mortem computed tomography (pmct)
One study was included on the sensitivity and specificity of PMCT for both foetal-neonatal and paediatric patients, and an additional article on paediatric patients [fig_ref] Table 1 Table: of evidence of diagnostic performance of PMCT in foetuses, neonates and paediatric... [/fig_ref].
## Foetal-neonatal
PMCT and PMMRI were both compared to autopsy, and to each other in 53 foetuses, finding 40% of the PMCT's nondiagnostic in foetuses below 24 weeks of gestation (n = 35) compared to 11% of PMMRI's, with twice as many correct diagnoses on PMMRI compared to PMCT (10 vs. 5, p < 0.005) [bib_ref] Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus..., Arthurs [/bib_ref]. In foetuses above 24 weeks of gestation (n = 18), 22% of PMCT's were non-diagnostic, compared to 0% of PMMRI's (p < 0.005). In cases where radiology was diagnostic, both PMCT and PMMRI showed a 50% sensitivity and 100% specificity for main diagnosis or cause of death. Also, no significant differences were observed for identification of pathological lesions in individual organ systems, irrespective of contribution to death.
## Paediatric
Sensitivity of PMCT for cause of death determination depends on the type of pathology and age of the child [bib_ref] Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus..., Arthurs [/bib_ref] [bib_ref] Ventilated postmortem computed tomography in children: feasibility and initial experience, Arthurs [/bib_ref]. The same study as for foetuses and neonates, included 29 children with an average age of 6.9 months (range 1 day-16 years) [bib_ref] Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus..., Arthurs [/bib_ref]. In this small group, both PMCT and PMMRI showed a 50% sensitivity and 100% specificity for the main diagnosis or cause of death. The overall concordance was slightly lower for PMCT than PMMR (59.4% vs. 62.8%). In another study with 12 children under the age of 1 year, PMCT's of the lungs were non-diagnostic in 75% prior to post-mortem ventilation, compared to 0% of PMCT's with ventilation [bib_ref] Ventilated postmortem computed tomography in children: feasibility and initial experience, Arthurs [/bib_ref]. A 100% sensitivity and 63% specificity were found for the detection of abnormal lung areas with ventilated PMCT. Therefore, ventilated PMCT could be used to improve identification of abnormal areas of the lungs.
## Post-mortem magnetic resonance imaging (pmmri)
Seven articles were included on the diagnostic performance of PMMRI in foetuses and neonates, along with five articles on paediatric patients [fig_ref] Table 2 Table: of evidence of diagnostic performance of PMMRI in foetuses, neonates and paediatric... [/fig_ref]. The majority of these studies reported on the Magnetic Resonance Imaging Autopsy Study (MaRIAS) (sub)population [bib_ref] Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus..., Arthurs [/bib_ref] [bib_ref] Postmortem cardiovascular magnetic resonance imaging in fetuses and children: a masked comparison..., Taylor [/bib_ref] [bib_ref] Diagnostic accuracy of post-mortem MRI for thoracic abnormalities in fetuses and children, Arthurs [/bib_ref] [bib_ref] Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses..., Arthurs [/bib_ref] [bib_ref] Diagnostic accuracy of post mortem MRI for abdominal abnormalities in foetuses and..., Arthurs [/bib_ref] [bib_ref] Diagnostic accuracy of postmortem MRI for musculoskeletal abnormalities in fetuses and children, Arthurs [/bib_ref]. MaRIAS is a large, 3.5 year, double-blind prospective study in 277 foetuses (185 foetuses of 24 weeks gestation or less and 92 foetuses of 24 weeks gestation or more) and 123 children (42 neonates, 53 infants up to 1 year of age, and 28 children above 1 year of age), which compared the diagnostic accuracy of 1.5 T PMMRI to conventional autopsy [bib_ref] Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation..., Thayyil [/bib_ref] [bib_ref] Post mortem magnetic resonance imaging in the fetus, infant and child: a..., Thayyil [/bib_ref].
## Foetal-neonatal
Before the MaRIAS study, a systematic review, investigating the diagnostic accuracy of PMMRI, included five studies on foetuses [bib_ref] Diagnostic accuracy of post-mortem magnetic resonance imaging in fetuses, children and adults:..., Thayyil [/bib_ref]. In four of those five studies, a complete autopsy was used as the reference standard. The included studies were of moderate quality as the groups were small and the population heterogeneity large. There was a pooled sensitivity of 69% (95%CI 56-80) and a pooled specificity of 95% (95%CI 88-98) for detection of clinically significant abnormalities. The MaRIAS study reported high sensitivities (82-100%) and high specificities (93-97%) for both major and minor cardiac pathology, as well as for structural and non-structural heart disease in foetuses below and above 24 weeks of gestation [bib_ref] Postmortem cardiovascular magnetic resonance imaging in fetuses and children: a masked comparison..., Taylor [/bib_ref]. Votino et al. (2012) compared high-field PMMRI (9.4 T) to lower-field PMMRI (1.5 T and 3.0 T) and stereomicroscopic autopsy (MIA). In contrast to lower-field PMMRI, the heart situs, four-chamber view and outflow tracts could be visualised in all foetuses with 9.4 T, irrespective of gestational age. High-field PMMRI identified seven out of eight cases with major congenital heart disease. In foetuses below and above 24 weeks of gestation, MaRIAS reported low sensitivities of 30 and 38% and high specificities of 96 and 88% respectively for the detection of non-cardiac, thoracic abnormalities with 1.5 T [bib_ref] Diagnostic accuracy of post-mortem MRI for thoracic abnormalities in fetuses and children, Arthurs [/bib_ref]. Based on these results and the reasonable negative predictive values of approximately 85%, PMMRI appeared to be more useful in the exclusion of thoracic abnormalities, rather than in its identification. Detection of pulmonary tract infection and diffuse alveolar haemorrhage was difficult, whereas PMMRI was most sensitive for detection of anatomical abnormalities, including pleural effusions and lung hypoplasia.
Based on MaRIAS, very high sensitivities (80-100%) and specificities (87-100%) were found for the detection of brain malformations [fig_ref] Figure 4 a: b Example of abnormalities of the central nervous system diagnosed at... [/fig_ref] and minor and major intracranial bleedings [bib_ref] Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses..., Arthurs [/bib_ref]. A lower sensitivity of 30% was found for the detection of hypoxic-ischaemic brain injury in foetuses above 24 weeks of gestation. Furthermore, cerebral PMMRI provided clinically important information in 23 out of 43 foetuses in whom neuropathological examination was nondiagnostic due to maceration.
PMMRI showed moderate sensitivities of 77 and 65% for abdominal abnormalities in foetuses below and above 24 weeks gestation, respectively [bib_ref] Diagnostic accuracy of post mortem MRI for abdominal abnormalities in foetuses and..., Arthurs [/bib_ref]. Diagnostic accuracy was variable per organ system, with the highest sensitivity for renal abnormalities (18/21 = 86%) and the lowest for intestinal abnormalities (2/7 = 29%). In addition, MaRIAS reported moderate and very low sensitivities for detection of musculoskeletal abnormalities in foetuses below and over 24 weeks of gestation, respectively 69 and 17% [bib_ref] Diagnostic accuracy of postmortem MRI for musculoskeletal abnormalities in fetuses and children, Arthurs [/bib_ref].
## Paediatric
MaRIAS reported a 100% sensitivity and 98% specificity for major and minor structural heart defects in neonates and children with 1.5 T PMMRI [bib_ref] Postmortem cardiovascular magnetic resonance imaging in fetuses and children: a masked comparison..., Taylor [/bib_ref]. A substantial lower sensitivity of 62% was observed for any cardiac pathology, both structural and non-structural. Identification of non-cardiac, thoracic abnormalities was difficult, especially in case of pneumonia [bib_ref] Diagnostic accuracy of post-mortem MRI for thoracic abnormalities in fetuses and children, Arthurs [/bib_ref]. Sensitivities of 100% and specificities of 98-100% were reported for the detection of brain malformations and minor and major intracranial haemorrhages [bib_ref] Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses..., Arthurs [/bib_ref]. In contrast to foetuses, PMMRI showed a high sensitivity (93%) for ischaemic brain injury in neonates and children. Just as in foetuses, PMMRI showed a moderate sensitivity (71%) and high specificity (87%) for abdominal abnormalities [bib_ref] Diagnostic accuracy of post mortem MRI for abdominal abnormalities in foetuses and..., Arthurs [/bib_ref]. The sensitivity for skeletal abnormalities was poor (31%) [bib_ref] Diagnostic accuracy of postmortem MRI for musculoskeletal abnormalities in fetuses and children, Arthurs [/bib_ref].
## Minimal invasive autopsy (mia)
One article included from the literature search reported on MIA in both foetal-neonatal and paediatric patients (MaRIAS) [bib_ref] Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation..., Thayyil [/bib_ref]. This study compared the diagnostic accuracy of MIA to conventional autopsy. MIA consisted of PMMRI, combined with other post-mortem radiology, genetic and metabolic tests (ante-mortem and post-mortem blood sampling), a review of the clinical history, external examination, and examination of placental tissue, if available. No foetal-neonatal or paediatric studies combining PMMRI or PMCT with tissue biopsies or angiography met the inclusion criteria.
## Foetal-neonatal
Both a high sensitivity (100%, 95%CI 97-100) and high specificity (98%, 95%CI 88-100) were reported for the detection of major pathological abnormalities or cause of death in foetuses below 24 weeks of gestation [bib_ref] Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation..., Thayyil [/bib_ref]. In foetuses above 24 weeks of gestation, sensitivity and specificity were also high (respectively 96%, 95%CI 86-99, and 95%, 95%CI 84-99). Moreover, MIA had a higher sensitivity and specificity compared to PMMRI alone. In both groups of foetuses, the When visualisation was possible sensitivity and specificity for detection of non-infectious pathologies were above 95%. Sensitivity for infectious pathologies was with 80% (95%CI 38-96) lower in foetuses above 24 weeks of gestation than in foetuses below 24 weeks of gestation (100%, 95%CI 92-100).
## Paediatric
A 69% sensitivity (95%CI 58-78) and 93% specificity (95%CI 81-98) were found for major pathological abnormalities or cause of death in children [bib_ref] Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation..., Thayyil [/bib_ref]. Sensitivities of ) procedure is a stepwise approach to investigate the cause of death in children with an assumed natural unexpected and unexplained death [bib_ref] The value of postmortem computed tomography in paediatric natural cause of death:..., Van Rijn [/bib_ref] respectively 94% (95%CI 84-98) and 27% (95%CI 14-44) were reported for the detection of non-infectious and infectious pathologies, with specificities of respectively 96% (95%CI 89-99) and 100% (95%CI 96-100). Pneumonia and myocarditis were the main undetected abnormalities. This study showed an increase in the diagnostic accuracy of post-mortem radiology when PMMRI was extended with additional (minimal-invasive, genetic and metabolic) tests or examination of placental tissue. Like in the foetal patient group, MIA showed better results than PMMRI alone.
## Dutch post-mortem imaging guideline
The Dutch guideline working group developed an evidence and practice-based flowchart for post-mortem radiology in non-forensic foetal and neonatal deaths [fig_ref] Figure 5: Flowchart for post-mortem radiology in foetal and neonatal deaths* [/fig_ref] , and paediatric deaths [fig_ref] Figure 6: Flowchart for post-mortem radiology in paediatric deaths* [/fig_ref]. It must be emphasised that, based on the literature, due to the low GRADE level of evidence, post-mortem radiology without clinical autopsy should be considered as insufficient for best-practice post-mortem diagnosis.
# Discussion
Autopsy is traditionally considered as the gold standard for post-mortem diagnoses and quality assessment of provided health care. However, the declining autopsy rates of the last decennia result in decreasing expertise, especially in foetalneonatal and paediatric cases where mortality rates are low. Although autopsy remains the preferred diagnostic method in foetal, neonatal, and paediatric death, post-mortem radiology, after consent, can be used in adjunct to autopsy or as an alternative in cases without consent for conventional autopsy. In general, PMMRI is advised in foetuses, neonates, and young children, as PMMRI has a higher soft-tissue contrast compared to PMCT. The small body size enables high-resolution whole-body imaging in a reasonable amount of time. The limited value of PMCT in young children is illustrated in a study of 54 children (median age 1.0 years old, range 2 days-17.9 years) who died of an assumed natural cause, where PMCT could establish the cause of death in mere 12.9% [bib_ref] The value of postmortem computed tomography in paediatric natural cause of death:..., Van Rijn [/bib_ref]. In older children, just as in adults, PMCT is the preferred modality because of the lack of evidence of superiority of PMMRI over PMCT, its high availability, lower costs, and reduced scan time compared to PMMRI. With the limited PMCT and PMMRI showed a volvulus of the ileum around its mesentery (whirl sign) (arrow). Ischemic haemorrhagic volvulus of the ileum was confirmed by autopsy (b) as the cause of death amount of studies in children, it is not possible to be more specific about the age range where PMCT and PMMRI have equal diagnostic performances. The Dutch guideline for paediatric post-mortem radiology describes PMCT as a possible adjunct to PMMRI and autopsy, in children of 2 to 5 years of age . Furthermore, either PMCT or PMMRI is advised in children of 5 years or older, depending on the type of pathology expected. Given the limited amount of evidence, we would like to underline that, especially in infants and children, post-mortem imaging should be seen as an adjunct to the autopsy and not as a replacement. The cut-off age levels were the results of combined expert opinion, this as there is insufficient evidence to define a set cut-off age level.
No eligible paediatric studies on post-mortem CR were included. Nevertheless, in deceased children up to 4 years of age, a skeletal survey (consisting of 20-30 images) is advised to detect fractures, potentially caused by non-accidental injury [bib_ref] Use of the skeletal survey in the evaluation of child maltreatment, Belfer [/bib_ref] [bib_ref] Yield of radiographic skeletal surveys for detection of hand, foot, and spine..., Kleinman [/bib_ref] [bib_ref] Educational paper: imaging child abuse: the bare bones, Van Rijn [/bib_ref] [bib_ref] ACR appropriateness criteria(R) suspected physical abuse-child, Wootton-Gorges [/bib_ref]. In deceased children of 5 years or older, with possible child abuse, conventional radiographs of the areas of interest are advised on a low-threshold basis. This is despite a lack of evidence for the supplementary value of a skeletal survey or conventional radiographs in natural causes of death. In a study in 542 perinatal deaths (from 16 weeks gestation to 1 week after birth), the diagnostic value was very limited: 30% had abnormal radiographs, of which only 0.9% were of diagnostic importance for establishing the cause of death [bib_ref] Diagnostic value of radiography in cases of perinatal death: a population based..., Olsen [/bib_ref].
Although ultrasound did not meet the inclusion criteria for the guideline it is a technique that could be considered in selected cases where parents do not approve the use of PMCT or PMMRI [bib_ref] Is postmortem ultrasonography a useful tool for forensic purposes?, Charlier [/bib_ref] [bib_ref] Comparison of postmortem ultrasound and X-ray with autopsy in fetal death: retrospective..., Prodhomme [/bib_ref] [bib_ref] Application of compact ultrasound imaging device to postmortem diagnosis, Uchigasaki [/bib_ref]. Due to open sutures and absence of inhaled air, the brain and lungs can be examined by ultrasonography in cases of foetal demise [bib_ref] Principles of fetal postmortem ultrasound: a personal review, Prodhomme [/bib_ref]. In 88 foetuses of 11-40 weeks of gestation sensitivities of 91, 88, and 87% and specificities of respectively 90, 92, and 95% were reported with ultrasound for respectively brain, thoracic and abdominal anomalies [bib_ref] Minimally invasive fetal autopsy using three-dimensional ultrasound: a feasibility study, Votino [/bib_ref].
To meet the demand for less invasive alternatives to autopsy [bib_ref] Acceptance, reliability and confidence of diagnosis of fetal and neonatal virtuopsy compared..., Cannie [/bib_ref] [bib_ref] Parental acceptance of minimally invasive fetal and neonatal autopsy compared with conventional..., Kang [/bib_ref] , as well as a high diagnostic performance, it is likely that a combination of imaging and minimal invasive tissue acquisition will be increasingly used in future. Other minimal invasive techniques such as genetic and metabolic testing as well as virology and microbiology sampling can b Example of the difference in resolution between 1.5 (a) and 7 (b) Tesla PMMRI in a foetus of 18 weeks and 2 days of gestation. The 7 T image shows development of polymicrogyria (arrow) of the left temporal cortex, which is not detectable at the 1.5 T images Examples of normal post-mortem findings. (a) Opacification dorsal in the lung lobes due to septal oedema and pleural fluid (arrow). (b) Distension of bowel lumen due to post-mortem gas formation, and portal venous (1) and ventricular gas [bib_ref] Times have changed! Forensic radiology-a new challenge for radiology and forensic pathology, Flach [/bib_ref] be added on indication. The more post-mortem radiology is expanded with minimally invasive investigations, the higher the diagnostic yield will be; the border area of a minimal invasive radiological test and a restricted autopsy demands for close collaboration between these two specialities. Furthermore, the diagnostic performance of post-mortem radiology will increase by improvements of diagnostic techniques such a high-field PMMRI , post-mortem angiography, and post-mortem ventilation [bib_ref] Ventilated postmortem computed tomography in children: feasibility and initial experience, Arthurs [/bib_ref] [bib_ref] Lung aeration on post-mortem magnetic resonance imaging is a useful marker of..., Barber [/bib_ref] [bib_ref] Post-mortem examination of human fetuses: a comparison of whole-body high-field MRI at..., Thayyil [/bib_ref]. Non-or minimally invasive autopsy evokes much less objections from parents compared to conventional autopsy, resulting in overall increasing post-mortem investigation rates [bib_ref] Acceptance, reliability and confidence of diagnosis of fetal and neonatal virtuopsy compared..., Cannie [/bib_ref] [bib_ref] Parental acceptance of minimally invasive fetal and neonatal autopsy compared with conventional..., Kang [/bib_ref]. Hence, post-mortem radiology can increase post-mortem investigation rates, and subsequently improve family counselling and quality control of clinical diagnosis.
As post-mortem radiology is a relatively new subspecialty, images should be evaluated by an experienced radiologist. This should preferably be a paediatric radiologist who is familiar with normal post-mortem changes, which to the untrained eye can mimic pathologic abnormalities [bib_ref] Normal pediatric postmortem CT appearances, Klein [/bib_ref] [bib_ref] Post-mortem CT and MRI: appropriate post-mortem imaging appearances and changes related to..., Offiah [/bib_ref]. Therefore, it is advised for non-specialised centres to ask assistance from experienced radiologists.
To conclude, post-mortem radiology without clinical autopsy is yet considered as insufficient to establish the cause of death, due to the low GRADE level of evidence. Autopsy is therefore still regarded as the reference standard [bib_ref] Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus..., Arthurs [/bib_ref]. Postmortem radiology, especially as part of a MIA procedure, is considered a useful adjunct or valuable alternative in cases where autopsy is not performed. In general, neonatologists or paediatricians will be the referring physicians and as such they will be the ones obtaining parental informed consent. Therefore, it is imperative that they are aware of the advantages and limitations of post-mortem imaging. A multidisciplinary approach including clinicians, radiologists, and pathologists seems most beneficial. At present, PMMRI is the imaging modality of choice in foetuses, neonates, and young children, whereas PMCT is preferred in in older children.
## Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
## Appendix 1. materials and methods
Text adjusted from Acta Orthopedica (Besselaar et al [bib_ref] Guideline on the diagnosis and treatment of primary idiopathic clubfoot, Besselaar [/bib_ref] ; PubMed PMID: 28266239).
## Guideline working group
This guideline was developed and sponsored by the Radiological Society of the Netherlands (NVvR), using governmental funding from the Stichting Kwaliteitsgelden Medisch Specialisten in the Netherlands (SKMS, Quality foundation of the Dutch Federation of Medical Specialists). The early preparative phase started July 2015 and the guideline will officially be authorized by the Radiological Society of the Netherlands at the end of 2017. The working group had nine in-person meetings (between September 2015 and September 2017) and otherwise communicated by phone and email. Decisions were made by consensus. At the start of guideline development, all working group members completed conflict of interest forms.
## Target group and aims
This guideline was developed for Dutch radiologists concerned with postmortem radiology, and other medical specialists involved in postmortem diagnostics. The main purpose of the guideline is to provide best possible care to fetuses or neonates, children and their relatives in a postmortem radiology setting, by informing optimal treatment decisions, and reduce unwarranted variation in the delivery of postmortem diagnostic care.
# Methodology
The guideline was developed in agreement with the criteria set by the advisory committee on guideline development of the Federation of Medical Specialists in the Netherlands (Medisch Specialistische Richtlijnen 2.0; OMS, which are based on the AGREE II instrument (Brouwers [bib_ref] AGREE II: Advancing guideline development, reporting and evaluation in healthcare, Brouwers [/bib_ref] ; www.agreetrust.org). The guideline was developed using an evidence-based approach endorsing GRADE methodology, and meeting all criteria of AGREE-II. Grading of Recommendations Assessment, Development and Evaluation (GRADE) is a systematic approach for synthesizing evidence and grading of recommendations offering transparency at each stage of the guideline development [bib_ref] GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables, Guyatt [/bib_ref].
The guideline development process involves a number of phases, a preparative phase, development phase, commentary phase, and authorization phase. After authorization, the guideline has to be disseminated and implemented, and uptake and use have to be evaluated. Finally, the guideline has to be kept up-to-date. Each phase involves a number of practical steps (see Schünemann [bib_ref] Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline..., Schünemann [/bib_ref].
A methodologist together with the chairman of the working group drafted a concept list of key issues which was extensively discussed in the working group. The selected (high priority) issues were translated into carefully formulated clinical questions, defining patient/problem, intervention, and prioritizing the outcomes relevant for decision-making. Particular attention was paid to relevant outcomes for relatives of fetuses or children undergoing postmortem radiology and defining minimal clinically important differences. Therefore, a focus group was organized in cooperation with the Federation of Patient Organizations in the Netherlands.
The literature was systematically searched using the databases MEDLINE (Ovid) and Embase (a detailed search strategy is available upon request). Selection of the relevant literature was based on predefined inclusion and exclusion criteria and was carried out by members of the working group (JE, RR) in collaboration with the methodologist (EK). For each of the clinical questions, the evidence was summarized by the guideline methodologist using the GRADE approach: a systematic review was performed for each of the relevant outcomes and the quality of evidence was assessed in one of four grades (high, moderate, low, very low) by analyzing limitations in study design or execution (risk of bias), inconsistency of results, indirectness of evidence, imprecision, and publication bias. The evidence synthesis was complemented by a working group member (JE or RR) considering any additional arguments relevant to the clinical question, including relatives values and preferences, and resource use (costs, organization of care issues). Evidence synthesis, complementary arguments, and concept recommendations were extensively discussed in the working group and final recommendations were formulated. Final recommendations are based on the balance of desirable and undesirable outcomes, the quality of the body of evidence across all relevant outcomes, values and preferences, and resource use. The strength of a recommendation reflects the extent to which the guideline panel was confident that desirable effects of the intervention outweigh undesirable effects, or vice versa, across the range of patients for whom the recommendation is intended. The strength of a recommendation is determined by weighting all relevant arguments together, the weight of the body of evidence from the systematic literature analysis, as well as the weight of all complementary arguments. Guideline panels must use judgment in integrating these factors to make a strong or weak recommendation. Thus, a low quality of the body of evidence from the systematic literature analysis does not exclude a strong recommendation, and weak recommendations may follow from high quality evidence.
After reaching consensus in the working group, the concept guideline was subjected to peer review by all relevant stakeholders. Amendments were made and agreed upon by the working group, and the final text was presented to the Dutch societies of medical specialists and other organizations that participated in the working group for approval and formal authorization. The guideline will be published and be freely accessible in the Dutch guideline database (Richtlijnendatabase, www.richtlijnendatabase.nl). The Dutch guideline database has a modular structure, with each clinical question as a separate entry, thus allowing for modular updates.
[fig] Figure 1: Foetal-neonatal study selection. * Several papers had multiple reasons for full text exclusion. Maximum one reason per article was scored, according to the order presented [/fig]
[fig] Figure 2: Paediatric study selection. * Several papers had multiple reasons for full text exclusion. Maximum one reason per article was scored, according to the order presented [/fig]
[fig] Figure 3: Example of a diagnostic babygram. This pregnancy was terminated at 22 weeks of gestation because of micromelia on prenatal 2nd trimester ultrasound, suspected to be a skeletal dysplasia. The babygram showed skeletal abnormalities with shortened ribs, metaphyseal flaring (1) and shortened and bowed long bones (2). Histology revealed abnormalities in the liver, kidneys, lungs, bone and cartilage compatible with ciliopathy with major skeletal involvement. Jeune syndrome is the most likely diagnosis [/fig]
[fig] Figure 4 a: b Example of abnormalities of the central nervous system diagnosed at PMMRI in a female foetus. This pregnancy was terminated at 23 weeks of gestation because of corpus callosum agenesis (1), an interhemispheric cyst (2) and fossa posterior anomalies on prenatal 2nd trimester ultrasound, which were confirmed by PMMRI and/or conventional autopsy. A non-cystic dilatation of the fourth ventricle (3) was found on PMMRI along with the additional findings of a left choroid plexus cyst (4) and polymicrogyria(5). Furthermore, autopsy diagnosed a choroid plexus papilloma in the left lateral ventricle, but the additional finding of polymicrogyria (5) on PMMRI revealed Aicardi syndrome as the most likely diagnosis. a Axial. b Sagittal [/fig]
[fig] Figure 5: Flowchart for post-mortem radiology in foetal and neonatal deaths*. * adapted from the Dutch guideline for clinical foetal, neonatal, and paediatric post-mortem radiology[17]. GA: gestational age. US: ultrasonography. The 'routine 2 nd trimester ultrasound' is a standard prenatal US in all growing foetuses. The 'US for foetal death determination' is a second, separate antenatal US by the gynaecologist in order to confirm death. PMMRI: post-mortem magnetic resonance imaging. CNS: central nervous system. NODOK:: The Dutch 'Nader Onderzoek naar de DoodsOorzaak van Kinderen' (i.e. 'further examination of cause of death in children' [/fig]
[fig] Figure 6: Flowchart for post-mortem radiology in paediatric deaths*. * adapted from the Dutch guideline for clinical foetal, neonatal, and paediatric post-mortem radiology[17]. PMMRI: post-mortem magnetic resonance imaging. PMCT: post-mortem computed tomography. NODOK:The Dutch 'Nader Onderzoek naar de DoodsOorzaak van Kinderen' (i.e. 'further examination of cause of death in children') procedure is a stepwise approach to investigate the cause of death in children with an assumed natural unexpected and unexplained death[34] Fig. 7 a, bExample of a PMCT (a) of a 4-year-old child with an unexpected and unexplained but assumed natural cause of death. Cardiopulmonary resuscitation was performed but not successful. [/fig]
[table] Table 1 Table: of evidence of diagnostic performance of PMCT in foetuses, neonates and paediatric patients Author (ref) Year Study design Anatomical system [/table]
[table] Table 2 Table: of evidence of diagnostic performance of PMMRI in foetuses, neonates and paediatric patients Author (ref) Year Study design [/table]
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Recommendation on screening for chlamydia and gonorrhea in primary care for individuals not known to be at high risk
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Recommendation on screening for chlamydia and gonorrhea in primary care for individuals not known to be at high risk
## Key messages for the public
- Chlamydia and gonorrhea are common sexually transmitted infections that are treatable with antibiotics.
- If you are younger than age 30 and sexually active, your health care provider may offer screening for chlamydia and gonorrhea every year, even if you do not have symptoms.
- Screening is done to find and treat infections in people who aren't showing symptoms, which may reduce complications like pelvic inflammatory disease. These infections are often without symptoms.
- Talk to your doctor about screening more than once per year if you think you are at increased risk of infection (e.g., you have had a sexually transmitted infection, you have had unprotected sex, sex with multiple partners, or another reason).
- Chlamydia and gonorrhea infections are automatically reported to local public health units. This is to help with treatment for people who test positive and also with confidentially notifying sexual partners so that they may be tested and treated as required.
concerns.Opportunistic screening is distinct from a system atic population screening program, in which invitations for screening are sent to all eligible participants, monitored for uptake and evaluated through a centralized program, usually at the provincial level.
National guidance from the Public Health Agency of Canada currently recommends screening for chlamydia in pregnant women, annual screening for sexually active individuals younger than 25 years, and targeted screening of atrisk individ uals older than 25 years (e.g., those with previous STIs, sex trade workers).This guidance is not based on formal sys tematic reviews and does not include recommendations for gonorrhea screening.
The last guideline on chlamydia screening from the Canadian Task Force on the Periodic Health Examination (now Task Force on Preventive Health Care) was published in 1996;it also did not include recommendations on gonorrhea. Therefore, the task force identified a need for an updated Canadian guideline that considers current evidence on the potential harms, benefits, and patient values and preferences of screening for chlamydia and gonorrhea.
## Scope
This guideline is intended for clinicians in primary care settings who are positioned to offer opportunistic screening for chla mydia and gonorrhea directly to sexually active individuals who are not specifically seeking care for a possible STI and are not known to belong to a highrisk group. Readers should refer to rel evant national, provincial or local guidance for the screening of individuals known to have specific highrisk behaviours (these will vary by jurisdiction, but may include having multiple sexual partners, previous STIs or sex without condoms; testing of individuals seeking care for symptoms; pregnant individuals; and for selection of appropriate antibiotic treatment, partner notifi cation, retesting and forensic testing strategies. The terms "male" and "female," when used, refer to sex (i.e., biological attributes, particularly the reproductive or sexual anatomy at birth), unless otherwise indicated.
## Recommendation
We recommend opportunistic screening of sexually active individ uals younger than 30 years who are not known to belong to a high risk group, annually, for chlamydia and gonorrhea at primary care visits, using a self or cliniciancollected sample (conditional rec ommendation; very lowcertainty evidence).
A summary of the recommendation is provided in Box 1.
Providers should refer to relevant national, provincial or local guidance for screening of individuals known to belong to specific highrisk groups.
In the systematic review conducted for this guideline, all rel evant studies (9 randomized controlled trials [RCTs], 5,6,8,27-32 1 controlled clinical trial 33 and 2 retrospective cohort stud ieson the potential benefits of chlamydia screening pro vided indirect evidence (i.e., low applicability) on how and to whom screening would be offered in Canadian primary care. For example, 4 RCTs offered screening (regardless of uptake) by mailed invitation or through public education and screening encouragement 6,29 rather than via direct discussion, and 1 clus ter RCT provided cliniclevel interventions (packages to help encourage clinicians to offer screening) 5 rather than direct clin ician engagement, yielding low clinician participation and offers of screening. Three trials evaluated only those who accepted screening (acceptors of screening),and 1 trial evaluated an offer to screen among those preselected owing to an interest in screening (offer to screen, preselected),which is indirect to the varied screening interest and acceptance among Canadian primary care patients. No studies on the effects of screening for gonorrhea for any outcomes of interest were identi fied in generalrisk populations.
Eleven studies were identified on harms of screening for chlamydia. One RCT reported on adverse antibiotic events,and 10 uncontrolled cohort studies reported on psychosocial harms.No studies examined harms of screening for gonorrhea.
Fourteen studies examined values and preferences of screen ing for chlamydia or gonorrhea: 4 studies measured health state utility values (a measure of preference for being in a particular state of healthfor several of the benefit outcomes of screening for chlamydia and gonorrheainfection, and 10 (survey and qualitative) studies considered the relative importance of bene fits to harms of chlamydia screening.Benefits of screening Offer to screen, regardless of uptake Metaanalysis of 2 RCTs (n = 141 362) found very lowcertainty evidence for little to no difference in pelvic inflammatory disease rate among females aged 16-29 years, over 1 to 3 years using an annual offer of chlamydia screening via selfcollected vaginal samples (0.3 more in 1000 [95% confidence interval (CI) 7.6 fewer to 11 more]).One RCT (n = 15 459) found very uncertain effects on infertil ity and very lowcertainty evidence for little to no difference in ectopic pregnancy rates for females aged 21 to 24 years, over 9 years from a single offer of chlamydia screening via self collected vaginal samples (0.2 more in 1000 [95% CI 2.2 fewer to 3.9 more]). 6
## Box 1: summary of recommendation for clinicians, policy-makers and patients
We recommend opportunistic screening of sexually active individuals younger than 30 years who are not known to belong to a highrisk group, annually, for chlamydia and gonorrhea at primary care visits, using a self or cliniciancollected sample (conditional recommendation; very lowcertainty evidence).
Providers should refer to relevant national, provincial or local guidance for screening of individuals known to belong to specific highrisk groups.
Metaanalysis of 3 RCTs (n = 41 709) found lowcertainty evidence for little to no difference in chlamydia transmission for individuals aged 15-29 years, over 1 to 3 years from a sin gle offer of chlamydia screening via selfcollected vaginal or urine samples fewer per 1000 [95% CI 21.0 fewer to 12.6 more]). Offer to screen, preselected individuals interested in screening One RCT (n = 2607) -among females aged 18-34 years (81% younger than 24 yr) preselected based on completing a pre screening questionnaire on chlamydia risk and then accepting an offer of a primary care appointment (suggesting an interest in being screened) -found lowcertainty evidence that offering a single chlamydia screening via cliniciancollected cervical swabs may reduce pelvic inflammatory disease
## Harms of screening
One RCT (n = 37 543 tested; n = 4574 patients who received a diagnosis of chlamydia; number treated not reported) reported no adverse events from antibiotic treatment for chlamydia (very lowcertainty evidence).Cohort studies 20,36-44 reported on a vari ety of psychosocial harms of screening that were synthesized narratively; low or very lowcertainty evidence indicated that undergoing screening may lead to feelings of stigmatization (e.g., guilt, embarrassment, social disapproval) or anxiety about future infertility, sexuality or risk of infection in a small to moderate proportion of individuals (50-400 per 1000 individuals screened). The number of individuals affected in the entire eligible screen ing population is likely smaller. The exact duration and severity of these symptoms is unknown.
## Patient values and preferences
Considering benefits relative to harms, surveys and qualitative studies found that individuals considering screening (n = 777)or undergoing screening (n = 77) 56-58 placed greater relative importance on potential reproductive health and decreased transmission benefits than on anxiety or stigma of screening (very lowcertainty evidence). No studies considered patient val ues related to adverse events from medication.
Similarly, the patient engagement study that the task force conducted for this guideline (described in Methods) showed that patients likely prioritize potential benefits of screening (all rated critical or important) over harms (all rated important) and have a strong preference to be screened; this was the case even when participants were presented with the evidence and its uncertainty.Considering the relative prioritization of different screening benefits, studies reporting health state utilities found that while utility values are similar across benefit outcomes, 11,46-48 when considering durations of the health states, the avoidance of infertility and chronic pelvic pain may be more important to females than ectopic pregnancy, pelvic inflammatory disease or cervicitis (lowtomoderate certainty). 61
## Resource use
The task force did not conduct a systematic review on resource use or costeffectiveness. In the judgment of the task force, the recommendation to screen all eligible patients at opportunistic visits could involve additional (moderate) costs, largely because of additional clinician time at these encounters and testing costs.
Costeffectiveness estimates based on opportunistic screen ing scenarios suggest that high versus low rates of screening may improve costeffectiveness,and that screening may be cost effective in Canada provided that the probability of chlamydia progressing to pelvic inflammatory disease is at least 10%,although this is of very low certainty.
## Feasibility, acceptability, cost and equity
Screening is currently a part of primary care practice and there fore judged to be feasible and likely acceptable to primary care practitioners and patients. Notably, 1 included RCT showed that patients accepted screening 80% of the time that it was offered(although the overall screening rate in this trial was low [24%] because of lack of offer).The task force anticipates that public health and other policy makers will find the recommendation to screen acceptable, given the number of people affected, increasing incidence of chlamydia and gonorrhea infection,and availability of effective treatment.
In the judgment of the task force, the recommendation would likely improve health equity by normalizing screening as routine for sexually active individuals and thereby reducing important barriers to screening, such as fear of disapproval or discrimina tion and feelings of stigmatization.Additionally, because females carry most of the burden of the clinical consequences of infection, screening of males (a reservoir of infection for females) may improve health equity for females.
## Rationale
## Benefits
The indirectness (low applicability) of available evidence to inform opportunistic screening in Canada represents a major source of uncertainty, in addition to the very uncertain or lack of evidence for some outcomes of interest for chlamydia screening and for all outcomes of interest for gonorrhea screening. All evi dence on benefits was of low or very low certainty, largely because of concerns about indirectness as well as imprecision (Appendix 1, available at www.cmaj.ca/lookup/doi/10.1503/ cmaj.201967/tabrelatedcontent). Pelvic inflammatory disease may be reduced for those accepting and undergoing chlamydia screening 8,28,33 and for those interested in being screened who are offered it (low certainty). Very uncertain evidence found little to no difference in pelvic inflammatory disease when chlamydia screening was offered, via mailed invitation or clinic level packages that encouraged screening. The task force judged that the true benefit of chlamydia screening when offered directly by Canadian primary care practitioners, who are posi tioned to identify those eligible and to offer screening oppor tunistically, would likely lie within this observed range of screen ing effectiveness.
The recommendation to screen individuals younger than 30 years is based on the fact that almost all of the underlying evi dence comes from studies of individuals in this age group. Fur ther, the rates of chlamydia and gonorrhea are increasing among those aged 25-29 years in Canada, with rates and total cases sim ilar to those aged 15-19 years.Conversely, rates of chlamydia for those aged 30-39 years are less than 50% of those for individ uals 15-19 and 24-29 years, and less than 25% of those for indi viduals aged 20-24 years.Similarly, rates in those aged 40-59 years are less than 25% of those in individuals aged 30-39 years.Considering the properties of sexual networks, this recom mendation to screen sexually active males as well is intended to reduce chlamydia and gonorrhea infection and its negative con sequences in females, through their role in the transmission of these infections (although there were no available studies informing this rationale).
The task force made the recommendation to screen for gon orrhea as well (despite the lack of available evidence) given that many gonorrhea cases are asymptomatic;up to 40% of those with gonorrhea may have concurrent chlamydia; 67-69 and current Canadian clinical and laboratory practice is to combine testing for gonorrhea with chlamydia using a single sample (most commercial nucleic acid amplification test [NAAT] assays test for both organisms simultaneously with a single speci men. The incremental costs of screening for both chlamydia and gonorrhea (versus, for example, chlamydia alone) is uncer tain but likely minimal, as some provincial schedules already include NAAT for chlamydia and gonorrhea together under a single price. 70
## Harms
The task force placed a lower priority on the very uncertain evi dence of no serious adverse effects of antibiotic treatment for chlamydia and gonorrhea and uncertain evidence for psycho social harms of screening (anxiety, shame and stigma) that are likely to be experienced by a small proportion of those eligible for screening.
The task force judged that the potential benefits of screening for chlamydia and gonorrhea to reduce pelvic inflammatory dis ease in females, albeit very uncertain, outweigh possible harms. Evidence suggests that most Canadian patients also prioritize the benefits over the harms of screening for chlamydia and gon orrhea, even when provided with the evidence and its uncer tainty.Therefore, considering the balance of benefits and harms as well as evidence uncertainty, the task force provides a conditional recommendation in favour of opportunistic screen ing for chlamydia and gonorrhea in primary care for individuals younger than 30 years.
# Methods
The Canadian Task Force on Preventive Health Care is an inde pendent panel of clinicians and methodologists that makes rec ommendations on primary and secondary prevention in pri mary care (www.canadiantaskforce.ca). A working group of 6 task force members developed this recommendation, with scientific support from the science team at the Public Health Agency of Canada. The working group established the research questions and the analytical framework for the systematic review (Appendix 2, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.201967/tab relatedcontent). The Evidence Review and Synthesis Centre at the University of Alberta (Edmonton) conducted the systematic review on which the recommendation is based, which evaluated the effectiveness of chlamydia and gonorrhea screening and the relative importance of screening outcomes (benefits and harms) to patients.A search for eligible studies was conducted using Ovid MEDLINE, Ovid Embase, Wiley Cochrane Library, CINAHL via EBSCOhost, and Ovid PsycINFO from database inception to Jan. 26, 2020, with supplemental searches for grey literature. For the relative importance of potential benefit outcomes, a 2013 review on health state utility values was also updated.The sys tematic review was registered (PROSPERO CRD42018100733), and a protocol for the review was published.In the systematic review, potential benefits of screening examined included reduced pelvic inflammatory disease, ectopic pregnancies, cervicitis and chronic pelvic pain in females; and for both females and males, reduced infertility and transmission (prevalence). Potential harms examined included serious adverse antibiotic reactions and negative psychosocial implica tions of screening (e.g., anxiety, sexual relationship distress including partner violence, stigmatization, blame). Thresholds for minimally important differences in benefit outcomes were determined before the task force examined the results. Details can be found in the systematic review.The task force used the Grading of Recommendations, Assess ment, Development and Evaluation (GRADE) approach to deter mine the certainty of evidence and strength of recommendation (Box 2). See Appendix 3, available at www.cmaj.ca/lookup/ doi/10.1503/cmaj.201967/tabrelatedcontent. The entire task force approved the recommendations. More information about the task force's methods are avail able at the task force website (http://canadiantaskforce.ca/ methods).
## Patient engagement
The Knowledge Translation team at St. Michael's Hospital (Toronto) engaged members of the public from across Canada, recruited via advertisements on public websites (i.e., Craigslist and Kijiji), on behalf of the task force at 2 stages of guideline development. As a first step, 16 sexually active participants (9 identified as female, and 7 identified as male) aged 24-38 years rated the importance of screening outcomes via online survey and participated in a focus group to share their rationale for their ratings and discuss factors that affect the per ceived importance of various outcomes.Outcomes con sidered critical and important to decisionmaking by both partici pants and task force members were included in the systematic review. After the evidence review was completed, 17 different sexually active participants aged 24-38 years (13 participants
## Box 2: grading of recommendations
Recommendations are graded according to the Grading of Recommendations Assessment, Development and Evaluation system (GRADE).Whether a recommendation is strong or conditional is based on considerations such as certainty in the effects of an intervention, including magnitude, as well as estimates of how patients value and prioritize outcomes, variability of these estimates and wise use of resources.
## Strong recommendations
- Strong recommendations are those for which the Canadian Task Force on Preventive Health Care is confident that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention). A strong recommendation implies that most people will be best served by the recommended course of action.
- Strong recommendations are typically based on highcertainty evidence (i.e., high confidence in the estimate of the effect of an intervention). Strong recommendations may recommend in favour of an intervention (when there is high confidence of net benefit) or against an intervention (when there is high confidence of net harm). However, there are circumstances in which a strong recommendation may be considered based on low or very low certainty evidence, or when there is absence of evidence.- When there is an absence of evidence to provide confidence that there is benefit from implementing a new prevention service or when a conclusion of possible benefit requires a high level of speculation on linkages of uncertain evidence, but there is high certainty that some patients would be harmed or scarce health care resources expended, the task force may make a strong recommendation against service implementation. 74 This is consistent with the GRADE approach, in which strong recommendations are sometimes made with lowcertainty evidence combined with high certainty of harm or resource implications, and with the value that the task force places on using scarce primary care resources wisely. 74
## Conditional recommendations
- Conditional recommendations are those for which the desirable effects probably outweigh the undesirable effects (conditional recommendation in favour of an intervention) or undesirable effects probably outweigh the desirable effects (conditional recommendation against an intervention) but appreciable uncertainty exists. Conditional recommendations are made when the certainty of evidence is lower, when the margin between desirable and undesirable consequences is small and the balance depends on patient values and preferences, or when there is high variability in the values and preferences of patients. Conditional recommendations may also be applied when the balance of cost and benefits is ambiguous, key stakeholders differ about the acceptability or feasibility of the implementation, or the effects on health equity are unclear.
- In certain cases where a conditional recommendation for an intervention is made, clinicians are encouraged to engage in shared decisionmaking, to recognize that different choices will be appropriate for individual patients, and to help each person arrive at a management decision consistent with their values and preferences.
Evidence is graded as high, moderate, low or very lowcertainty, based on how confident the task force is that the estimates of effect are correct. identified as male, 3 identified as female, and 1 identified as non binary) rated the importance of screening outcomes via online survey, this time after being provided with a summary of system atic review results.Knowledge translation tools to support recommendation implementation, informed by feedback from clinicians and patients, were developed (available at https://canadiantaskforce. ca/toolsresources/chlamydiaandgonorrhea/).
## External and content expert review
The protocol,systematic reviewand draft guideline were each reviewed by stakeholders, peer reviewers, and clinical and con tent experts (see Acknowledgements). Clinical and content experts served as advisors to the working group; they partici pated in working group meetings and reviewed documents for accuracy, but did not have input into or vote on the direction or strength of recommendations.
## Management of competing interests
The task force follows Guidelines International Network prin ciples for disclosures of interests and management of compet ing interests.The task force's oversight committee for evaluating and adjudicating competing interests consists of the task force chair and vicechair and the director of the Global Health and Guidelines Division of the Public Health Agency of Canada.Funding for the task force is provided by the Public Health Agency of Canada. The task force did not consider the views of the funding body in developing the guideline.
All task force members are required to disclose financial and other relevant interests annually when new topics are selected and at each inperson meeting of the task force (3 times per year). These disclosures are available on the task force website (https://canadiantaskforce.ca/about/members/). There were no conflicts of interest among task force members for this guideline.
Clinical and content experts also disclose relevant interests at the outset of their participation and annually thereafter (see Appendix 4, available at www.cmaj.ca/lookup/doi/10.1503/ cmaj.201967/tabrelatedcontent). The task force did not judge any disclosures to represent conflicts of interest that precluded participation as a clinical or content expert.
## Implementation
To implement this screening recommendation, clinicians in primary care settings are advised to identify individuals who are eligible for screening (sexually active individuals younger than 30 years) and not seeking testing for a possible STI, and to offer chlamydia and gonorrhea screening opportunistically (i.e., without requiring a separate screening visit, and not only during sexual health visits). As noted above, results from 1 RCT suggest that patient acceptance of screening is high when offered.As individuals at high risk of chlamydia and gonor rhea infection may not always readily selfidentify or be easily identified by clinicians, this routine offer of screening applies to all sexually active individuals without clinician knowledge of their membership of a highrisk group. Sexually transmitted infections are associated with shame, embarrassment and substantial stigma, which could prevent patients from seeking screening and treatment.Routinely offering screening to all sexually active individuals has been suggested as one way to reduce stigma associated with STI testing.Those seeking testing or who are known to belong to a highrisk group should be managed according to relevant national, provincial or local guidance applicable to those populations. Sexual activity can be generally defined as ever having oral, vaginal or anal intercourse.
Informed consent, which is required for STI testing, is an additional implementation consideration. The main issues to address are those related to privacy, reporting of positive test results to local public health offices, and potential partner notification. Screening for sexually transmitted infection may cause embarrassment and anxiety for some patients. Offering screening requires sensitivity to stigmatization and fear of social disapproval, especially regarding gender, culture, behaviour and other vulnerabilities.
Although the optimal screening interval is unknown, an annual offer of screening may be appropriate for individuals at general risk, recognizing that encounters with primary care may occur less frequently. Most identified studies used annual screeningand, in 1 study, most pelvic inflammatory disease cases occurring within 1 year were in individuals who were chlamydia negative at baseline (general risk).A falsepositive result could cause harm without benefit to some individuals. This is particularly relevant when prevalence of chlamydia in the population is lower (e.g., 2%-3%), where the number of false positives from NAAT tests may be quite high (e.g., about 30%-60% at specificities of 97%-99%).
Although we did not identify evidence that would allow rec ommendation of specific screening strategies, acceptability and uptake of screening 79-81 may be improved by minimally invasive sample collection methods, of which selfcollected vaginal swabs from females and urine samples from males are the most accu rate (NAAT).Cliniciancollected swabs are likely acceptable and feasible during certain encounters (e.g., Pap testing).Ulti mately, patient preference and the clinical scenario will likely dictate the preferred sampling method. Clinicians are reminded to consider pharyngeal and rectal swabs if clinically warranted, although we did not identify any evidence to evaluate screening using samples from these sites.
In cases of actual or suspected child abuse, clinicians are directed to their local, provincial and territorial authorities (pub lic health offices, child protection services, pediatricians and clinical experts), for STI testing, treatment, reporting and management.
## Monitoring and evaluation
Rates of offer and uptake of screening among patients in primary care settings are a key performance measure for this guideline. Rates of reported chlamydia and gonorrhea infections represent another performance metric.
## Sexually active women
The USPSTF recommends screening for chlamydia in sexually active women aged 24 years and younger and in older women who are at increased risk for infection (Grade B recommendation).
The USPSTF recommends screening for gonorrhea in sexually active women aged 24 years and younger and in older women who are at increased risk for infection (Grade B recommendation).
## Sexually active men
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for chlamydia and gonorrhea in men (I statement).
Public Health England (2018)Chlamydia Annually or on change of sexual partner, tests should be offered to men and women younger than 25 years who have ever been sexually active. Providers should use every opportunity to offer chlamydia screening across primary care and access to services for sexual and reproductive health and genitourinary medicine.
## Other guidelines
Guidelines from several groups within Canadaand inter nationallysimilarly recommend that clinicians opportunis tically offer screening to sexually active individuals for chla mydia. Some, but not all, also include recommendations to screen for gonorrhea. The present recommendation extends to age 29 years (see recommendation rationale above),whereas other guidelines recommend screening to age 25 years, except for Australia, which recommends screening to age 30 years.
## Gaps in knowledge
We did not identify any trials that carried out screening for chla mydia or gonorrhea in a manner consistent with how screening is offered directly to patients, opportunistically, in Canadian pri mary care. There was also limited evidence on health outcomes of screening for chlamydia or gonorrhea in males or their specific female partners (considering sexual networks). Almost no stud ies included participants older than 30 years (which may be because of the low prevalence in this population). Studies com paring the impacts of different screening intervals or different screening strategies in primary care settings on health outcomes are required.
# Limitations
Thresholds for a minimally important difference were devel oped for benefit outcomes of interest to determine the magni tude of effect and certainty of the evidence. These thresholds were created by task force clinicians and topic experts, taking into account Canadian epidemiologic and natural history data. 13,We did not seek patient input on these thresholds, which for some preventive interventions with substantial harms would be useful to identify patient perspectives of the threshold of benefit. We did not assess the impact of gonorrhea treatment on antimicrobial resistance, as we focused on patientimportant outcomes of screening. It is not necessarily a limitation, but the task force has made a priori choices to pool study data in a way that may differ from other groups. We did not deter mine the average effect of screening across all included trials because of our predetermined interest in the effects of an offer to screen, regardless of uptake, and the large variability between the trial designs in this respect. Decisionmakers less concerned about this variability may have analyzed the data and judged the magnitude of effects differently, although the direction of this recommendation would not likely change.
# Conclusion
Opportunistic screening for chlamydia and gonorrhea among sexually active individuals younger than 30 years confers uncer tain but potentially important benefits, particularly for preven tion of pelvic inflammatory disease in females. Psychosocial harms of screening are anticipated to be relatively mild, and patients likely prioritize potential screening benefits over harms. The task force conditionally recommends in favour of screening, at primary care visits, sexually active individuals younger than 30 years who are not known to belong to a high risk group for chlamydia and gonorrhea. Informed consent is required for screening.
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CMAJ | APRIL 19, 2021 | VOLUME 193 | ISSUE 16 E549 I n Canada, Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhea) are the most commonly reported sex ually transmitted bacterial infections (STIs),1,2 with reported cases in the population increasing annually since 2000.3 In 2018, reported cases were highest in people aged 15–29 years, with rates of 1.0%–1.9% for chlamydia and 0.2%–0.3% for gonorrhea in this population,4 while rates among individuals older than 30 years were less than 0.5% for chlamydia and less than 0.2% for gonor rhea.4 Many infected individuals, however, are asymptomatic or do not seek care, and are not included in reported cases.3 Taking into account underreporting, the true prevalence of chlamydia in people aged 15 to 29 years may be as high as 5%–7%.3–6 Consequences of untreated chlamydia in females can include cervicitis in 10%–20%,7 pelvic inflammatory disease in 10%– 16%,8,9 infertility in up to 5%,10 chronic pelvic pain in 3%–8%,10,11 and ectopic pregnancy in up to 2%.10 Consequences of untreated gonorrhea may include rates of pelvic inflammatory disease that exceed those for chlamydia.12 In males, chlamydia may be associ ated with epididymitis in up to 7%, with or without orchitis,6,13 and, very rarely, infertility.14 Consequences of chlamydia affect ing both sexes include urethritis in 4% of females and up to 3% of males;15 pharyngitis; proctitis; reactive arthritis lasting longer than 6 months in 1%–4% (when considering both chlamydia and gonorrhea);16,17 and disseminated gonococcal infection in less than 1%, which can rarely lead to sepsis, meningitis, endocarditis or osteomyelitis.18 Screening sexually active individuals for chlamydia and gon orrhea could reduce clinical complications and transmission, but should be done only if benefits from screening exceed harms19,20 and resource use is justifiable. In Canada, STI screening is most commonly offered oppor tun istically by clinicians in a variety of primary care settings (e.g., family practice, sexual health clinics, school health centres) during visits that may or may not be for sexual health–related GUIDELINE CPD
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Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update on organizational stroke management
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Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update on organizational stroke management
# Abstract
Aim Stroke is characterised by high morbidity, mortality and disability, which seriously affects the health and safety of the people. Stroke has become a serious public health problem in China. Organisational stroke management can significantly reduce the mortality and disability rates of patients with stroke. We provide this evidence-based guideline to present current and comprehensive recommendations for organisational stroke management. Methods A formal literature search of MEDLINE (1 January 1997 through 30 September 2019) was performed. Data were synthesised with the use of evidence tables. Writing group members met by teleconference to discuss data-derived recommendations. The Chinese Stroke Association's Levels of Evidence grading algorithm was used to grade each recommendation. results Evidence-based guidelines are presented for the organisational management of patients presenting with stroke. The focus of the guideline was subdivided into prehospital first aid system of stroke, rapid diagnosis and treatment of emergency in stroke centre, organisational management of stroke unit and stroke clinic, construction of regional collaborative network among stroke centres and evaluation and continuous improvement of stroke medical quality. Conclusions The guidelines offer an organisational stroke management model for patients with stroke which might help dramatically.
Stroke has become a serious global public health problem. To further reduce incidence rate, disability rate, mortality rate and recurrence rate of stroke and improve China's standardised prevention and treatment of cerebrovascular diseases, the Chinese Stroke Association organised a domestic expert to write the Chinese Stroke Association Guidelines for Clinical Management of Cerebrovascular Disorders. The guideline fully combines the research of Chinese scholars and the widely used clinical interventions in China to elaborate the clinical comprehensive management of the diagnosis, treatment, prevention and rehabilitation of a series of stroke-related diseases, so as to help medical service providers make better clinical decisions, improve the quality of medical services and maximise the benefits of patients. Evidence-based medical evidence confirms that the organisational stroke management model can benefit all patients with stroke, and significantly improve the survival rate and independent living ability of patients with stroke.Stroke organisational management covers prehospital first aid system of stroke, rapid diagnosis and treatment of emergency in stroke centre, organisational management of stroke unit and stroke clinic, construction of regional collaborative network among stroke centres at all levels and evaluation and continuous improvement of stroke medical quality related to the above-mentioned links. This chapter will elaborate on the above-mentioned content.
reCoMMended ClAssifiCATion And evidenCe level of The guideline This guideline adopts the recommended classification and evidence level specified in the guidelines for the development of Stroke Society of China. This recommended classification and evidence level are consistent with the system adopted in the latest American Heart Association and American Stroke Association (AHA/ ASA) guidelines. 1. Recommended classification -Class I: there is evidence to prove or unanimously agree that the operation or treatment given is effective.
Open access -Class II: there are controversial evidences or opinions on the effectiveness of operation or treatment. How to provide the best diagnosis and treatment services for patients with stroke, especially in rural and township areas, is still a serious challenge. High-quality planning and evaluation of patients with stroke is an essential part of acute stroke treatment, which can improve the quality of medical services and clinical outcomes. Professional treatment with evidence-based medical evidence is one of the most effective ways to reduce the mortality and disability rate after stroke. Therefore, it is necessary to build a reasonable stroke diagnosis and treatment system in qualified stroke centres according to clinical guidelines, to provide the best medical services, and actively explore the construction pattern of stroke centres that can adapt to various hospital scales.
reCoMMendATions organisational management of stroke emergency Main contents of stroke emergency management Rapid collection of clinical data ► Emergency teams should rapidly identify patients with AIS and initiate thrombolytic procedures whenever possible for thrombolysis or endovascular therapy. (Class I, level of evidence A) ► Emergency teams need to start the stroke diagnosis and treatment procedures for patients who have been notified in advance; emergency nurses should notify emergency doctors to receive and start the diagnosis and treatment procedures for patients who have arrived at the hospital after triage. (Class I, level of evidence B) ► After initiating the thrombolytic or intravascular treatment process, emergency nurses need to quickly send the patient's laboratory samples, including blood routine, blood biochemistry and coagulation spectrum, which should not exceed 30 min after the Patients should first receive non-contrast CT to exclude bleeding, and/or choose CT angiography (CTA) to assess whether blood vessels are occluded, or CT perfusion (CTP) to assess the cerebral core Continuous quality improvement of emergency green channel ► Apply Toyota Production System (TPS) to improve the quality of green channel, set up TPS improvement team, and analyse the delays in the current intravenous thrombolysis process. According to its importance and difficulty, list the problems that can be improved quickly and in a short time, and formulate specific solutions accordingly. (Class IIa, level of evidence B) ► Apply PDCA (Plan, Do, Check, Action) cycle method to continuously improve the quality of green channel through four steps of cycle: Plan (making process time-consuming plan and problem); Do (implementing improvement plan); Check (checking and evaluating legacy problems) and Action (continuing implementation and execution). (Class IIa, level of evidence B) ► Apply 6-SIGMA management method to improve the quality of green channel, implementing 'Define (setting process improvement objectives); Measure (decomposing process to measure the time needed in current process); Analysis (using various statistical strategies to analyse the reasons for failure to achieve standards); Improve (problem-based adjustment to improve process); Control (continuously monitoring process, ensuring continuous improvement of green channel quality)'. Five-step cycle. (Class IIa, level of evidence B) ► Apply quality control circle, establish quality control circle within stroke team, promote circle cooperation ChApTer 3: regionAl CooperATive neTwork ConsTruCTion of sTroke CenTre The purpose of establishing stroke centre is to improve stroke medical staff and facilities, so as to adapt them to the methods of stroke treatment and improve the level of stroke diagnosis and treatment.The US health facility accreditation programme classifies stroke centres into three levels: CSC, PSC and stroke ready hospital. As early as 2000, BAC published a proposal to develop PSC, so as to improve the level of stroke diagnosis and treatment in the USA and improve stroke outcomes.Based on a large number of literature searches and the consultation of alliance members, the proposal requires PSC to have stroke team, stroke centre, fixed operating procedures, integrated emergency system, 24 hours CT examination and image interpretation, rapid laboratory examination and strong administrative support. Studies have shown that PSC using procedural procedures significantly improves the outcome of patients with stroke, compared with hospitals that do not use procedural procedures or have no stroke centres.In 2005, BAC launched a second proposal to define the standard of main medical types of CSC.Through evidence-based medicine, BAC has identified the following key steps: medical staff equipped with neurosurgery and neurovascular expertise; advanced nervous system imaging capabilities, such as cerebral angiography; surgery and intravascular operation technology, including aneurysm clipping, carotid endarterectomy, intra-arterial treatment and other infrastructure, such as neurointensive care unit. These measures may improve the prognosis of patients with complex cerebrovascular disease. Based on the basis of evidence-based medicine and the current situation of domestic medical environment, the expert committee of stroke field of the Center for Medical Quality Control of Neurological Medicine of the National Health and Family Planning Commission has initially formed a guideline for the construction of stroke centres in China in 2015 to standardise the access standards of stroke medical institutions,improve the quality of medical services and rationally distribute medical resources, which provided the basis for the allocation of medical resources and quality supervision of health administrative departments and reasonable and optimised treatment for patients with stroke, and improved the overall construction of stroke medical service system in China.
pattern of development and construction for stroke centre ► We should actively promote the establishment of stroke centres at all levels, and all types of acute patients with stroke should enter the stroke centres for diagnosis and treatment. (Class I, level of evidence A) ► For large-scale ischaemic or haemorrhagic stroke, stroke with unknown aetiology, stroke requiring special examination and treatment, stroke that PSC cannot complete and stroke requiring multidisciplinary treatment, direct entry or transfer to CSC is recommended for treatment. (Class I, level of evidence A) ► Third-party stroke centre certification is strongly recommended. (Class I, level of evidence B) Construction of regional emergency network for stroke ► Stroke centres with different treatment capabilities should establish a regional emergency network system with clear responsibilities, resource sharing and winwin cooperation. (Class II, level of evidence B) ► It is suggested that stroke education programme be implemented for EMS personnel. (Class I, level of evidence B) ► It is suggested that EMS personnel use the stroke assessment system to initiate the preliminary treatment of stroke on the spot and notify the receiving hospital of the suspected patients with stroke before arriving, so that the hospital can mobilise the corresponding resources before the arrival of the patients.
(Class I, level of evidence B) ► The stroke emergency map should be jointly carried out with the 120 emergency centres, regional comprehensive stroke centres and other qualified medical institutions (stroke prevention and control centre, Operation and management of telemedicine ► Comprehensive stroke centres should actively promote telemedicine, strengthen the integration of medical resources and form a stroke medical network covering the surrounding primary stroke centres or primary hospitals. (Class IIb, level of evidence B)
ChApTer 4: evAluATion And ConTinuous iMproveMenT of MediCAl quAliTy of sTroke Medical quality is the work quality of medical preventive institutions and the standard to measure the level of medical staff. It covers the content of medical quality, and emphasises patient satisfaction, medical work efficiency, medical technology and economic effect (input-output relationship), continuity and systematic effect of medical treatment. Therefore, medical quality is a comprehensive reflection of medical technology, management methods and economic benefits.
improvement of medical service quality in patients with stroke ► Establish a stroke registration system for quality improvement, monitor medical quality and provide reliable data for quality improvement. Ideal stroke registration should have appropriate management structure and supervision methods to ensure the normal operation of the registration work. At the same time, the follow-up system should be improved to verify whether the quality improvement is related to the prognosis of patients. In order to ensure the authenticity and standardisation of data, the Quality Improvement Commissioner should check and upload data regularly. (Class I, level of evidence B) ► Establishment of clinical pathway for stroke and written standardised operating procedures with continuous quality improvement. Organise multidisciplinary collaborative team to discuss continuous quality improvement. Analyse the current situation, find out the problems, put forward the possible solutions, put them into practice and test the feasibility of the scheme. Based on this, the standard operation process is updated to ensure its effectiveness and operability. (Class I, level of evidence B) ► Establish standardised assessment and measurement criteria for stroke medical services, namely key performance indicators. Supervisory departments should strengthen link quality control, implement the existing evidence-based medicine guidelines to the greatest extent possible and supervise whether the centres implement the standard operating procedures. Setting up standard quality management standards, eliminating regional differences in medical quality and realising standardisation of medical services. (Class IIa, level of evidence B)
Open access quality indicators of medical services in primary stroke centres Mandatory quality indicators of PSC stroke diagnosis and treatment To be strengthened and regularly controlled. Indicators of medical services at discharge ► The proportion of non-cardiogenic patients with ischaemic stroke treated with antiplatelet drugs. ► The proportion of patients with atrial fibrillation receiving anticoagulation therapy. ► The proportion of patients with low-density lipoprotein cholesterol >2.6 mmol/L receiving statins. ► The proportion of hypertension patients treated with antihypertensive therapy. ► The proportion of patients with diabetes mellitus treated with antidiabetic medication. ► The proportions of previous or current smokers receiving smoking cessation education. ► Average hospitalisation days and mortality. ► Average hospitalisation expenses and average hospitalisation drug expenses. ► Health education on risk factors and control of cerebrovascular disease, symptoms of stroke attack, medication compliance, rehabilitation treatment, etc.
## Quality indicators of medical services during acute hospitalisation
## Additional quality indicators for psc stroke diagnosis and treatment
At least three of them should be met: ► The proportion of patients with atherosclerotic ischaemic stroke treated with statin during hospitalisation. ► The proportion of hypertensive patients treated with antihypertensive therapy during hospitalisation. ► The proportion of patients with stroke whose hospitalisation days are <14 days. ► It is suggested that patients should be followed up in stroke prevention clinic 3 months and 6 months after discharge to evaluate the efficacy of stroke unit and ensure that patients receive standard secondary prevention. ► Courses on stroke warning and prehospital training for hospital staff are designed to identify stroke symptoms quickly and to be admitted to stroke centres immediately.
quality indicators of medical services in comprehensive stroke centres Mandatory quality indicators of CSC stroke diagnosis and treatment Establishment of clinical pathway management ► Central venous thrombolysis intervention plan compiled according to current clinical guidelines. ► Establishment of emergency-related clinical standard process. ► Standard clinical pathway and start-up process of intravascular therapy based on current guidelines. ► Standard process of preoperative and postoperative management of multidisciplinary endovascular treatment of stroke. ► Standard process of preoperative and postoperative management of multidisciplinary surgical intervention of stroke. ► Standard procedure of dealing with two or more patients with complex cerebrovascular diseases at the same time.
Quality indicators of medical services for patients with acute ischaemic stroke receiving endovascular therapy ► The average time from admission to multimode CT or multimode MRI (only one of them) in patients within 6 hours after onset of stroke. ► The proportion of patients with AIS treated with endovascular therapy. ► Average time from admission to intravascular therapy (door-to-groin) in patients with ischaemic stroke. ► The proportion of intracranial haemorrhage with clinical symptoms within 36 hours after treatment in patients undergoing endovascular therapy.
Quality indicators of medical services for diagnosis and treatment of intracranial and extracranial vessels ► The proportion of stroke or death after diagnostic cerebral angiography.
► The proportion of stroke or death within 30 days after carotid artery dissection or stenting. ► The proportion of stroke or death within 30 days after intracranial angioplasty and/or stenting for atherosclerosis.
## Quality indicators of medical services for sah and ich
► The proportion of patients with SAH and ICH who had written records of the initial severity assessment. ► The proportion of aneurysm clipping and interventional treatment in the past year. ► The average time from admission to clipping or interventional treatment of ruptured aneurysms for patients with SAH with ruptured aneurysms within 48 hours from onset. ► The proportion of patients with SAH confirmed ruptured aneurysm treated with nimodipine within 24 hours of diagnosis and continued to discharge or 21 days after bleeding. ► Mortality rate of patients with ICH undergoing haematoma clearance.
Quality indicators of medical services for neurosurgery ► Mortality rate of patients with massive cerebral infarction undergoing decompressive craniectomy. ► The proportion of patients with ischaemic or haemorrhagic stroke undergoing ventricular drainage. ► The proportion of patients with ischaemic or haemorrhagic stroke who underwent ventricular drainage and complicated with ventriculitis.
Quality indicators of medical services for warfarin-related intracranial haemorrhage ► The average time from admission to the reversal measures of international normalised ratio in patients with warfarin-related intracranial haemorrhage.
## Additional quality indicators for csc stroke diagnosis and treatment
At least three of them should be met: ► Frequency of non-invasive vasospasm monitoring in patients with aneurysmal SAH during 3-14 days. ► The proportion of complications in patients undergoing aneurysm clipping or embolisation. ► The proportion of patients with stroke with arteriovenous malformations treated surgically or with intravascular therapy within 30 days. ► The average interval from telephone notification to CSC arrival in patients with ischaemic stroke or haemorrhagic stroke or transient ischaemic attack (TIA) who has written records of referrals from another hospital to CSC. ► The proportion of patients with ischaemic stroke, SAH, intracranial haemorrhage, TIA, intracranial and extracranial vascular stenosis enrolled in clinical trials.
Construction of information platform for stroke medical quality monitoring and continuous quality improvement ► Establish an information platform for medical quality monitoring and continuous quality improvement, strengthen the management of medical quality control, promote feedback of medical service safety and provide decision-making basis for the improvement of medical service quality in medical institutions at all levels. (Class I, level of evidence B)
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https://svn.bmj.com/content/svnbmj/5/3/260.full.pdf
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Aim Stroke is characterised by high morbidity, mortality and disability, which seriously affects the health and safety of the people. Stroke has become a serious public health problem in China. Organisational stroke management can significantly reduce the mortality and disability rates of patients with stroke. We provide this evidence-based guideline to present current and comprehensive recommendations for organisational stroke management. Methods A formal literature search of MEDLINE (1 January 1997 through 30 September 2019) was performed. Data were synthesised with the use of evidence tables. Writing group members met by teleconference to discuss data-derived recommendations. The Chinese Stroke Association’s Levels of Evidence grading algorithm was used to grade each recommendation. Results Evidence-based guidelines are presented for the organisational management of patients presenting with stroke. The focus of the guideline was subdivided into prehospital first aid system of stroke, rapid diagnosis and treatment of emergency in stroke centre, organisational management of stroke unit and stroke clinic, construction of regional collaborative network among stroke centres and evaluation and continuous improvement of stroke medical quality. Conclusions The guidelines offer an organisational stroke management model for patients with stroke which might help dramatically.
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8b6dc1353441c52326a151e78c9571c11dcedf47
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pubmed
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Social Media Guidelines and Best Practices: Recommendations from the Council of Residency Directors Social Media Task Force
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Social Media Guidelines and Best Practices: Recommendations from the Council of Residency Directors Social Media Task Force
Social media has become a staple of everyday life among over one billion people worldwide. A social networking presence has become a hallmark of vibrant and transparent communications. It has quickly become the preferred method of communication and information sharing. It offers the ability for various entities, especially residency programs, to create an attractive internet presence and "brand" the program. Social media, while having significant potential for communication and knowledge transfer, carries with it legal, ethical, personal, and professional risks. Implementation of a social networking presence must be deliberate, transparent, and optimize potential benefits while minimizing risks. This is especially true with residency programs. The power of social media as a communication, education, and recruiting tool is undeniable. Yet the pitfalls of misuse can be disastrous, including violations in patient confidentiality, violations of privacy, and recruiting misconduct. These guidelines were developed to provide emergency medicine residency programs leadership with guidance and best practices in the appropriate use and regulation of social media, but are applicable to all residency programs that wish to establish a social media presence. [West J Emerg Med. 2014;15(1):26-30.]
# Introduction
The term "social media" encompasses a wide variety of Internet-based resources to share content among users. This term includes social networking sites, video-or picturesharing sites, forums, blogs, and other tools. Information
## Pillow et al
Social Media Guidelines and Best Practices medicine (EM), "…use of social media among emergency physicians is unusually strong… emergency physicians have embraced the healthcare side of social media in a way not seen among other specialists."In addition to the various EM blogs and sites covering daily practice issues, there has even been a call for integrating social media into emergencypreparedness efforts. [bib_ref] Integrating Social Media Into Emergency-Preparedness Efforts, Merchant [/bib_ref] Social media has now become a preferred method of communication and information sharing. It offers the ability for various entities, especially residency programs, to create an attractive Internet presence and "brand" the program.Social media, while having significant potential for communication and knowledge transfer, carries with it legal, ethical, personal, and professional risks. [bib_ref] Revisiting Social Network Utilization by Physicians-in-Training, Black [/bib_ref] [bib_ref] Health professions students' use of social media, Giordano [/bib_ref] [bib_ref] Medical professionalism in the age of online social networking, Guseh [/bib_ref] [bib_ref] professionalism and Facebook: a dilemma for young doctors, Macdonald [/bib_ref] [bib_ref] The Intersection of Online Social Networking with Medical Professionalism, Thompson [/bib_ref] [bib_ref] Professionalism in the digital age, Mostaghimi [/bib_ref] [bib_ref] Online professionalism: social media, social contracts, trust, and medicine, Snyder [/bib_ref] The negative side of social media is highlighted in multiple publications, which illustrate problems including disclosure of private information and lapses in professionalism. [bib_ref] Online Posting of Unprofessional Content by Medical Students, Chretien [/bib_ref] [bib_ref] It's your own risk: Medical students' views on online posting, Chretien [/bib_ref] [bib_ref] Physician, monitor thyself: professionalism and accountability in the use of social media, Lagu [/bib_ref] [bib_ref] professionalism and Facebook: a dilemma for young doctors, Macdonald [/bib_ref] [bib_ref] Facebook activity of residents and fellows and its impact on the doctor-patient..., Moubarak [/bib_ref] [bib_ref] How facebook almost ended my career with a single click, Strausburg [/bib_ref] Due to the unique climate of social media, even simple actions like "friending" (a function of social media platform Facebook ® , whereby one user can request to be a "friend") can be misinterpreted as violations of professional or personal boundaries. Despite the dangers, social media offer tremendous benefits for recruiting, communication, and education. [bib_ref] How facebook saved our day!, Ben-Yakov [/bib_ref] [bib_ref] Twitter: an essential tool for every physician leader, Bottles [/bib_ref] [bib_ref] Twittering healthcare: social media and medicine, Terry [/bib_ref] Implementation of a social networking presence must be deliberate, transparent, and optimize potential benefits while minimizing risks.
These guidelines are designed to provide guidance to EM residency programs not only for the development and use of a program-specific social media presence, but also for the education of residents in potentially problematic use of social media that may impact professional functions in their private life. They are designed to complement and do not supersede any institutional guidelines or local, state or federal laws. The social media guidelines outlined in this paper constitute an expert consensus opinion for best practices and are approved by the Council of Emergency Medicine Residency Directors (CORD) Board of Directors as of November 2012.
# Methodology
Several hundred EM residency directors and other academic faculty members attended a lecture on the issues of social media in resident selection at the March 2011 CORD Academic Assembly. Following that session, a Social Media Task Force was assembled consisting of 14 geographically diverse educational leaders. The group met regularly over the next 14 months to review available literature and policies.
Policies from the institutions represented on the task force were reviewed when they existed (including Mayo Clinic,Regions Hospital,University of Michigan,Baylor University,Eastern Carolina University, and Carolinas Medical Center. In addition, policies from national organizations were obtained and reviewed including those from Society of Academic Emergency Medicine (SAEM),American Medical Association (AMA),and Indiana State Bar Association (ISBA).A literature search was performed for additional resources using search terms of social media, education, graduate medical education and professionalism.
There was considerable variation among these institutions as to the presence and content of a social media policy. While many universities and professional organizations had social media policies designed to restrict employee activity to protect the institution, few if any encouraged social media use. None addressed the unique needs of residents and residency leadership. Much of the literature reports residents unintentionally or unknowingly violating institutional policies and suffering professional consequences.
After review of the literature and existing institutional and organizational guidelines, the task force developed a graduate medial education (GME)-specific set of recommendations. These were then independently reviewed by Tobi Tanzer, J.D., vice president of integrity and compliance for Health Partners-Regions Hospital. The guidelines were then submitted to the CORD Board of Directors for review and endorsement.
## Recommendations
It is our strong recommendation that each residency program develop a social media policy and education effort. [bib_ref] Social media policies at US medical schools, Kind [/bib_ref] [bib_ref] Social media in medical school education, Wells [/bib_ref] Institutional officials should be involved in the development of these materials. The initial discussions should be held with the designated institutional officer (DIO), public affairs, legal or privacy officer, and information technology (IT) departments for consideration of any existing policies and procedures, as well as subtleties of law relevant to public versus private institutions.
## Content management
When a program initiates a sponsored social media site, it should designate a content manager (moderator) who is a permanent employee (i.e. not a trainee) who will assume responsibility for the maintenance and monitoring of posted content. That content manager needs to be proficient in the operation of the chosen platform as it pertains to administrative issues regarding posting, access, and privacy. That person also needs to ensure routine updating and monitoring of the site. In addition, plans for transfer of content management should be made in advance to facilitate a smooth transition. Areas of responsibility for the content manager include: Site management is an evolving realm with unforeseen risks. Content managers may be responsible or liable per individual institutional requirements, for all content posted on the sites. [bib_ref] A legal primer for social media, Burke [/bib_ref] [bib_ref] Online Professional Networks for Physicians: Risk Management, Hyman [/bib_ref] It is recommended that content managers frequently communicate with the institution regarding site content and any questions be vetted by the institution before posting. It is important to note that once content is placed on an institutionally sponsored site, it is then owned by the institution and not the posting individual or the content manager. [bib_ref] A legal primer for social media, Burke [/bib_ref]
## Communication plan
A program should have a communications plan/policy that proactively addresses the use of social media and potential issues. This should encompass: - Plans to deal with adverse events, including spam, negative comments, complaints, and unprofessional behavior.
## Residency program-specific issues education
Residency programs should provide guidance and education to residents, fellows, faculty, and other personnel under their supervision regarding appropriate social media use. Particular attention should be paid to professionalism issues, including personal reputation and medical privacy.Direct policing of individual resident or personnel activities on the Internet (aside from on the department-sponsored social media site) is discouraged as it represents a significant intrusion into resident privacy and is beyond the capability and purview of a residency program. However, should an issue involving a personal site be brought to the attention of a program, it is the responsibility of the program to take appropriate action to protect privacy and professionalism standards.
## Professionalism and privacy
Professionalism and privacy issues are accentuated on social media. The same standards of professionalism and privacy are required online as in person, but normal standards may not be sufficient to avoid misperceptions or legal issues. Residents should familiarize themselves with the American Medial Associations' Professionalism in the Use of Social Media guidelines. [bib_ref] Report of the AMA Council on Ethical and Judicial Affairs: professionalism in..., Shore [/bib_ref] Posted content must be assumed to be permanent, public, and even if deleted may still exist in an archive, database, or download formats. Information may prove to be damaging to an individual's reputation among colleagues and patients, and may affect future relationships and employment.Privacy settings are relatively easy to circumvent and should not be relied upon to protect postings from public disclosure. Respect for patient confidentiality is essential as federal and state confidentiality laws apply to social media sites. [bib_ref] A legal primer for social media, Burke [/bib_ref] [bib_ref] Patient privacy and social media, Hader [/bib_ref] [bib_ref] The decision to access patient information from a social media site: what..., Jent [/bib_ref] Even de-identified discussion of patients and specific medical cases on social media sites should be avoided.
## Recruitment & educational relationships
A program should recognize the potential for inequitable relationships to exist through social media. Institutional guidelines with regard to harassment and appropriate relationships should be applied to interactions on social media as in other venues. It is our strong recommendation that people in a position of power/authority not initiate a personal online relationship with an individual in a subordinate position. Exceptions may be made for situations where it is appropriate for monitoring a remediation/probationary circumstance or for primarily educational group experience, such as with an online journal club hosted on a social media platform.
A program director or other individuals in positions of authority (e.g. chief resident) should apply a consistent action to requests for a social media relationships to avoid favoritism or perception of such. It is recommended that individuals in a position of authority maintain a separate public presence that may be used for residency purposes such as facilitating online educational interactions (e.g. Facebook ® journal club) or monitoring a trainee for remediation purposes, including monitoring of professionalism if previous issues have existed.
Significant controversy exists with regard to whether a program should search for online information about prospective residents. [bib_ref] Protected health information on social networking sites: ethical and legal considerations, Thompson [/bib_ref] Each program should individually decide whether and how they will use online information and consistently apply the same standard to all applicants. This decision should encompass consideration of:
# Conclusion
Every residency program should develop a social media policy and educational effort for learners with early involvement of institutional personnel. The program should designate a content manager who is responsible for the site, including compliance with institutional regulations. The program should also have a communications plan that addresses the use of social media in an anticipatory manner. Proper use of social media is a key professionalism issue, and it is the responsibility of the program to provide education to residents, fellows, faculty, and other staff under their supervision. Although social media can be a powerful tool, programs should recognize that the potential for inequitable relationships exist. Individuals in a position of authority, in general, should not initiate an online relationship with an individual in a subordinate position.
These guidelines were developed to assist residency program leadership with appropriate use of social media platforms. Additional resources are being made available online through CORD to assist with educational efforts. These will be found at http://cord.sharepointsite.net/default.aspx.
[fig] •: Target audience Purpose of the site, including educational objectives and explicit consideration of the function of the site such as degrees of access and interactivity planned Level of privacy and security required Issues of medical advice and redirection of patients to appropriate venues [/fig]
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https://cloudfront.escholarship.org/dist/prd/content/qt8jh2p2mq/qt8jh2p2mq.pdf?t=p7e9b3
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Social media has become a staple of everyday life among over one billion people worldwide. A social networking presence has become a hallmark of vibrant and transparent communications. It has quickly become the preferred method of communication and information sharing. It offers the ability for various entities, especially residency programs, to create an attractive internet presence and “brand” the program. Social media, while having significant potential for communication and knowledge transfer, carries with it legal, ethical, personal, and professional risks. Implementation of a social networking presence must be deliberate, transparent, and optimize potential benefits while minimizing risks. This is especially true with residency programs. The power of social media as a communication, education, and recruiting tool is undeniable. Yet the pitfalls of misuse can be disastrous, including violations in patient confidentiality, violations of privacy, and recruiting misconduct. These guidelines were developed to provide emergency medicine residency programs leadership with guidance and best practices in the appropriate use and regulation of social media, but are applicable to all residency programs that wish to establish a social media presence.
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389c0a0f627188275e033b5b4b508c9b65658e66
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pubmed
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International consensus statement on robotic hepatectomy surgery in 2018
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International consensus statement on robotic hepatectomy surgery in 2018
# Introduction
In 1987, Mouret performed the first laparoscopic cholecystectomy, which started the era of minimally invasive hepatobiliary surgery. In the 1990s, the use of laparoscopic hepatectomy for benign and malignant tumors was independently reported by Katkhouda, Reich, and others [bib_ref] Laparoscopic excision of benign liver lesions, Reich [/bib_ref] [bib_ref] Laser resection of a liver hydatid cyst under videolaparoscopy, Katkhouda [/bib_ref]. After decades of development, the application of laparoscopic techniques in hepatectomy has become more mature. In 2008, the first consensus guidelines for laparoscopic hepatectomy were published in Louisville, signifying the gradual standardization of minimally invasive hepatectomy . Meanwhile, with the advancement of technology, robot-assisted laparoscopic surgical systems have also continuously evolved. In 1997, Himpens et al [bib_ref] Telesurgical laparoscopic cholecystectomy, Himpens [/bib_ref] successfully performed robotic cholecystectomy, and this new type of laparoscopic surgical systems began to be implemented in clinical practice. In 2000, the new generation da Vinci robotic surgical system was officially approved by the United States Food and Drug Administration and was then gradually accepted by surgeons. Robot-assisted laparoscopic surgical systems possess advantages, such as providing a clear, stable, and magnified field of vision, flexibility, it is ergonomic, and has a tremor filter. Specifically, the flexibility and the clear and stable vision have overcome the major disadvantages of conventional laparoscopy. However, the absence of tactile feedback, high cost of mainstream models, and the lack of available surgical instruments, also limit its clinical development and application.
In 2003, Giulianotti et al [bib_ref] Robotic hepatectomy: The Korean experience and perspective, Choi [/bib_ref] [bib_ref] Surgical treatment of hiatus hernia and gastroesophageal reflux disease in complex cases..., Schraibman [/bib_ref] [bib_ref] Radical Robot-Assisted Liver Resection for Alveolar Echinococcosis, Efanov [/bib_ref] [bib_ref] Robotic Left Hepatectomy: A Case Report (First Reported Case of Robotic Hepatectomy..., Goja [/bib_ref] [bib_ref] Robotics in general surgery: Personal experience in a large community hospital, Giulianotti [/bib_ref] [bib_ref] Robotic hepatectomy: Initial experience of a single institution in Singapore, Kam [/bib_ref] reported for the first time the application of robotassisted laparoscopic system in segmental hepatic resection. Since then, countries such as the United States, Europe, China, South Korea, Singapore, Russia, India, and Brazil have reported their own experience on robotic hepatectomy. For example, in China, the Da Vinci robot-assisted laparoscopic surgical system has completed 26765 operations in mainland China as of 2017, which is more than 5 times the number of completed cases in 2014 (4982 operations). The annual growth rate is approximately 45%, with robotic hepatobiliary surgery accounting for approximately 10% of the total number of robotic operations.
Meanwhile, liver surgeons are also attempting to gradually expand the indications of robotic hepatectomy. The earliest cases of robotic hepatectomy included wedge hepatectomy, hemihepatectomy, and extended hemihepatectomy. Some surgeons also utilized robotic hepatectomy to perform segmental resection of posterosuperior segments, liver donor hepatectomy, and the associating liver partition with portal vein ligation for staged hepatectomy [bib_ref] Pioneering Robotic Liver Surgery in Germany: First Experiences with Liver Malignancies, Croner [/bib_ref] [bib_ref] Hepatobilio-pancreatic robotic surgery: Initial experience from a single center institute, Quijano [/bib_ref]. However, due to the complexity of the techniques involved in liver surgery, the implementation and popularization of minimally invasive hepatectomy, including robotic hepatectomy, has remained challenging. In 2014, a nationwide survey on hepatectomy conducted by the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) showed that minimally-invasive hepatectomy accounted for 17.9% of all hepatectomy cases in the United States, of which robotic hepatectomy merely accounted for 5.3% of minimally invasive hepatectomy cases [bib_ref] Predictors and implications of unplanned conversion during minimally invasive hepatectomy: An analysis..., Stiles [/bib_ref]. According to the statistics reported by the Italian National Survey Study Group, between January 1, 1995 and February 28, 2012, the proportion of minimally-invasive hepatectomy was approximately 10.3% . A retrospective analysis of a large surgical oncology program conducted by the University of Pittsburgh Medical Center between 2009 and 2014 (1236 surgeries were analyzed, including 157 robotic liver surgeries) showed that the conversion rate was 3.1%, overall incidence rate of complications was 18.6%, and 90day mortality rate was 1.1%. Among cases of perioperative mortality, 91% were from robotic hepatobiliary procedures. For robotic liver/bile duct procedures, the incidence of complications was 26.1%, mortality rate was 3.2%, and conversion rate was 7.6%, which were all above the overall mean values of robotic procedures [bib_ref] Safety in Numbers: Progressive Implementation of a Robotics Program in an Academic..., King [/bib_ref]. Buchs et al analyzed 884 cases of robotic surgery performed at the University of Illinois Hospital between April 2007 and June 2010 and found that hepatectomy was considered as an advanced robotic procedure, and multivariate analysis showed that advanced procedure was a factor significantly associated with a higher risk for complications.
Although most reports to date show that robotic hepatectomy are safe, feasible and effective, the majority of these studies are case reports and case series from highvolume centers. There are relatively few case-control studies with large sample sizes, and high-quality randomized controlled studies are lacking [bib_ref] Robotic hepatectomy: The Korean experience and perspective, Choi [/bib_ref] [bib_ref] Robotic hepatectomy: Initial experience of a single institution in Singapore, Kam [/bib_ref]. According to the findings of current studies, the effectiveness of robotic hepatectomy is essentially identical to that of open surgery and traditional laparoscopic hepatectomy. However, conclusions on operative time, intraoperative blood loss, conversion rate, incidence of postoperative complications, and overall cost-benefit ratio remain divided in different reports, with the main controversy surrounding the application of certain procedure modalities. These factors severely limit the application of robotic hepatectomy [bib_ref] Robotic hepatectomy: The Korean experience and perspective, Choi [/bib_ref] [bib_ref] Financial Impact of the Robotic Approach in Liver Surgery: A Comparative Study..., Daskalaki [/bib_ref] [bib_ref] Robotic Liver Resection: A Case-Matched Comparison, Kingham [/bib_ref] [bib_ref] Robotic versus laparoscopic resections of posterosuperior segments of the liver: A propensity..., Montalti [/bib_ref] [bib_ref] The safety and efficacy of approaches to liver resection: A meta-analysis, Jackson [/bib_ref] [bib_ref] Use of robotics in liver donor right hepatectomy, Benedetto [/bib_ref]. Some researchers have pointed out that it is undesirable to simply increase economic expenses and aggressively apply robotassisted laparoscopic surgical system for procedures such as living-donor hepatectomy while therapeutic efficacy is not improved [bib_ref] Pushing the frontiers of living donor right hepatectomy, Kim [/bib_ref]. Other opinions point out that as a developing and advancing surgical technology,robotic surgery will become effective enough to allow us to correct any complications with its own techniques [bib_ref] Modern surgeons: Still a Master of His Trade or Just an Operator..., Krawczyk [/bib_ref].
To promote the development and standardization of robotic hepatectomy and improve patient safety, we identified a group of robotic surgeon experts (based on the number of robotic liver surgeries and published papers to screen experts with international influence) to provide clinical statements related to robotic surgery. We searched the online databases for published articles related to robotic surgery; with evidence-based methods. All evidences were graded using the GRADE system and upgraded or downgraded after integrating experts' opinions until a final consensus was reached.
# Methods
We referred to the World Health Organization Handbook for Guideline Development and established the Consensus Steering Group, consisting of five experts in the field from all around the world, with the following missions: To (1) approve the use of PICOs (population, intervention, comparator, outcomes); (2) supervise the literature search and systematic reviews; (3) check the grade of the evidence; (4) draft the final recommendations using a modified Delphi approach; and (5) approve the publication of the consensus. The Consensus Development Group is a multidisciplinary group of 30 experts, including clinicians, methodologists, and economists, with the following missions: To (1) define the scope of the consensus, draft the PICOs; (2) grade the quality of the evidence; (3) draft preliminary recommendations; (4) write the draft consensus; and (5) publish and promote the consensus. The Consensus Secretary Group is responsible for conducting systematic reviews and investigation of patients' views and preferences, along with the Chinese GRADE Center, for providing methodological support. All members of the Consensus Steering Group and the Consensus Secretary Group were required to disclose potential conflicts of interest, which were reviewed by the chairs. No relevant conflicts of interest were noted.
We have held 4 meetings until now on questions focusing on hepato-pancreatobiliary minimally invasive surgery, in Beijing (April, 2017), Lanzhou (October, 2017), Beijing (April, 2018), and Hong Kong (October, 2018) involving more than 60 clinical experts. Finally, we formulated sixteen PICO questions for the consensus. Published articles and conference abstracts were identified from PubMed, Embase, the Cochrane Library. Additionally, we used the GRADE approach to rate the quality of evidence and the strength of recommendation. The experts in the Consensus Development Group voted on the recommendations according to the quality of evidence, patients' views and preferences, and economic evaluation. The GRADE Grid method and Delphi vote were used to formulate the recommendations. Three rounds of voting were conducted. When 70% of the experts approved a recommendation, a consensus was assumed to have been reached.
The formulated recommendations were submitted to 24 experts, who have a broad clinical experience in hepatobiliary minimally invasive surgery. The external reviewers were not involved in the development of the consensus. The Consensus Steering Group discussed the external reviews in a meeting and revised the recommendations based on this feedback [fig_ref] Table 1 2018: International statement on robotic hepatectomy [/fig_ref]. The Consensus Steering Group plans to update the guideline again before 2022. A flow chart describes the process of the consensus developmentRH has similar effectiveness for liver malignancy lesion compared to OH. Regarding the oncological outcome there is no significant difference in the radical resection rate, overall survival rate and recurrence rate between RH and OH.
## Recommendation 1: robotic hepatectomy is as safe and feasible as traditional open hepatectomy. robotic hepatectomy has longer operative time, less
## 2d
3
As a minimally invasive surgery, RH is as safe and feasible as traditional LH. RH has longer operative time, more intraoperative blood loss, and higher cost. RH has similar overall complication rate and LOS compared to OH. Conversion rate of RH would decrease with the experience accumulation.
## 2d 4
As minimally invasive surgery, RH has similar effectiveness for liver malignancy disease compared to LH. Regarding the oncological outcome there is no significant difference in the radical resection rate, overall survival rate and recurrence rate between RH and LH.
## 2d
5
For minor hepatectomy, RH as safe and feasible as LH and OH. RH has longer operative time than LH for minor hepatectomy. The intraoperative blood loss, overall postoperative complication rate and overall cost of robotic minor hepatectomy are comparable to that of laparoscopic minor hepatectomy.
## 2d
6
For major hepatectomy, RH as safe and feasible as LH and OH. RH has longer operative time than LH for major hepatectomy. The intraoperative blood loss, overall postoperative complication rate and overall cost of robotic major hepatectomy are comparable to that of laparoscopic major hepatectomy. There is no significant difference in the operative time, intraoperative blood loss and complication rate between RH and OH for minor hepatectomy.
## Intraoperative blood loss, less length of hospital stays, lower complication rate and lower severe complication rate. the intraoperative blood loss of robotic hepatectomy is comparable to that of open hepatectomy. the level of evidence: low. level of recommendation: weak (grade 2c)
Although the volume of minimally-invasive hepatectomy has been increasing each year since the minimally-invasive technique was applied in hepatectomy in the 1990s, in the United States and Italy, minimally-invasive hepatectomy merely accounts for 17.9% and 10.3% of hepatectomy cases, respectively [bib_ref] Predictors and implications of unplanned conversion during minimally invasive hepatectomy: An analysis..., Stiles [/bib_ref]. When subjected to the technical limitations of conventional laparoscopy, from the perspective of operative difficulty, most procedures are still mainly focused on the less complex minimally invasive wedge resection/segmentectomy (44.9%) and minimally-invasive left lateral sectionectomy (20.3%) . The robot-assisted laparoscopic systems overcome the disadvantages of conventional laparoscopy by providing flexibility and sharp field of vision, but the lack of feedback and high cost have also led to some controversies regarding their applications. Compared with open hepatectomy, robotic hepatectomy is characterized by longer operative time, less intraoperative blood loss, lower blood transfusion rate, less length of hospital stays (LOS), and lower complication rate [bib_ref] Financial Impact of the Robotic Approach in Liver Surgery: A Comparative Study..., Daskalaki [/bib_ref] [bib_ref] Robotic Liver Resection: A Case-Matched Comparison, Kingham [/bib_ref] [bib_ref] Robot-assisted versus open liver resection in the right posterior section, Patriti [/bib_ref] [bib_ref] Oncological and surgical result of hepatoma after robot surgery, Wang [/bib_ref]. Wong et al reported a meta-analysis of 7 retrospective, case-control studies on Although it was previously believed that high cost is a major disadvantage of robotic hepatectomy, only a few reports have compared the cost of the 2 approaches and the conclusions are inconsistent. To date, the report with the largest sample size is published by Sham et al , who compared the cost of robotic hepatectomy (n = 71) and open hepatectomy (n = 88); their study was conducted in at a single center between 2011 and 2015. The results showed that although the perioperative costs were higher in the robotic surgery group (6026 vs 5479$, P = 0.047), the postoperative costs were lower (68570 vs 13425$, P < 0.001), and the total cost was lower (14754 vs 18998$, P < 0.001).
Daskalaki et al [bib_ref] Financial Impact of the Robotic Approach in Liver Surgery: A Comparative Study..., Daskalaki [/bib_ref] Open hepatectomy is currently the standard for surgical treatment of liver cancer.
There is yet to be a large-scale randomized controlled trial comparing the efficacy of robotic hepatectomy and open hepatectomy in malignant tumors, and most studies have been retrospective, case-control studies. Hepatocellular carcinoma is the most common primary malignant tumor of the liver.
In 2013, Lai et al [bib_ref] Robot-assisted laparoscopic liver resection for hepatocellular carcinoma: Short-term outcome, Lai [/bib_ref] reported that among patients with hepatocellular carcinoma who received robotic hepatectomy, the R0 resection rate was 93%. After a median follow up of 14 mo, the 2-year overall and disease-free survival was 94%, and 74%, respectively. In the most recent single-center study published by Wang et al [bib_ref] Oncological and surgical result of hepatoma after robot surgery, Wang [/bib_ref] in 2018, the follow-up results in patients newly diagnosed with hepatocellular carcinoma who underwent robotic hepatectomy (n = 63) and open hepatectomy (n =177) between June 2013 and July 2016 showed that the 2 approaches had no significant differences with regard to the R0 resection rate (93.7% vs 96%, P = 0. [bib_ref] Robotic versus laparoscopic resection of liver tumours, Berber [/bib_ref]
## Recommendation 3: as a minimally invasive surgery, robotic hepatectomy is as safe and feasible as traditional laparoscopic hepatectomy. robotic hepatectomy has longer operative time, more intraoperative blood loss, and higher cost. robotic hepatectomy has similar overall complication rate and length of hospital stays compared to open hepatectomy. conversion rate of robotic hepatectomy would decrease with the experience accumulation. level of evidence: very low. level of recommendation: weak (grade 2d)
Data from the ACS NSQIP showed that between 2000 and 2011, robotic liver surgery accounted for 7.4% of all minimally invasive liver surgeries [bib_ref] A comparison of open and minimally invasive surgery for hepatic and pancreatic..., Ejaz [/bib_ref]. In 2010, Berber et al [bib_ref] Robotic versus laparoscopic resection of liver tumours, Berber [/bib_ref] from the Cleveland Clinic in the United States was the first to compare robotic hepatectomy (n = 9) and conventional laparoscopic hepatectomy (n = 23) at single center. The results showed that the two groups had no significant differences in operative time (259 ± 28 vs 234 ± 17 min, P = 0.6), intraoperative blood loss (136 ± 61 vs 155±54 mL), and resection margin (11±8 vs. 14 ± 10 mm). Guan et al [bib_ref] Clinical efficacy of robot-assisted versus laparoscopic liver resection: A meta analysis, Guan [/bib_ref] reported a metaanalysis of 13 retrospective, case-control studies on robotic and laparoscopic hepatectomy conducted between 2010 and 2017. The analysis evaluated the intraoperative and short-term outcome in 435 cases of robotic hepatectomy and 503 cases of conventional laparoscopic hepatectomy in Italy, China, France, the United States, Korea, Germany, and Belgium. The results showed that compared with conventional laparoscopic hepatectomy: (1) Intraoperative parameters indicated that robotic hepatectomy had a longer operative time (MD = 65.49 min; 95%CI: 42.00, 88.98) and increased intraoperative blood loss (MD = 69.88 mL; 95%CI: -27.11, 112.65), but there were no significant differences in blood transfusion rate [odds ratio (OR) = 0.96; 95%CI: 0.47, 1.97] and conversion rate (OR=0.75; 95%CI: 0.45, 1.25); (2) there were no statistically significant differences in the overall complication rate (OR = 0.80; 95%CI: 0.56, 1.14), major complication rate (Clavien-Dindo grade III or higher [bib_ref] Classification of surgical complications: A new proposal with evaluation in a cohort..., Dindo [/bib_ref] (OR = 1.0; 95%CI: 0.49, 2.06), R1 resection rate (OR = 1.03; 95%CI: 0.41, 2.55), and LOS (MD = 0.12 d; 95%CI: -0.52, 0.77); (3) the overall hospital cost of robotic hepatectomy was higher than that in the laparoscopic group (MD = 4.24, 95%CI: 3.08, 5.39); (4) subgroup analysis on robotic hepatectomy and conventional laparoscopic hepatectomy conducted after 2010 showed that the robotic group had a lower conversion rate (OR = 0.34; 95%CI: 0.13, 0.87), and there were no statistically significant differences in operative time and intraoperative blood loss.
The meta-analyses published by Qiu et al [bib_ref] A systematic review of robotic-assisted liver resection and meta-analysis of robotic versus..., Qiu [/bib_ref] and Montalti et al [bib_ref] Outcomes of robotic vs laparoscopic hepatectomy: A systematic review and meta-analysis, Montalti [/bib_ref] had also drawn similar conclusions. In addition, the meta-analysis published by Hu et al in 2018 that analyzed the efficacy of robotic surgery in liver tumors also obtained similar conclusions. The analysis also found that the robotic group had a longer postoperative fasting time (weighted MD = 1.2, 95%CI: 0.24, 2.17), but the two groups showed no significant difference postoperative mortality (OR = 0.67, 95%CI: 0.16, 2.83). Subgroup analyses in some studies had suggested that the robotic group may be superior to conventional laparoscopic surgery when used for major hepatectomy or tumors localized in the superior and posterior segments . In 2018, Marino et al compared laparoscopic right hepatectomy (n = 20) and robotic right hepatectomy (n = 14) and found that the robotic group had shorter operative time than the laparoscopic group (425 ± 139 vs 565.18 ± 183.73 min, P = 0.022), whereas intraoperative blood loss, postoperative complications, LOS, and surgical costs were not significantly different between the groups.
Although the flexibility and the clarity and stability of the visual fields are more superior in the robotic laparoscopic surgical system than in conventional laparoscopic surgery, minimally-invasive hepatectomy is still currently predominated by conventional laparoscopy [bib_ref] Predictors and implications of unplanned conversion during minimally invasive hepatectomy: An analysis..., Stiles [/bib_ref]. Studies have indicated that compared with conventional laparoscopic hepatectomy, robotic hepatectomy has a longer operative time, increased intraoperative blood loss, and a higher cost, whereas no significant differences are observed with regard to blood transfusion rate, R0 resection rate, LOS, overall complication rate, and severe complication rate between the two groups. With the accumulation of surgical experience, the conversion rate of the robotic group gradually decreases.
## Recommendation 4: as minimally invasive surgery, robotic hepatectomy has similar effectiveness for liver malignancy disease compared to laparoscopic hepatectomy. regarding the oncological outcome there is no significant difference in the radical resection rate, overall survival rate and recurrence rate between robotic hepatectomy and laparoscopic hepatectomy. level of evidence: very low. level of recommendation: weak (grade 2d)
Khan et al evaluated the long-term oncologic outcomes of patients undergoing robotic liver surgery (n = 61) for primary hepatobiliary malignancies between 2006 and 2016 and showed that the R0 resection rates of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and gallbladder carcinoma were 94%, 68%, and 81.8%, respectively. The median follow-up time was 75 mo (95%CI: 36,113), 5-year overall survival and disease-free survival were 56% and 38%, respectively, and the 3year survival rates of hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and gallbladder cancer were 94%, 65%, and 49%, respectively.
Hu et al [bib_ref] Effectiveness and safety of robotic-assisted versus laparoscopic hepatectomy for liver neoplasms: A..., Hu [/bib_ref] published a meta-analysis of 17 retrospective, case-control studies on robotic and laparoscopic hepatectomy conducted between 2010 and 2017. The analysis evaluated the intraoperative and short-term outcomes in 487 cases of robotic hepatectomy and 902 cases of conventional laparoscopic hepatectomy in Italy, China, France, the United States, Korea, Germany, and Belgium. The results showed that compared with conventional laparoscopic hepatectomy, there was no significant difference in R0 resection rate (OR = 2.20, 95%CI: 0.78, 6.23) and R1 resection rate (OR = 1.10, 95%CI: 0.45, 2.73) between two groups. The meta-analyses published by Qiu et al [bib_ref] A systematic review of robotic-assisted liver resection and meta-analysis of robotic versus..., Qiu [/bib_ref] , Guan et al [bib_ref] Clinical efficacy of robot-assisted versus laparoscopic liver resection: A meta analysis, Guan [/bib_ref] and Montalti et al [bib_ref] Outcomes of robotic vs laparoscopic hepatectomy: A systematic review and meta-analysis, Montalti [/bib_ref] had also drawn similar conclusion. As there are few comparative studies on long-term prognosis, there is no meta-analysis report on the long-term prognosis of robotic hepatectomy and laparoscopic hepatectomy. Lai et al reported a single-center study evaluating the long-term prognosis of patients with liver cancer treated with robotic hepatectomy (n = 100) and conventional laparoscopic hepatectomy (n = 35) and found that compared with conventional laparoscopic surgery, the robotic hepatectomy for liver cancer had no statistically significant differences in R0 resection rate (96% vs 91.4%, P = 0.72), 5-year overall survival (65% vs 48%, P = 0.28), and 5-year disease-free survival (42% vs 38%, P = 0.65). The report from Troisi [bib_ref] Robot assistance in liver surgery: A real advantage over a fully laparoscopic..., Troisi [/bib_ref] evaluated the long-term prognosis of patients with colorectal cancer liver metastases who underwent robotic hepatectomy (n = 24) and conventional laparoscopic hepatectomy (n = 108), and the results showed that the 1year and 3-year disease-free survival rates were 79% and 62% in the robotic group and 81% and 41% in the open hepatectomy group.
## Recommendation 5: for minor hepatectomy, robotic hepatectomy as safe and feasible as laparoscopic hepatectomy and open hepatectomy. robotic hepatectomy has longer operative time than laparoscopic hepatectomy for minor hepatectomy. the intraoperative blood loss, overall postoperative complication rate and overall cost of robotic minor hepatectomy are comparable to that of laparoscopic minor hepatectomy. level of evidence: very low. level of recommendation: weak (grade 2d)
Based on the published articles, the minimally-invasive hepatectomy is mainly used in minor hepatectomy, which includes resections of the left lateral lobes and local liver lesions. Tsilimigras et al systematically reviewed 31 comparative studies between 2008 and 2017 that included a total of 1148 patients and found that robotic minor hepatectomy accounted for 72.7% of all robotic hepatectomy cases, with a mean operative time of 242.2 ± 89 min, intraoperative blood loss of 317.1 ± 331 mL, conversion rate of 8.1%, mean postoperative hospital stay of 6.1 ± 2.9 d, and incidence of postoperative complications of 14.8%. The meta-analysis published by Guan et al [bib_ref] Clinical efficacy of robot-assisted versus laparoscopic liver resection: A meta analysis, Guan [/bib_ref] included 5 retrospective, case-control studies on robotic and laparoscopic liver surgeries conducted between 2010 and 2017, including 95 cases of robotic minor hepatectomy and 163 cases of conventional laparoscopic minor hepatectomy. The evaluation of intraoperative and short-term postoperative outcomes showed that compared with conventional laparoscopic minor hepatectomy, robotic minor hepatectomy had a longer operative time (MD = 50.29 min; 95%CI: 10.52, 90.05), but there were no significant differences in perioperative outcomes such as intraoperative blood loss and complications. Laparoscopic hepatectomy is currently recommended for left lateral segmentectomy . Salloum et al [bib_ref] Minimally invasive left lateral sectionectomy robot vs laparoscopy, Salloum [/bib_ref] published a single-center study comparing robotic left lateral segmentectomy (n = 16) and laparoscopic left lateral segmentectomy (n = 80) and showed that the 2 groups had no statistically significant differences in operative time (190 vs 162 min, P = 0.10), intraoperative blood loss (247±239 vs 206 ± 205 mL, P =0.50), overall complication rate (12% vs 11%, P = 0.77), LOS (7 ± 8 vs 6 ± 4 d, P = 0.74), and total cost (5522€ vs 6035€, P = 0.70).
## Recommendation 6: for major hepatectomy, robotic hepatectomy as safe and feasible as laparoscopic hepatectomy and open hepatectomy. robotic hepatectomy has longer operative time than laparoscopic hepatectomy for major hepatectomy. the intraoperative blood loss, overall postoperative complication rate and overall cost of robotic major hepatectomy are comparable to that of laparoscopic major hepatectomy. there is no significant difference in the operative time, intraoperative blood loss and complication rate between robotic hepatectomy and open hepatectomy for minor hepatectomy. level of evidence: very low. level of recommendation: weak (grade 2d)
Nguyen et al reviewed the current status of laparoscopic hepatectomy in 127 studies worldwide. Based on the definition of major hepatectomy stated in the Fukuoka Declaration , they found that major hepatectomy accounted for 17.3% of all laparoscopic hepatectomy cases. In view of the disadvantages of conventional laparoscopy such as limited flexibility, fulcrum effect, and poor visual field stability, it is believed that robotic hepatectomy may compensate the limitations of conventional laparoscopic surgery in major hepatectomy, such as hemi-hepatectomy and extended hepatectomy, which require precise dissection of the porta hepatis . Tsilimigras et al systematically reviewed 31 comparative studies between 2008 and 2017 and found that robotic major hepatectomy (n = 115) accounted for 27.3% of all robotic hepatectomy cases, with a mean operative time of 403.4 ± 107.5 min, intraoperative blood loss of 543.4 ± 371 mL, conversion rate of 8.6%, mean LOS of 10.5 ± 4.8 d, and complication rate of 17%.
Giulianotti et al [bib_ref] Totally robotic right hepatectomy: Surgical technique and outcomes, Giulianotti [/bib_ref] reviewed 24 cases of right hepatectomy conducted by a single surgical team between 2005 and 2010. The results showed that the mean operative time was 337 min, mean intraoperative blood loss was 457 mL, blood transfusion rate was 12.5%, conversion rate was approximately 4.2%, and incidence rate of postoperative complications was 25%. No perioperative mortality occurred, and the perioperative outcome was similar to that of laparoscopic hepatectomy conducted during the same period. Spampinato et al [bib_ref] Perioperative outcomes of laparoscopic and robot-assisted major hepatectomies: An Italian multiinstitutional comparative..., Spampinato [/bib_ref] compared robotic hemi-hepatectomy (n = 25) and laparoscopic hemi-hepatectomy (n = 25) in their study, which conducted in 2 centers in Italy and Belgium between 2009 and 2012. The results showed that the 2 groups had no statistically significant differences in operative time (430 vs 360 min, P = 0.070), intraoperative blood loss (250 vs 400 mL, P = 0.95), conversion rate (4% vs 4%, P =1), overall complication rate (16% vs 36%, P = 0.2), R0 resection rate in malignant tumors (100% vs 91%, P = 0.49), and LOS (8 vs 7 d, P = 0.48). According to the definitions of minimally-invasive major hepatectomy in the Fukuoka Declaration and Louisville Declaration , when considering the difficulty of the surgery, resections of lesions in the superior posterior segments of the liver should also be classified as major hepatectomy. Patriti et al [bib_ref] Robot-assisted versus open liver resection in the right posterior section, Patriti [/bib_ref] compared the efficacy of robotic hepatectomy (n = [bib_ref] Safety in Numbers: Progressive Implementation of a Robotics Program in an Academic..., King [/bib_ref] and open hepatectomy for the resection of liver segments 6 and 7 in 2 centers in Italy. Compared with open hepatectomy, robotic hepatectomy had a longer operative time (303 ± 132.3 vs 233.9 ± 81 min, P = 0.002). There were no statistically significant differences with regard to the volume of intraoperative blood loss (376.3 ± 410 vs 457.5 ± 365.5 mL, P = 0.40), overall complication rate (15.8% vs 13%, P = 0.70), severe complications rate (5.3% vs 1.4%, P = 0.80), and LOS (6.7 ± 3 vs 7.9 ± 4.4 d, P = 0.60).
## Procedure should only be performed by experienced surgeons, and the true benefits of robotic donor hepatectomy need further investigation in the future. level of evidence: very low. level of recommendation: weak (grade 2d)
In 2012, Giulianotti et al reported for the first robotic living-donor hepatectomy of the right inferior lobe. Compared with conventional laparoscopic surgery, the robotic surgical system provided a magnified and stable 3D field of vision with higher accuracy in intraoperative suture during the living-donor hepatectomy . At present, countries such as Italy, South Korea, China, and India have carried out robotic livingdonor hepatectomy, but no report has been published on robotic liver transplantation [bib_ref] Robotic hepatectomy: The Korean experience and perspective, Choi [/bib_ref] [bib_ref] Liver transplantation in india-where are we? Single team experience of 131 pediatric..., Mujeeb [/bib_ref].
The only comparative study on robotic living-donor hepatectomy and standard open living-donor hepatectomy was published by Chen et al , which was a retrospective, case-control study on 13 cases of robotic hepatectomy and 54 cases of open hepatectomy conducted at a single center between May 2013 and August 2015. The results showed that the robotic group had a longer operative time (596 vs 383 min, P < 0.001), reduced dosage of postoperative analgesics (0.58 vs 0.84 ng/kg, P = 0.03), and a higher postoperative cost (13436$ vs 5019.1$, P < 0.001), but there were no significant differences in intraoperative blood loss, LOS, and overall complications. No open conversion was required in the robotic group. Even though robotic livingdonor hepatectomy is considered safe and feasible based on published case and case series reports and comparative studies, it does not show significant superiority in therapeutic efficacy compared with open and conventional laparoscopic approaches. Although robotic living-donor hepatectomy is technically safe and feasible, critics have pointed out that minimally-invasive surgery for living-donor hepatectomy cannot be truly considered as "minimally-invasive surgery", as it merely moves the midline incision to the lower abdomen at the cost of increasing 3 to 5 small incisions for port sites. Therefore, it should be considered as "minimal incision surgery" [bib_ref] Pushing the frontiers of living donor right hepatectomy, Kim [/bib_ref]. Furthermore, the complex anatomy of the liver, together with the absence of inflow control and the need for a short ischemic time, may result in a higher risk for both donor and graft safety .
[fig] Figure 1: Flow chart describes the process of the consensus development. robotic and open hepatectomy conducted between 2013 and 2016. The analysis evaluated the intraoperative and short-term postoperative outcome in 329 cases of robotic hepatectomy and 426 cases of open hepatectomy in Italy, the United States, Switzerland, and China. The results revealed that compared with open hepatectomy: Regarding intraoperative parameters, robotic hepatectomy had a longer operative time [mean difference (MD) = 61.47 min; 95% confidence interval (CI): 7.03, 115.91], but there were no significant differences in intraoperative blood loss (MD = 220.44 mL; 95%CI: -447.47, 6.58), blood transfusion rate [risk ratio (RR) = 0.78; 95%CI: 0.33, 1.83], and Pringle maneuver usage (RR= 0.98; 95%CI: 0.09,11.34). The mean conversion rate of patients in the robotic surgery group in these studies was 4.4%; regarding short-term postoperative outcome, robotic hepatectomy led to shorter LOS (MD = -2.57 d; 95%CI: -3.31, -1.82), lower overall complications rate (RR = 0.63; 95%CI: 0.46, 0.86), and lower major (Clavien-Dindo grade III or higher[67] ) complication rate (RR = 0.45; 95%CI: 0.22, 0.94). [/fig]
[table] Table 1 2018: International statement on robotic hepatectomy [/table]
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The robotic surgical system has been applied in liver surgery. However, controversies concerns exist regarding a variety of factors including the safety, feasibility, efficacy, and cost-effectiveness of robotic surgery. To promote the development of robotic hepatectomy, this study aimed to evaluate the current status of robotic hepatectomy and provide sixty experts’ consensus and recommendations to promote its development. Based on the World Health Organization Handbook for Guideline Development, a Consensus Steering Group and a Consensus Development Group were established to determine the topics, prepare evidence-based documents, and generate recommendations. The GRADE Grid method and Delphi vote were used to formulate the recommendations. A total of 22 topics were prepared analyzed and widely discussed during the 4 meetings. Based on the published articles and expert panel opinion, 7 recommendations were generated by the GRADE method using an evidence-based method, which focused on the safety, feasibility, indication, techniques and cost-effectiveness of hepatectomy. Given that the current evidences were low to very low as evaluated by the GRADE method, further randomized-controlled trials are needed in the future to validate these recommendations.
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Expert consensus on prevention and control of COVID-19 in the neurological intensive care unit (first edition)
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Expert consensus on prevention and control of COVID-19 in the neurological intensive care unit (first edition)
# Introduction
Since December 2019, an outbreak of pneumonia caused by a new coronavirus infection in Wuhan city, Hubei Province, has rapidly spread worldwide. The WHO has officially named the pathogen as 'severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)'. SARS-CoV-2 mainly attacks the respiratory system, but may also affect multiple other organs including digestive, cardiovascular, haematological, urinary and neurological systems. The WHO has since declared the pandemic as COVID-19. In view of its high transmissibility, general susceptibility and lack of targeted treatment, the National Health Commission of People's Republic of China announced that COVID-19 is to be added to the 'Law of the People's Republic of China on the Prevention and Treatment of Infectious Diseases' as Class B infectious disease and shall be managed as Class A infectious disease on 20 January 2020.
The outbreak occurred in the winter and spring, seasons with high incidence of cerebrovascular disease. The middle-aged and elderly population with high incidence of cerebrovascular and chronic diseases are also at high risk of getting COVID-19 and often severe. Some patients with COVID-19 may show neurological symptoms in the early stage, while symptoms of pneumonia such as fever and dry cough are mild or even asymptomatic, which can be easily misdiagnosed. Therefore, even strict screening is done before admission, it is impossible to completely avoid inadvertent transmission and nosocomial infection of a patient with atypical COVID-19 to a ward. Nosocomial infection is an infection transmitted by healthcare personnel. When prevention is inadequate, the rate of nosocomial infection can reach 41%. [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] The neurological intensive care unit (NCU) is a closed environment and has a high proportion of critically ill patients with open airways; therefore, the risk of nosocomial infections is significantly higher. It is essential to effectively identify patients with COVID-19 and implement steps to protect the safety of medical staff and other hospitalised patients.
In order to enhance the pertinent, effective and accurate management of patients with COVID-19 in the NCU, we present this 'Expert consensus on prevention and control of COVID-19 in the neurological intensive care unit'. This consensus was based on the Guidelines for the prevention and control of the novel coronavirus infections in medical institutions (first edition),and Diagnosis and treatment of the novel coronavirus pneumonia (trial version 7) 3 published by the National Health Commission of PRC, and the latest literature and clinical experience during this pandemic. We aimed to discuss COVID-19 prevention and control for NCU patients who have undiagnosed COVID-19 after routine prehospital screening, as well as treatment of NCU patients with suspected or confirmed COVID-19. This consensus will be updated as needed when more information is available.
## Overview of the covid-19
Aetiological characteristics SARS-CoV-2 belongs to the β-type novel coronavirus and exists in the form of RNA.
## Open access
It is highly homologous to that of bat coronavirus with an overall genome sequence similarity of 96.2%, and has 79.5% sequence homology to SARS coronavirus. [bib_ref] A pneumonia outbreak associated with a new coronavirus of probable bat origin, Zhou [/bib_ref] SARS-CoV-2 is sensitive to ultraviolet light and heat. Heat at 56°C for 30 min, ether, 75% ethanol, chlorinecontaining disinfectant, peroxyacetic acid, chloroform and other fat solvents can effectively inactivate viruses, but not chlorhexidine.
## Epidemiological characteristics
## Source of infection
Mainly patients with COVID-19. Asymptomatic patients may also be source of infection.
## Route of transmission
Main transmission routes are respiratory droplets and contact. Aerosol transmission with prolonged exposure to high concentrations in a relatively closed environment is possible.
## Susceptible population
All population is generally susceptible.
## Clinical characteristics and management clinical characteristics
The incubation period of COVID-19 is between 1 and 14 days, generally 3-7 days, and the most extended period was about 24 days. Patients with COVID-19 often have a fever, dry cough and fatigue as the main symptoms. Some patients present with nasal congestion, runny nose, throat pain, diarrhoea and conjunctivitis. Neurological symptoms, such as headache, dizziness and muscle pain, have been observed. Their blood pressure may suddenly surge.
According to the severity of symptoms, clinical presentation can be divided into mild, common, severe and critical stages. Mild patients have light symptoms with normal pulmonary imaging. The common type has fever and respiratory symptoms with inflammatory changes on imaging. In severe cases, dyspnoea usually occurs within 1 week of onset, and in critical cases, it quickly progresses to acute respiratory distress syndrome, shock, refractory metabolic acidosis, electrolyte disturbance and coagulation abnormalities, leading to multiorgan failure.
## Laboratory examination
White blood cell counts are normal or decreased with lymphopenia in the early stages; most patients had elevated C reactive protein and erythrocyte sedimentation rate, but normal procalcitonin; some patients had increased liver enzymes, creatine and myoglobin. In severe cases, D-dimer is increased, with progressive lymphopenia and thrombocytopenia. The SARS-CoV-2 nucleic acid can be detected in specimens such as nasopharyngeal swabs, sputum, lower respiratory tract secretions, blood and stool.
## Imaging examination
Early chest CT may show multiple small patchy shadows and interstitial changes, apparent on pulmonary bandaris. It can develop into ground-glass opacities and pattern of infiltration. In severe cases, lung consolidation may occur; however, pleural effusions are rare.
diagnosis Based on 'Diagnosis and treatment of the novel coronavirus pneumonia (Trial version 7)' 3 published by the National Health Commission of the People's Republic of China, and in combination with a comprehensive analysis of epidemiological history and clinical manifestations, this is the current way of diagnosing COVID-19 infection:
Suspected cases a. Epidemiological history: travel history to or living history in Wuhan city and surrounding areas, or other communities with confirmed cases within 14 days before onset; history of direct contact with patients with COVID-19 (nucleic acid test positive) within 14 days before onset; history of direct contact with patients with fever or respiratory symptoms from Wuhan city and surrounding areas, or other communities with confirmed cases within 14 days before onset; clustered incidence. b. Clinical manifestations: fever and/or respiratory symptoms; with the above-mentioned imaging features of COVID-19; normal or decreased white blood cell counts with lymphopenia in the early stages. A patient should be suspected of COVID-19 if he/ she meets any one of the epidemiological criteria and two of the clinical criteria; if there is no definite epidemiological history, he/she must meet all three clinical manifestations.
## Confirmed cases
Suspected cases with one of the following aetiological evidence: a. Positive real-time fluorescent reversetranscription-PCR test of SARS-CoV-2 nucleic acid. b. Highly homologous viral gene sequencing to known SARS-CoV-2. c. Positive novel coronavirus-specific immunoglobulin M (IgM) and IgG antibodies; serum novel coronavirusspecific IgG antibodies change from negative to positive or antibody titre in the recovery period is four times or higher than the acute period.
## Treatment principles
Determine or change the treatment site according to the condition Suspected and confirmed cases should be isolated and treated in designated hospitals with effective isolation and protective conditions. Suspected patients should be isolated in single-bed rooms. Confirmed patients can be admitted to the same ward with multiple beds.
## Treatment protocol
In general, comprehensive individualised treatment strategies are adopted, including symptomatic supportive care, oxygen therapy and traditional Chinese medicine. If there is no clear evidence of bacterial infection, routine use of antibiotics is not recommended. Patients with a disease course of more than 1 week should be concerned for secondary bacterial and fungal infections. Antiviral treatment can include α-interferon, lopinavir, ribavirin, chloroquine phosphate and abidor. Be aware of drug interactions. It is not recommended to administer three or more antibiotics at the same time, and the course of each medication should be less than 10 days. A phase III randomised double-blind clinical trial of remdesivir is currently underway. The preliminary report of compassionate-use remdesivir showed clinical improvement rate of 68%. [bib_ref] Compassionate use of Remdesivir for patients with severe Covid-19, Grein [/bib_ref] For severe or critically ill patients, clinicians should pay attention to the prevention of complications, secondary infections, and provide organ supportive therapy when needed, such as continuous renal replacement therapy and the use of extracorporeal membrane oxygenation.Severe patients can be on short-term glucocorticoids, although currently there is no general agreement of usage. Plasma treatment is suitable for severe or critically ill patients and patients with rapid progress.
## Challenges and countermeasures of covid-19 management in the ncu ncu patient and environmental difficulties
In the COVID-19 epidemic region, middle-aged and elderly people are the main population of severe and critically ill patients, especially those with chronic diseases such as hypertension and diabetes mellitus. This population is also a high-risk group for cerebrovascular disease. The abnormal increase of D-dimer in critically ill COVID-19 patients is not uncommon, which greatly increases the probability of embolic vascular events. It has been suggested that early application of anticoagulant therapy can be used in patients with severe COVID-19 to improve outcome; however, no specific inclusion or exclusion criteria have been pointed out so far.Clinically, patients with COVID-19 can concurrently have acute ischaemic stroke. 9 SARS-CoV-2 can bind to the ACE2 receptor of vascular endothelial cells, 10 resulting in abnormally increased blood pressure in hypertensive patients, increasing the risk of intracranial haemorrhage. In addition, patients with severe COVID-19 often have thrombocytopenia, which may increase their risk of developing intracerebral haemorrhage. The NCU is an enclosed environment. Many critically ill patients have open airways that can produce high density of the formed droplets/aerosol per unit volume in the air. Many NCU patients are in the state of either unconsciousness or paralysed with compromised immunity. They are prone to nosocomial infections from multidrug-resistant bacteria. Moreover, due to coma and encephalopathy or aphasia, patients cannot describe their symptoms during sickness, making it more difficult to distinguish between aspiration pneumonia and COVID-19. Once a case of COVID-19 appears in the NCU, serious transmission will happen if the protective measures are not in place.
## Challenges and countermeasures
Some middle-aged or elderly critically ill COVID-19 patients may only show moderate to low or even no fever. Patients may present with complaints of common neurological symptoms such as stroke, headache, dizziness, delirium and so on. It is easy to miss the diagnosis of COVID-19, and rapid diagnosis is especially difficult during the incubation period. For patients with acute ischaemic stroke who need intravenous thrombolysis and/or endovascular treatment, and patients who need invasive intracranial haematoma evacuation, how to make quick treatment decision while avoiding being infected because of admitting a patient with COVID-19 in the NCU is a huge challenge.
COVID-19 epidemic has had an impact on the treatment of critically ill neurological patients. For example, in Hubei province, especially Wuhan city, due to restrictions on travel and overloading of the public emergency system, the onset-to-hospital time has been greatly prolonged. Due to the need to contain and prevent crossinfection, the stroke centre green pathway and NCU medical staff reassignment may affect other treatment process. The stroke centre green pathway is designed to promote timely treatment, enhance quality of care and optimise patient outcomes for patients who suffered acute stroke. In order to reduce the risk of nosocomial infections, in principle, clinicians should minimise invasive procedures on patients with suspected or confirmed COVID-19 if possible. Therefore, during the pandemic, COVID-19 prevention and control should be our primary target. Acute and critically ill patients should be given timely treatment after completing a full screening and risk assessment for COVID-19 to avoid transmission and ensure the safety of non-COVID-19 patients and medical staff.
nCu mAnAgemenT prInCIples durIng The CovId-19 epIdemIC Triage process based on patient classification Classifying patients and their management According to the official regulations, patients with acute neurological and critical illness should be managed according to classification. All critically ill neurological patients who are diagnosed with or suspected of COVID-19 should be treated at designated hospitals assigned by the local government. All critically ill neurological patients with fever should be screened for COVID-19 according to the requirements of epidemic prevention and control. After being diagnosed with COVID-19, they should be transferred to a designated hospital as soon as possible.
In non-epidemic areas, critical patients excluded of COVID-19 should be treated routinely and be admitted
## Open access
to the NCU of the hospital where they are admitted. Whether a negative SARS-CoV-2 nucleic acid test result is needed should be determined by the local hospital.
Patients cannot be ruled out of COVID-19 if they meet the following conditions: (1) negative for epidemiological history, fever and/or respiratory symptoms, blood tests and chest CT. Before the test results are available, the patient needs to be temporarily quarantined in a single room. Patients who suffered acute stroke going through stroke care green pathway can be treated first under certain protective conditions, then isolated in a single room and wait for nucleic acid test results; (2) negative for epidemiological history, but with one or two of the three COVID-19 clinical manifestations. Even if the nucleic acid test is negative, the patient must be treated in a single room under observation for 3 days, with at least two consecutively negative nucleic acid tests (interval greater than 24 hours) and no lymphopenia. Re-examine chest CT after 24-72 hours if necessary. If CT imaging does not show typical COVID-19-related changes, the patient can be transferred to the general ward. When not sure where to triage, consult the expert group immediately, and subsequent treatment should be carried out according to the expert group's recommendation.
In areas of high incidence, due to the relatively large number of asymptomatic patients or patients in the incubation period, all critically ill patients can be regarded as patients with suspected COVID-19.
## Patient admission process
During the epidemic, all patients who come to the clinic should first undergo preliminary COVID-19 assessment, and those suspected of COVID-19 should enter through the fever clinic (figure 1). The acute stroke green pathway and the neurological emergency room (including the consultation room, CT/MRI rooms, interventional operation room and so on) should be strictly separated from the general emergency department and fever clinics. In order to avoid omissions in the preliminary assessment, the neurological physician should ask the patient and family members again if they have travel or residential history from communities with positive case reports, whether they have direct contact with patients diagnosed or suspected COVID-19 and whether they have symptoms related to COVID-19. If the patient is positive for any of the above, the patient should be transferred to a fever clinic and follow their stroke treatment process and go through stroke care green pathway. The neurologist can be an on-site consultant or perform a consultation through telephone. If a patient comes from a nonhigh-incidence area, a routine chest CT should be done while going through the acute stroke care green pathway. If conditions permit, 'emergency transitional screening area' should be set up. Patients receiving thrombolysis and thrombectomy should avoid entering the NCU directly and be placed in the transitional ward for treatment. Nucleic acid tests should be arranged as soon as possible, and triage to the appropriate ward based on the results (see classified management).
## Ward layout ward isolation
In order to avoid cross-transmission inside the hospital between newly admitted asymptomatic patients (or patients in the latent period) and other patients or the medical staff, it is recommended that the NCU be set up as individual private rooms to facilitate isolation. It can also be modified according to the local standards to achieve the principle of 'three areas and two channels'. There are three areas, namely, sterile, semicontaminated and contaminated areas. Two channels are for medical staff and patient, respectively. If possible, units can be transformed into negative pressure single wards.
Strictly limit the access to the hospital and ICU. Suspend family member staying and visitation. The entrance of the NCU should be guarded and they are responsible for checking temperature and recording medical staff entering the ward.
## Environment and disinfection of equipment
Open the windows two to four times a day for more than 30 min each time in occupied rooms. If necessary, use fans to mechanically enhance air flow, or use a circulating ultraviolet air disinfection machine for disinfection. Disinfect unoccupied rooms by ultraviolet light once a day for more than 1 hour each time. Windowless rooms and storage rooms should be regularly ventilated and disinfected with ultraviolet light. Due to the positive pressure generated by the laminar flow, the contaminated air may be transmitted to the clean area. Therefore, the laminar flow system should be closed in high-incidence areas, and the windows should be opened for ventilation. The floor and corridors of the ward can be wiped or sprayed with disinfectant (chlorine concentration of 1000 mg/L) twice a day. If the surface and the floor of environmental objects are contaminated with patient excretions, secretions, vomit and so on, first, remove the visible pollutant with disposable absorbent materials such as paper towels; second, cover the area with a towel soaked in 2000 mg/L chlorine disinfectant for 30 min; and third, wipe clean. The surfaces of the frequently contacted objects (such as bed rails, bed head boards, bed end boards, tables, pagers, monitors, door handles) in the wards should be wiped and disinfected two to three times a day with a 1000 mg/L chlorine disinfectant. Stethoscopes, infusion pumps, sphygmomanometers and other commonly used items should be thoroughly wiped and disinfected with a 1000 mg/L chlorine disinfectant or paper towels containing peracetic acid and hydrogen peroxide after each use. 11
## Pollutant disposal
In hospitals equipped with a sewage treatment system, patient excretions, secretions, vomit and so on can be directly discharged into the sewage pond after increasing Open access the dosage of sewage disinfectant to ensure that the residual chlorine content is greater than 6.5 mL/L. Bed sheets and quilts used by patients with suspected or confirmed COVID-19 can be sterilised by circulating steam or boiling for 30 min; or soaked in 500 mg/L chlorine-containing disinfectant for 30 min and then routinely sterilised; or sealed with orange-soluble packaging exclusively used for medical supplies and transported to the washing centre (keeping a record of handover). After each discharge, the ward should be thoroughly disinfected. [bib_ref] Possible central nervous system infection by SARS coronavirus, Lau [/bib_ref] medical personnel self-protection Hospitals and departments should conduct COVID-19 education and the practice of isolation and protection for medical personnel. To balance the work-life during this crisis, a shift changing system should be implemented.
Encourage all to exercise regularly and pay attention to nutritional support. Medical staff should monitor their body temperature every day. If fever or other suspected symptoms occur, immediate observation and isolation should be implemented. Basic protective equipment for the medical staff include masks/respirators, goggles, masks, disposable protective clothing/isolating suits and gloves, and so on. Appropriate protective equipment should be selected based on the need, exposure level and exposure time. During the current pandemic, NCU medical personnel should use level 2 protection (scrubs, isolation gowns, medical protective masks, goggles/protective screens, disposable round caps and latex gloves, overshoes if necessary). Level 3 protection (scrubs, isolation gowns, overshoes, medical protective Open access masks, full-face protective masks or full-face respirator, disposable round cap and latex gloves) should be used when doing procedures such as tracheal intubation/ extubation and sputum suction. In non-epidemic areas, NCU medical personnel should routinely wear surgical masks (valid for 4 hours), disposable caps and gloves, and strictly implement the hand hygiene practice. management of artificial airway and mechanical ventilation Sputum suction in NCU will cause aerosol, which is a highrisk procedure during the COVID-19 outbreak. Standardising airway management operation techniques and processes is essential in order to prevent cross-infection.
## Airway management requirements for suspected or confirmed covid-19 cases
According to the Recommendations for airway management in severe novel coronavirus pneumonia patients (trial),at least level 2 protection should be implemented when managing the airway of patient with suspected or confirmed COVID-19. For bronchoscopy, tracheal intubation/extubation, tracheotomy, sputum suction, and respiratory tract sampling and operations that may produce large amount of airway secretions, droplets and aerosols, level 3 protection should be implemented.
When contacting a patient with suspected or confirmed COVID-19 on non-invasive ventilation, medical staff should strictly wear protective equipment, keep patient isolated in a single room with negative pressure, reduce unnecessary exposure and strictly monitor the medical staff for signs and symptoms of infection. We recommend using a double-arm circuit ventilator with an add-on virus/bacterial filter and a disposable line. The line and the filter should be managed as medical waste. The preferred protective equipment includes a helmet, followed by a full-face mask or a well-sealed mask, not a regular mask. The patient's airway is connected via a virus bacterial filter placed between the mask and the leak valve. It is recommended that the mask be put on first and then turn on the machine; also, turn off the ventilator before removing the mask.
The protective principle of artificial airway is to minimise the risk of patients coughing and spreading of droplets. Tracheal intubation is preferred for the establishment of artificial airways. It is recommended to use a video electronic laryngoscope or a fibre bronchoscope to guide intubation; a bronchoscope with a display screen is preferred. The indication for tracheotomy should be carefully evaluated from a protective perspective. During tracheal intubation, personal protective equipment should be worn according to the level 3 protection standard, preferably in a negative pressure ward, and a power air purifier turned on if possible. It is advocated to implement rapid endotracheal intubation in order to reduce patient coughing and droplet spreading. Medication, catheters, laryngoscopes, dental pads, tracheal guide wires, masks and other instruments must be used only one time, and the ward should be ventilated timely after intubation.
According to the patient's clinical manifestations, closed sputum suction is recommended. Use shallow suction, each session should be less than 15 s. It is not recommended to use conventional bedside tracheoscopy for suction. If necessary, a tee joint must be used to connect the breathing circuit.
For patients with suspected or confirmed COVID-19 on invasive mechanical ventilation, the management of the ventilator circuit should be reinforced, in particular, disconnection of the ventilator circuit should be avoided as much as possible to reduce the generation and discharge of contaminated aerosol. Try to choose a disposable ventilator circuit; install a bacteria/virus filter on the inhalation and exhalation ends of the ventilator; use a ventilator circuit with servo heating function; use a self-heating humidifier with automatic water filling; and avoid the use of artificial noses. Dispose condensed water by pouring it into disinfectants and disposing it as medical waste. The surface of the ventilator should be wiped daily and disinfected with 75% ethanol, and the disposable line should be disposed as infectious medical waste.
## Airway management requirements in different epidemic areas
It is recommended that all NCU patients be treated as COVID-19 suspected cases regardless of airway management in high-incidence areas.
NCUs in low-incidence regions may reduce or adjust the protection level according to the actual conditions. For example, patients without COVID-19 are admitted to the NCU as usual, and if on ventilator, the airways of these patients should be managed as usual. For patients unable to rule out COVID-19 and admitted to a regular ward, the level of protection needs to be upgraded when performing airway management. We recommend using level 2 protection and refer to the Recommendations for airway management in severe novel coronavirus pneumonia patients (trial edition)according to the actual conditions.
dIAgnosIs And TreATmenT of severe neurologICAl Illness durIng The CovId-19 epIdemIC The treatment of patients with neurological illness during the epidemic should be based on the risk level stratification. Medical treatment is considered as the first choice. Reduce the risk of COVID-19 transmission while treating patients as promptly as possible. NCU admission should be evaluated based on the following aspects: (1) whether he/she is a confirmed or suspected patient of COVID-19;whether treatment in the current period of epidemic prevention and control is beneficial and examine the level of possible benefit; (3) improving the recognition of symptoms caused by COVID-19 such as impaired consciousness, convulsions, headache, dizziness and weakness.
## Open access
Ischaemic stroke Some patients with COVID-19 may have concurrent acute ischaemic strokes, particularly in those middle-aged and elderly. They are most likely to be critically ill if so. Such patients often have thrombocytopenia, increased D-dimer and other coagulation dysfunction. Their risks and benefits of intravenous thrombolysis and intraarterial thrombectomy should be carefully assessed. In the secondary prevention process, if antiplatelet aggregation and anticoagulation drugs are used, their complete blood count and coagulation parameters should be closely monitored. If statins are used, monitor liver function and muscle enzyme to adjust dose if needed.
In high-incidence areas, considering the high probability of COVID-19 in those asymptomatic patients, all patients with ischaemic stroke can be regarded as suspected COVID-19 patients, and isolation and protection is implemented. For patients in low-incidence areas, if COVID-19 is initially excluded, intravenous thrombolysis and intra-arterial thrombectomy can be arranged according to the process of acute stroke care green pathway. These patients receiving thrombolysis and thrombectomy should avoid entering the NCU ward directly. Instead, they should be placed in a transitional ward for treatment and observation, undergo complete nucleic acid testing as soon as possible and managed according to the NCU management principles during the COVID-19 epidemic.
Intracranial haemorrhage SARS-CoV-2 can bind to the ACE2 receptor of vascular endothelial cells, causing abnormally increased blood pressure. Critically ill COVID-19 patients often have severely reduced number of platelets and abnormal coagulation function, so patients have an increased risk of intracranial haemorrhage.
For patients in high-incidence areas requiring intracranial haematoma removal, operation need to be arranged in an isolated operating room, and the medical staff need level 3 protection. Patients in low-incidence areas should be operated as routine, and medical personnel should take at least level 2 protective measures.
## Endovascular treatment
For patients with subarachnoid haemorrhage who cannot completely exclude COVID-19, delay entering the angiography suite for interventional treatment if the condition permits and wait after COVID-19 is ruled out. If the condition is critical, isolation and protection is required in accordance with the requirements for suspected cases. Patients who have acute ischaemic stroke within the time window should be treated with intravenous thrombolysis. If endovascular treatment is required, the risk of COVID-19 should be fully evaluated. For patients with COVID-19 not excluded, clinicians should carefully evaluate if endovascular treatment is beneficial, and take appropriate prevention measures according to the epidemic condition of the area.
During the epidemic period, a special catheter room should be designated (preferably set in a negative pressure operating room or an isolated operating room with 'three areas and two channels'), disinfected regularly and strictly controlled for the number of personnel entering. All personnel in the catheterisation room must receive COVID-19 education and protection training. Medical staff in the catheterisation room in high-incidence areas need level 3 protection. In low-incidence areas, at least level 2 protection is needed for non-suspected or confirmed patients, and level 3 for suspected and confirmed patients.
## Status epilepticus
Some patients with COVID-19 may have seizures. Whether it originated from COVID-19 is unclear. In the late stage of critically ill patients, status epilepticus may be induced by hypoxia and secondary intracranial lesions. For the treatment of status epilepticus, in addition to conventional treatments such as intravenous/oral antiepileptic medication and dehydration, special attention should be paid to the protection of medical personnel during the establishment and maintenance of artificial airways. For specific measures and precautions, see the Management of artificial airway and mechanical ventilation section.
## Central nervous system infections and autoimmune encephalitis
Whether SARS-CoV-2 can directly cause central nervous system (CNS) infection is currently inconclusive. Researchers have detected SARS-CoV in patients' cerebrospinal fluid and on brain tissue at autopsy ; therefore, it is speculated that the possibility of infection exists. However, ACE2 receptors are not clearly expressed in brain tissue. 14 Further research is need to define whether SARS-CoV-2 can directly cause CNS infection. Currently, there is no report of autoimmune encephalitis associated with SARS-CoV-2 infection. Some patients with COVID-19 may have symptoms such as fever, headache, vomiting and disturbance of consciousness that are similar to intracranial infections. NCU physicians should be vigilant with diagnosis. When a patient with confirmed or suspected COVID-19 needs lumbar puncture, his/her cerebrospinal fluid should be regarded as a pollutant, and the operator should wear level 3 protection. After the operation, the equipment and environment should be disinfected accordingly. Treatment protocol should be determined by combining the treatment principles of intracranial infection and COVID-19. neuroimmune and neuromuscular diseases Some patients with COVID-19 may have early or secondary symptoms of muscle damage such as fatigue, myalgia and increased muscle enzymes. Therefore, patients with these symptoms should complete COVID-19 assessment as soon as possible. Guillain-Barré syndrome (GBS) can also be caused by an autoimmune response induced by a viral infection. Patients with myasthenia gravis (MG) and
Open access concurrent SARS-CoV-2 infection are susceptible to crisis. In addition to the rapid assessment of COVID-19, physicians should pay attention to the need of establishing artificial airways and avoid using medication that aggravate the symptoms of MG. During the epidemic, immunoglobulin (0.4 g/kg/day, 5-day treatment course) is the first choice of immune modulation treatment for patients with severe GBS and MG. Corticosteroids should be used carefully if the patient has COVID-19.
# Conclusion
During the prevention and control of the COVID-19 epidemic, the treatment of critically ill patients with neurological crisis has become more difficult and challenging. Based on strict compliance with the Law of the People's Republic of China on the Prevention and Treatment of Infectious Diseases, clinicians should take measures according to their local standard and resources. Prevention and control of COVID-19 epidemic is the top priority. Measures for comprehensive screening and risk assessment should be implemented. Treatment should weigh on the risk and benefits against the goal of reducing the risk of COVID-19 transmission.
[fig] Figure 1: Flowchart of emergency admissions. ER, emergency room; NCU, neurological intensive care unit. [/fig]
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https://svn.bmj.com/content/svnbmj/5/3/242.full.pdf
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During the COVID-19 epidemic, the treatment of critically ill patients has been increasingly difficult and challenging. During the epidemic, some patients with neurological diseases also have COVID-19, which could be misdiagnosed and cause silent transmission and nosocomial infection. Such risk is high in a neurological intensive care unit (NCU). Therefore, prevention and control of epidemic in critically ill patients is of utmost importance. The principle of NCU care should include comprehensive screening and risk assessment, weighing risk against benefits and reducing the risk of COVID-19 transmission while treating patients as promptly as possible.
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ede8d3cfac4561cf016f8682e8191aec1548697c
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pubmed
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Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States
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Updated CDC Recommendations for Using Artemether-Lumefantrine for the Treatment of Uncomplicated Malaria in Pregnant Women in the United States
One meta-analysis (5) and five randomized openlabel controlled trials performed in Uganda and Thailand examined the efficacy of ACTs for uncomplicated P. falciparum in women during their second and third trimesters of pregnancy and found cure rates ≥94.9%, with ACTs performing equal to or better than quinine-based regimens(Table 1) (6-10). A meta-analysis of African and Asian studies found lower but statistically similar treatment failure rates by days 28-63 in
## Updated cdc recommendations for using artemether-lumefantrine for the treatment of uncomplicated malaria in pregnant women in the united states
Sarah-Blythe Ballard, MD, PhD 1,2 ; Allison Salinger, MPHc 2,3 ; Paul M. Arguin, MD 2 ; Meghna Desai, PhD 2 ; Kathrine R. Tan, MD 2 Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin. However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemetherlumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2,. This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.
# Background
Each year, approximately 1,700 cases of imported malaria occur in the United States; approximately 630 (37%) of these cases occur in women, including 5%-6% who are pregnant at the time they are infected [bib_ref] Malaria surveillance-United States, Mace [/bib_ref]. Treatment options for uncomplicated, chloroquine-resistant P. falciparum and P. vivax malaria infections in pregnant women in the United States are threatened by the spread of mefloquine resistance in Southeast Asia. Having only one quinine and mefloquine manufacturer in the United States can adversely affect access. In 2009, the Food and Drug Administration (FDA) approved AL for the treatment of uncomplicated malaria. At that time, this combination was not approved for use in pregnancy because animal research data indicated a potential association with poor pregnancy outcomes, and insufficient human data were available. Since then, global experience has contributed substantial evidence of the safety and efficacy of AL throughout pregnancy. Given the need for an additional option to treat uncomplicated malaria in pregnant women in the United States, a systematic review of the literature was performed to evaluate the safety and efficacy of AL use during pregnancy, and findings were used to update CDC recommendations.
# Methods
A systematic review of English-language research articles listed in PubMed was conducted using the keywords "artemether," "lumefantrine," "Coartem," and "malaria in pregnancy." Clinical trials, observational studies, meta-analyses, and case reports of uncomplicated malaria treatment during pregnancy were included. Studies that did not include treatment or pregnancy outcomes were excluded, as were studies that did not identify the trimester of treatment. Review article and metaanalysis references were examined for additional primary source articles for inclusion. Online search results were compiled and deduplicated. Two independent reviewers determined the relevance of each article to the research objective based first on title, then abstract, then full text. If reviewers had discordant findings from title or abstract review, the article was included in the next review phase. The following data were abstracted and reviewed: participant age; geographic location; parity; reason for drug treatment (uncomplicated versus severe malaria); trimesters during which treatment occurred; medication dose administered; treatment duration; treatment outcomes; and pregnancy outcomes, which included miscarriage (pregnancy loss at <28 weeks' gestation), stillbirth (pregnancy loss at ≥28 weeks' gestation), preterm birth (<37 weeks' gestation), low birth weight (<2,500 g), congenital abnormalities, and any maternal adverse events reported.
women taking ACTs versus non-ACTs to treat uncomplicated malaria in the second and third trimesters of pregnancy (pooled risk ratio random effects = 0.41; 95% confidence interval (CI) = 0.16-1.06; six trials) [bib_ref] Artemisininbased combination therapy versus quinine or other combinations for treatment of uncomplicated..., Burger [/bib_ref]. With respect to AL efficacy during the second and third trimesters of pregnancy, a concern existed that a reduction in relative bioavailability of lumefantrine in pregnant women might affect treatment success later in pregnancy [bib_ref] Population pharmacokinetics and clinical response for artemether-lumefantrine in pregnant and nonpregnant women..., Mosha [/bib_ref] [bib_ref] Artemether-lumefantrine pharmacokinetics and clinical response are minimally altered in pregnant Ugandan women..., Nyunt [/bib_ref] [bib_ref] The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum..., Mcgready [/bib_ref] [bib_ref] Population pharmacokinetics of lumefantrine in pregnant women treated with artemether-lumefantrine for uncomplicated..., Tarning [/bib_ref] [bib_ref] Molecular and pharmacological determinants of the therapeutic response to artemetherlumefantrine in multidrug-resistant..., Price [/bib_ref]. However, the evidence presented indicates that treatment in pregnancy is efficacious at the doses currently recommended for nonpregnant women.
Second and third trimester safety. Data evaluating pregnancy outcomes in women taking ACTs during the second or third trimesters of pregnancy were available from 16 studies [fig_ref] TABLE 2: Summary of studies using artemisinin-based treatment for malaria in second and third... [/fig_ref]. No differences in pregnancy outcomes were identified in four trials comparing ACTs with quinine-based regimens in Uganda and Thailand [bib_ref] Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of..., Mcgready [/bib_ref] [bib_ref] Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with..., Piola [/bib_ref] [bib_ref] A randomized clinical trial comparing safety, clinical and parasitological response to artemether-lumefantrine..., Kaye [/bib_ref] , one of which used AL [bib_ref] Efficacy and safety of artemether-lumefantrine compared with quinine in pregnant women with..., Piola [/bib_ref] , and in four other trials comparing AL with other ACTs in Nigeria (two studies), Thailand, and multiple sites in Africa [bib_ref] A randomized trial of artesunate-amodiaquine versus artemetherlumefantrine for the treatment of acute..., Ukah [/bib_ref] [bib_ref] A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated Plasmodium falciparum..., Mcgready [/bib_ref] [bib_ref] Randomised trial of artemether versus artemether and mefloquine for the treatment of..., Sowunmi [/bib_ref]. A Zambian cohort study comparing treatment of uncomplicated malaria using AL with treatment using sulfadoxine-pyrimethamine found similar pregnancy outcomes between groups [bib_ref] Safety of artemetherlumefantrine in pregnant women with malaria: results of a prospective..., Manyando [/bib_ref]. In addition, two meta-analyses of women with malaria in the second and third trimester of pregnancy found no association between ACT treatment and congenital malformations or miscarriage [bib_ref] The safety of artemisinin derivatives for the treatment of malaria in the..., Kovacs [/bib_ref]. Overall, fewer maternal adverse events occurred among women taking ACTs than among those taking non-ACTs [fig_ref] TABLE 2: Summary of studies using artemisinin-based treatment for malaria in second and third... [/fig_ref]. One trial in Thailand found a relatively higher proportion of day 7 anemia among those treated with mefloquine-artesunate (67%) than among those treated with a quinine-based regimen (42%) [bib_ref] Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrugresistant falciparum..., Mcgready [/bib_ref]. Four trials and one meta-analysis comparing ACTs with quinine-based regimens found that pregnant women taking quinine had higher rates of tinnitus, dizziness, and vomiting than did pregnant women taking ACTs (5-9). The three trials comparing AL with other ACTs found no differences in rates of serious adverse maternal effects between groups [bib_ref] A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated Plasmodium falciparum..., Mcgready [/bib_ref].
First trimester safety. No randomized trials evaluating AL use during the first trimester of pregnancy were found [fig_ref] TABLE 3: Summary of safety outcomes in studies using artemisinin-based treatment for malaria in... [/fig_ref]. However, a meta-analysis of observational and other studies from six sub-Saharan African countries and the Thai-Burmese border included data from a total of 717 women taking ACTs during the first trimester of pregnancy [bib_ref] First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy..., Dellicour [/bib_ref]. Comparisons of pregnancy outcomes between women taking ACTs and those receiving a quinine-based regimen Miscarriage, 0 (0) Any defect, 0 (0) Not assessed Stillbirth, 0 (0) Premature, 0 (0)
## Table 2. (continued) summary of studies using artemisinin-based treatment for malaria in second and third trimesters of pregnancy and safety outcomes
anytime during the first trimester and treatment with ACTs versus quinine-based regimen during 6-12 weeks' gestational age demonstrated no differences in miscarriage, stillbirth, or pregnancy loss (miscarriage and still birth combined) for women treated with ACTs versus quinine-based regimens during either period. Although limited by sample size, the pooled prevalences of congenital anomalies in infants born to mothers taking ACTs versus quinine-based regimens in the first trimester were similar (1.5%, 95% CI = 0.6-3.5 versus 1.2%, 95% CI = 0.6-2.4, respectively) [bib_ref] First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy..., Dellicour [/bib_ref].
## Recommendation
Malaria infection during pregnancy can result in serious maternal and fetal complications. On the basis of the strength and quality of this evidence, CDC recommends AL as an additional option for treatment of uncomplicated malaria in pregnant women in the United States during the second and third trimesters of pregnancy at the same doses recommended for nonpregnant women. Women in the United States with uncomplicated malaria during the first trimester of pregnancy should be treated with the currently recommended options of either mefloquine or quinine plus clindamycin. However, when neither of these options is available, AL should be considered for treatment.
# Discussion
This update of CDC recommendations based on accumulated evidence of the safety of AL in pregnancy is in line with the malaria treatment guidelines of other countries without endemic malaria and WHO [bib_ref] European Society for Clinical Microbiology and Infectious Diseases Study Group on Clinical..., Askling [/bib_ref] [bib_ref] Chiodini PL; PHE Advisory Committee on Malaria Prevention in UK Travellers. UK..., Lalloo [/bib_ref]. On the basis of the current strength and quality of the first trimester safety and efficacy evidence, the addition of ACTs, including AL, as a first-line treatment option for uncomplicated malaria during the first trimester of pregnancy is being considered by WHO after the Malaria Policy Advisory Committee's review (2,3). Women seeking care in the United States will now have a third treatment option for uncomplicated malaria during the second and third trimesters of pregnancy, and during the first trimester of pregnancy when other treatment options are unavailable, that is safe and effective for treating P. falciparum infections acquired in regions with chloroquine resistance. To assess the implementation and impact of these updated recommendations in the United States, data from the National Malaria Surveillance System will be used to examine how antimalarials are used to treat uncomplicated malaria in pregnant women, as well as population-specific disease burden; in addition, the FDA Adverse Event Reporting System maintains adverse event and medication error data, which can be used to monitor adverse events associated with AL use during pregnancy.
[table] TABLE 1: Findings of randomized trials of artemisinin-based regimens for treatment of malaria in pregnancy [/table]
[table] TABLE 2: Summary of studies using artemisinin-based treatment for malaria in second and third trimesters of pregnancy and safety outcomes [/table]
[table] TABLE 3: Summary of safety outcomes in studies using artemisinin-based treatment for malaria in first trimester of pregnancyNot assessed Areg versus Q: aHR = 0.73 (95% CI = 0.44-1.21) Areg versus none: aHR = 1.16 (95% CI = 0.81-1. [/table]
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https://www.cdc.gov/mmwr/volumes/67/wr/pdfs/mm6714a4-H.pdf
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Malaria infection during pregnancy is associated with an increased risk for maternal and fetal complications. In the United States, treatment options for uncomplicated, chloroquine-resistant Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin (1). However, limited availability of quinine and increasing resistance to mefloquine restrict these options. Strong evidence now demonstrates that artemether-lumefantrine (AL) (Coartem) is effective and safe in the treatment of malaria in pregnancy. The World Health Organization (WHO) has endorsed artemisinin-based combination therapies (ACTs), such as AL, for treatment of uncomplicated malaria during the second and third trimesters of pregnancy and is currently considering whether to add ACTs, including AL, as an option for malaria treatment during the first trimester (2,3). This policy note reviews the evidence and updates CDC recommendations to include AL as a treatment option for uncomplicated malaria during the second and third trimesters of pregnancy and during the first trimester of pregnancy when other treatment options are unavailable. These updated recommendations reflect current evidence and are consistent with WHO treatment guidelines.
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47c77aef4257abf199779dfcdafb2c8d7d1fa45e
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pubmed
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Do not do in COPD: consensus statement on overuse
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Do not do in COPD: consensus statement on overuse
[bib_ref] Setting a research agenda for medical overuse, Morgan [/bib_ref] [bib_ref] Academic physicians' views on low-value services and the choosing wisely campaign: a..., Bishop [/bib_ref] [bib_ref] Choosing Wisely: how the UK intends to reduce harmful medical overuse, Wise [/bib_ref] [bib_ref] Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of..., Miravitlles [/bib_ref] [bib_ref] Global and regional mortality from 235 causes of death for 20 age..., Lozano [/bib_ref] [bib_ref] BOLD Collaborative Research Group, the EPI-SCAN Team, the PLATINO Team, and the..., Bernd [/bib_ref]
# Introduction
Overuse of resources for diagnosis and therapy puts patients at risk without providing sufficient clinical benefit. Moreover, overuse has cost implications and has been linked to errors in clinical treatment. [bib_ref] Setting a research agenda for medical overuse, Morgan [/bib_ref] We must seek to eliminate practices that run contrary to existing evidence; these include carrying out procedures that do not add value for the patient and/or subject patients to unnecessary risk and failing to take actions that have been shown to produce favorable patient outcomes.
Reports in the literature have described this phenomenon using the terms "overuse," "overdiagnosis," "overmedicalization," and "low-value care." [bib_ref] Setting a research agenda for medical overuse, Morgan [/bib_ref] [bib_ref] Academic physicians' views on low-value services and the choosing wisely campaign: a..., Bishop [/bib_ref] According to the definition of the Institute of Medicine, overuse consists of providing healthcare when there is no evidence in support of such decisions or when the benefit of the treatment fails to outweigh its risk. [bib_ref] Setting a research agenda for medical overuse, Morgan [/bib_ref] Overuse has been linked to unsafe, inappropriate, and/or inefficient care. [bib_ref] Setting a research agenda for medical overuse, Morgan [/bib_ref] To counter this trend, the movement called "Less is more medicine" has taken hold in recent years. [bib_ref] Academic physicians' views on low-value services and the choosing wisely campaign: a..., Bishop [/bib_ref] Driven by scientific societies, medical associations and institutions, and healthcare authorities across different countries, in recent years there has been a growing effort to eliminate certain aspects of medical practice that have been broadly shown to be inappropriate. [bib_ref] Choosing Wisely: how the UK intends to reduce harmful medical overuse, Wise [/bib_ref] Examples of this include initiatives by scientific institutions and 452 societies to issue "do not do" (DND) guidelines and informational and educational campaigns urging practitioners to "choose wisely."In an attempt to encourage patient participation in these measures, the foundation Advancing Medical Professionalism to Improve Health Care (ABIM)conducted an awarenessraising campaign among patients and care professionals to prevent improper use of resources within diagnosis and therapy. There is a well-known body of improper healthrelated beliefs and behaviors among patients, and these habits lead to harmful practices that must be eradicated if health outcomes are to be improved. [bib_ref] Choosing Wisely: how the UK intends to reduce harmful medical overuse, Wise [/bib_ref] Chronic obstructive pulmonary disease (COPD) varies in prevalence from country to country; [bib_ref] Epidemiology and costs of chronic obstructive pulmonary disease, Chapman [/bib_ref] in Spain, the prevalence of COPD is 10.2% among adults between the ages of 40 and 80. [bib_ref] Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of..., Miravitlles [/bib_ref] Of all the most prevalent illnesses, COPD is the only one that is on the rise. [bib_ref] Global and regional mortality from 235 causes of death for 20 age..., Lozano [/bib_ref] COPD is currently the third leading cause of death, behind ischemic heart disease and stroke. [bib_ref] Global and regional mortality from 235 causes of death for 20 age..., Lozano [/bib_ref] One of the main problems with this disease is underdiagnosis. [bib_ref] BOLD Collaborative Research Group, the EPI-SCAN Team, the PLATINO Team, and the..., Bernd [/bib_ref] The burden the disease poses for healthcare resources is substantial: the European Union estimates that the direct cost of COPD totals 38.6 billion euros in Europe, whereas the disease burden in the United States is also high, at 29.5 billion dollars.Major clinical guidelines for management of COPD, such as the Global Initiative for Chronic Obstructive Lung Disease (GOLD), an international standard,or the Spanish COPD guidelines (GesEPOC), 14 establish a series of recommendations on preventing, diagnosing, and treating this disease, both for stable as well as exacerbated cases, including indications adapted for different care levels.
Clinical guidelines advise healthcare professionals on appropriate procedures for diagnosis, treatment, and follow-up in step with evolving knowledge of the disease.Despite this information, guides are not always applied correctly and a number of inappropriate practices persist with a certain degree of frequency. [bib_ref] Clinical audit of COPD in outpatient respiratory clinics in Spain: the EPOCONSUL..., Rubio [/bib_ref] [bib_ref] European COPD Audit team. Variability of hospital resources for acute care of..., López-Campos [/bib_ref] [bib_ref] Overuse of short-acting betaagonist bronchodilators in COPD during periods of clinical stability, Fan [/bib_ref] Overuse continues in practice (defensive medicine or pressure from patients or relatives are common causes). [bib_ref] Physician response to patient request for unnecessary care, Kaul [/bib_ref] Moreover, the patient's health beliefs, customs, or misinterpretation could be causes of harm during self-care. These suboptimal measures can be ineffective, inefficient, or even deleterious for patients. [bib_ref] Physician response to patient request for unnecessary care, Kaul [/bib_ref] Making changes to routine clinical practice is less than simple, and requires sustained effort in the benefit of effective care. For this reason, a DND approach like the one presented here is useful in that it calls attention to certain aspects of clinical practice that were once widespread but are now known to be inappropriate -because there is no proof of their efficacy, due to scant or doubtful effectiveness, or because they are not cost-effective.This study aims to identify practices in diagnosis, therapy, and self-care of stable and exacerbated COPD that are inappropriate, have doubtful effectiveness, or are scarcely costeffective, and develop a list of DND recommendations for COPD health professionals and patients.
# Materials and methods
A qualitative research approach was applied. Qualitative research methods analyze phenomena from an overall perspective, attempting to describe reality without formulating hypotheses or setting concrete measures, thereby distinguishing them from quantitative approaches. [bib_ref] La investigación cualitativa: una alternativa también válida, Mira [/bib_ref] This study was carried out in two phases. The first phase comprised an exploratory analysis (using the Metaplan technique), in which we created a list of overused practices, whereas in the second phase we aimed to reach a consensus definition of DND guidelines pertaining to practices that are still relatively common despite the fact that evidence makes a clear case that they have a poor risk-benefit ratio (using a consensus conference technique). The Spanish health system is mainly a public system in which COPD patients are evaluated, at first, by general practitioners, who initiate the treatment and send the patient to a pulmonologist to complete the evaluation. If there is a problem in the evaluation of the patient, the general practitioner begins the treatment. Some COPD patients are treated by physiotherapists and most of them are evaluated by nurses. Therefore, a panel with several pulmonologists, general practitioners, physiotherapists, and nurses is adequate to make a correct evaluation. Ten healthcare professionals participated in this study, each with .10 years' experience in treating COPD patients and involved in research and committees in their professional groups and healthcare levels. This group of collaborators was chosen to include a variety of perspectives drawn from different experiences with clinical practice and by balancing primary and in-hospital care. To do this, six pulmonologists (with experience in hospitalization, consultation, emergencies, home care, mechanical ventilation, and healthcare administration), two general practitioners, one nurse, and one physiotherapist were recruited by the Board of Neumomadrid (Madrid Society of Pulmonology and Thoracic Surgery). Two of the expert pulmonologists and a researcher with expertise in qualitative approaches acted as coordinators.
Once the working group had been formed, both the pulmonologist coordinators and the expert in qualitative research
## 453
Do not do in COPD designed an action plan that called for an initial meeting to be attended by all specialists involved, so as to brainstorm care or self-care practices used in COPD having benefits that do not outweigh their risks. Poor risk-benefit ratio was understood as doubtful effectiveness or deleterious patient outcomes, thus indicating that they were not cost-effective. During this first meeting, the group debated the frequency with which these practices are employed and the strength of the evidence used to deter continued use of these practices. The Metaplan technique [bib_ref] Use of qualitative methods in published health services and management research: a..., Weiner [/bib_ref] was used to identify such practices, to elaborate on them, and to rank them based on frequency. All members of the group began the analysis by noting down the practices they considered to be ill-advised. Based on the results of this method, a decision was made to ask three questions to be answered consecutively [fig_ref] Figure 1: Summary of the methodology used in the study, including the number of... [/fig_ref] : 1) Indicate which practices you consider to be both widely used in the management of patients with stable COPD and also inappropriate because of their poor risk-benefit ratio.
2) Indicate which practices you consider to be both widely used in the management of patients with exacerbated COPD and also inappropriate because of their poor risk-benefit ratio.
3) Indicate which self-care practices you believe are widespread among COPD patients and are inappropriate because of their poor risk-benefit ratio. Responses to these questions were gathered individually, and each collaborator was able to present as many practices as they saw fit. Similar questions were grouped together.
Subsequently, an open, unmoderated debate was held to discuss each of the examples of overuse that had been proposed in the previous phase so that the participants could assess the pertinence, degree of consensus, and sources of evidence for each one. Lastly, each individual coauthor evaluated the different proposed inappropriate practices according to the degree of prevalence in routine clinical practice. For this, a scale of 1-5 was employed, with 1 indicating scarce frequency of use and 5 representing practices that are relatively frequent despite being inadvisable or not cost-effective -that is, those practices discouraged by scientific evidence or professional consensus. In addition, the analysis took into account proposals referring to the same practice which were made by more than one study participant (spontaneity) and the level of agreement between participants (coefficient of variation). During this initial phase, scores around the 75th percentile were considered the cutoff; therefore, practices
## 454
Villar-Álvarez et al that had been given an average score of 3.5 points or lower, as it was believed that there was no consensus opinion indicating that these were in widespread use (variability coefficient .0.27; [fig_ref] Figure 1: Summary of the methodology used in the study, including the number of... [/fig_ref] , were proposed as inappropriate.
The methodology used in the second phase was the consensus conference. [bib_ref] Uso adecuado de la evidencia en la toma de decisiones. Método RAND/UCLA...., Martínez-Sahuquillo Amuedo [/bib_ref] For this, a web application was used to select DND recommendations that were most widely chosen. Each inappropriate practice was assigned a DND recommendation.
To assign each DND recommendation, all inappropriate practices were individually assessed (a scale from 1 to 10 was used) again by the group of experts to establish their perceived frequency of use, the degree to which the practice was considered useless, deleterious, or failed to add value, and, lastly, whether the practice was more prevalent among specialists in pulmonology, primary care, or nursing. Moreover, this phase included an opportunity for the collaborators to propose modifications and clarifications to the language used in the originally proposed description of these inappropriate practices. The expert participants had been given information on the degree of consensus reached in the previous phase for each practice perceived to be inappropriate (ie, mean, spontaneity, and coefficient of variation). These recommendations were ranked according to the result obtained by applying the formula frequency × intensity (range 1-100) once they were grouped according to COPD into stable, exacerbated, or related to self-care. We set a data-driven cutoff point of 57 points, meaning that scores below this value indicated a lower level of consensus [fig_ref] Figure 1: Summary of the methodology used in the study, including the number of... [/fig_ref].
An operational description was created for each of the recommendations processed according to this method, and we evaluated the level of evidence justifying the proposed inappropriateness of the measure. For proposals made for patient self-care, we based these assessments on literature concerning patient education and clinical experience. The resulting recommendations were distributed among the participants, and a descriptive file was created for each one, including the following fields: recommendation title, operative definition of the practice to be eradicated, description of the practice to be eradicated, justification given for the eradication proposal, level of evidence and recommendation grade according to the Scottish Intercollegiate Guidelines Network (SIGN),bibliographical sources, and recommended indices to assess whether a change has taken place in the practice and to enable follow-up of the level of uptake of these DND recommendations [fig_ref] Figure 2: Description file for each "do not do" recommendation in COPD [/fig_ref].
# Results
When the Metaplan technique was applied, a total of 157 proposals were made concerning overuse practices in the treatment of patients with COPD, and 95 of these were intrinsically different from each other. Practices were eliminated if they received an average score of 3.5 points or lower, as it was believed that there was no consensus opinion surrounding them. This resulted in a total of 28 practices in stable COPD, 30 in exacerbated disease, and 37 self-care practices. Finally, we eliminated 40 examples of inappropriate practices for which there was insufficient consensus among the members of the research group or because they overlapped with others.
During the final phase, which consisted of a consensus conference, 55 proposals were assessed for possible inappropriateness or cost-ineffectiveness, and each one was assigned a DND recommendation: 17 for stable COPD, 18 for exacerbated COPD, and 20 concerning self-care among this population of patients. After the list was reviewed by the group of experts taking part in the study, the number of recommendations was reduced to 16 (after applying the formula frequency × intensity, and eliminating those recommendations with ,57 points): six for stable disease, six for exacerbated COPD, and four for patient selfcare [fig_ref] Table 1: Do not discontinue taking inhaled medication because an improvement in clinical symptoms... [/fig_ref].
## Practices discouraged for treatment of copd
## Name:
Operative definition of the practice that should be discontinued:
## Description:
Justification/remarks:
## Evidence:
Level of evidence:
Strength of recommendation:
## References:
Indicator proposed for follow-up of changes in the practice: The definitive list of six DND recommendations for stable COPD was as follows:
- Do not administer inhaled corticosteroids as routine treatment in patients with forced expiratory volume in 1 second (FEV 1 ) .60% and ,2 acute exacerbations in the previous year or in patients without an overlapping COPD-asthma phenotype. - Do not neglect to perform spirometry as part of the diagnostic work-up in patients with a past history of smoking and symptoms of COPD. - Do not assume that patients correctly administer inhaled medication in the absence of proper confirmation. - Do not initiate treatment without previously confirming the diagnosis by spirometry. - Do not change inhaled treatment without first assessing treatment compliance.
- Do not perform pulmonary function testing systematically at each follow-up visit if there is no change in symptoms, in the number of previous acute exacerbations, or in treatment. Six other DND recommendations, which concerned acute exacerbations of COPD, were as follows:
- Do not prescribe antibiotic treatment in all cases of acute exacerbation. - Do not prescribe nebulized medication in all cases of acute exacerbation. - Do not administer high-flow oxygen if oxygen saturation is .90% or if partial pressure of oxygen (PaO 2 ) is $60 mmHg. - Do not prescribe home oxygen therapy following an acute exacerbation if PaO 2 is $60 mmHg. - Do not prescribe corticosteroid therapy for periods of .14 days or with progressive reduction in therapy. Lastly, the four DND recommendations for self-care among patients with COPD were as follows:
- Do not discontinue taking inhaled medication because an improvement in clinical symptoms has taken place. - Do not use the inhaler incorrectly.
- Do not stop walking due to feelings of dyspnea.
- Do not take unprescribed treatments.
Subsequently, descriptive files containing technical specifications of each recommendation were created [fig_ref] Figure 2: Description file for each "do not do" recommendation in COPD [/fig_ref]. This file included the level of evidence and grade of recommendation -bases that justify DND recommendations -as well as indicators that allow for an assessment of the data collected [fig_ref] Table 2: level of evidence and grade of recommendation as indicated in sIgn 24... [/fig_ref]. Clinical guidelines, such as GOLDor GesEPOC,have been evaluated in the level of evidence and in the analysis of data collected.
# Discussion
Using a multi-phase methodology we identified a number of practices used in diagnosis, therapy, and other careincluding the self-care procedures that are the responsibility of patients -that are inappropriate, have doubtful effectiveness, or are not cost-effective for COPD patients. The results of this study should bring about an increase in care quality by reducing the frequency of practices that add no value or are harmful for patients, as well as by increasing patient safety, improving physician-patient communication, and better enabling patients to undertake self-care.
The National Physicians Alliance, a medical organization operating in the United States, set in motion a project called "Choosing Wisely," which called on a variety of medical societies -initially, those concerned with primary care, internal medicine, and pediatrics -to propose a list of five recommendations for medical practices with the aim of optimizing healthcare resources used to diagnose and treat different illnesses.In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has also published a set of DND recommendations, highlighting care practices that do not benefit patients or for which there is insufficient evidence upon which to base suggestions for use. Along these same lines, the American Thoracic Society (ATS), in partnership with the American College of Chest Physicians, created a list of five practices that are widely used to treat respiratory diseases in adults but that, nonetheless, should be avoided. [bib_ref] An official American Thoracic Society/American College of Chest Physicians policy statement: the..., Wiener [/bib_ref] Although none of these concern COPD, the previous list of ten practices contained two that are relevant to COPD -that is, "Do not perform frequent spirometry in patients with COPD in patients who are clinically stable and gOlDMiravitlles et al [bib_ref] Spanish guideline for COPD (GesEPOC). Update, Miravitlles [/bib_ref] Vogelmeier et al [bib_ref] Efficacy and safety of once-daily QVA149 compared with twice daily salmeterol-fluticasone in..., Vogelmeier [/bib_ref] Zhong et al [bib_ref] LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with..., Zhong [/bib_ref] Price et al [bib_ref] Management of COPD in the UK primary-care setting: an analysis of real-life..., Price [/bib_ref] have an established diagnosis" and "Do not routinely administer intravenous steroids for patients hospitalized for acute exacerbations of asthma and COPD." In Spain, the Ministry of Health, Social Services, and Equality launched the project titled "Commitment to Quality in Scientific Societies" 27 in order to reduce unnecessary interventions. As in the present study, the initiative took unnecessary interventions to mean those for which there was no proven efficacy, practices with scant or doubtful effectiveness, or procedures that are not cost-effective. A multitude of scientific societies took part in the initia-Miravitlles et al [bib_ref] Spanish guideline for COPD (GesEPOC). Update, Miravitlles [/bib_ref] Tashkin et al [bib_ref] UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary..., Tashkin [/bib_ref] Vogelmeier et al [bib_ref] POET-COPD Investigators. Tiotropium vs salmeterol for the prevention of exacerbations of COPD, Vogelmeier [/bib_ref] Wise et al [bib_ref] Tiotropium respimat inhaler and the risk of death in COPD, Wise [/bib_ref] Decramer et alCelli et al Indicators used for assessment of "do not do" recommendations
## Group "do not do" recommendations indicators
## Patients with stable copd
Do not administer inhaled corticosteroids as routine treatment for patients with FeV 1 .60% and ,2 acute exacerbations in the previous year or in patients without an overlapping COPD-asthma phenotype.
number of patients with FeV 1 .60% and with 0-1 acute exacerbations in the previous year and who receive inhaled corticosteroids as routine treatment (exclusive of patients with an overlapping COPD-asthma phenotype)/number of patients diagnosed with COPD who receive inhaled corticosteroids as routine treatment. Do not neglect to perform spirometry as part of the diagnostic work-up in patients with a past history of smoking and symptoms of COPD.
number of patients who are smokers (at least 10 pack-years) over age 35 presenting respiratory symptoms and who have not received spirometry/number of patients who are smokers and have a diagnosis of COPD. Do not assume that patients correctly administer inhaled medication in the absence of proper confirmation. number of patients for whom the patient chart contains references to inhaled therapy (direct observation or as obtained through compliance questionnaires such as Test of adherence to Inhalers [TaI])/total number of patients with COPD and inhaled treatment. Do not initiate treatment without previously confirming the diagnosis by spirometry. number of patients prescribed home oxygen therapy following an acute exacerbation with PaO 2 $60 mmhg/total number of cases prescribed home oxygen therapy following an acute exacerbation. Do not prescribe corticosteroid therapy for periods of .14 days or with progressive reduction in therapy.
number of patients prescribed with long-term (.14 days) treatment with corticosteroids/total number of patients undergoing corticosteroid therapy. number of patients prescribed to receive progressive reduction of corticosteroid therapy/total number of patients undergoing corticosteroid therapy. Do not perform spirometry in patients with known COPD. number of spirometry studies performed during acute exacerbations in patients with previously known COPD/number of COPD patients with acute exacerbations. self-care in patients with COPD Do not discontinue taking inhaled medication because an improvement in clinical symptoms has taken place.
number of consultations assessing degree of compliance and proper therapy administration/total number of consultations.
Do not use the inhaler incorrectly.
number of consultations assessing errors in dosage or inhaler use/total number of consultations. Do not stop walking due to feelings of dyspnea.
Daily/weekly/monthly log of distance walked compared to the results of the individual 6-minute walking test. Improved score on surveys and rating scales for physical activity or activities of daily living. Do not take unprescribed treatments.
Total number of COPD patients receiving unprescribed therapy/total number of patients with COPD.
Abbreviations: COPD, chronic obstructive pulmonary disease; FeV 1 , forced expiratory volume in 1 second; PaO 2 , partial pressure of oxygen.
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Do not do in COPD These working groups base their recommendations on the views of a group of subject-matter experts, selecting those practices that should not be subjected to assessment using qualitative methods. Each group works with a preliminary list of possible recommendations appearing in clinical practice guidelines, using these guidelines as a primary source. Use of this method allows for high levels of consensus on DND recommendations, although this method is limited in that, sometimes, discouraged practices are seldom used. We have taken measures to adjust for this by including recommendations that are commonly made in the context of routine practice.
In addition to the study's focus on a single disease such as COPD, one novel aspect of our article is the inclusion of DND recommendations concerning patient self-care. Specifically, we identified practices that are prevalent in COPD patient self-care despite their lack of effectiveness or even deleteriousness for these patients. Self-care in patients with COPD can improve health-related quality of life and reduce hospital admissions. [bib_ref] Five-year follow-up of a one-year selfmanagement program for patients with COPD, Lomundal [/bib_ref] [bib_ref] Chronic Obstructive Pulmonary Disease Axis of the Respiratory Health Network, Fonds de..., Gadoury [/bib_ref] Clari et al has provided evidence on the self-care behaviors and strategies that people with COPD undertake to prevent, control, and manage the physical, psychological, and social consequences of this pathology. [bib_ref] Self-care of people with chronic obstructive pulmonary disease: a meta-synthesis, Clari [/bib_ref] Our four recommendations for self-care in patients with COPD and the proposed indicators for their evaluation could enable COPD patients to reduce the physical, psychological, and social effects of COPD, and help healthcare professionals to tailor self-care educational programs to the experiences and priorities of these patients. [bib_ref] Self-care of people with chronic obstructive pulmonary disease: a meta-synthesis, Clari [/bib_ref] [bib_ref] Self-management programmes for COPD: moving forward, Effing [/bib_ref] Another strength of this study is its use of level of evidence and grade of recommendation in accordance with SIGN 24 and citations from the literature that support these recommendations.
Our study, furthermore, includes a series of proposals for follow-up of the frequency with which the cases of overuse included in the DND guidelines continue to be employed. These are COPD-related care-quality indicators that could be used by health authorities to assess outcomes. Additionally, these could be incorporated into the balanced scorecards used in care units or form part of the yearly targets set by management agreements. Proper deployment of recommendations enables appropriate oversight of the degree to which targets are being met and aids in target setting. These aspects have been scarcely used in other studies, [bib_ref] An official American Thoracic Society/American College of Chest Physicians policy statement: the..., Wiener [/bib_ref] although we believe them to be necessary to address the problem of overuse.
Due to its local setting in Spain and the implications that this setting had for the design of the study, one limitation of this research is this local nature, as results may vary in other locations. Moreover, we did not include an analysis of the frequency with which the practices selected as inadvisable are employed in current clinical practice or in patient home care. Despite this, the study focuses on clinical and self-care practices that become evident in the clinical context due to their prolonged time of use.
In addition, the study is limited by the fact that, to date, no DND indicators have been included in quality assessments and, as a result, data concerning the efficacy of these recommendations are scarce. We do, however, make a proposal which would allow for a follow-up to be conducted on the degree of uptake of these recommendations. The DND included in this study as examples of overuse were chosen because of their cost-ineffectiveness, but they are not based on empirical evidence. Moreover, the list of inappropriate practices is not supported by any investigation of real prevalence, and is based on level of agreement for opinion and experience of a small panel of experts. No quantitative study has been undertaken to measure the degree of agreement with these DND recommendations among professional groups or patient representatives, and further research should examine data on the implementation of these recommendations as well as continuous follow-up.
We can conclude from this study that DND recommendations in COPD are likely to improve management of patients with the disease by reducing the rate with which improper or scarcely cost-effective practices are used in clinical care and patient self-care. Furthermore, the use of these recommendations will lower care risks, improve physicianpatient communication, and empower patients to undertake in-home self-care.
# Acknowledgments
This study was carried out under the auspices of the Madrid Society of Pulmonology and Thoracic Surgery (Neumomadrid). The work was supported by the Spanish Society of Family and Community Medicine (semFYC) and was funded without restriction by a grant from the AstraZeneca pharmaceutical company. We are grateful to Oliver Shaw (IIS-FJD) for his valuable assistance in preparing the manuscript in English. S Núñez-Palomo declares that she has written monographs or participated in courses and conferences sponsored by Boehringher, Pfizer, Astra Zéneca, GSK, and Rovi, and has no other conflicts of interest in this work. P Vaquero-Lozano declares that in the last 5 years he has received payments for participating in meetings or congresses organized by the following pharmaceutical companies: Chiesi, AstraZeneca, Boehringer-Ingelheim, Almirall, Novartis, Sandoz, Pfizer, and Linde (Carburos Médica), and has no other conflicts of interest in this work.
# Disclosures
[fig] Figure 1: Summary of the methodology used in the study, including the number of ideas identified, selection criteria, and procedure used to screen "do not do" recommendations in COPD. Abbreviation: COPD, chronic obstructive pulmonary disease. International Journal of COPD 2018:13 submit your manuscript | www.dovepress.com Dovepress Dovepress [/fig]
[fig] Figure 2: Description file for each "do not do" recommendation in COPD. Abbreviation: COPD, chronic obstructive pulmonary disease. International Journal of COPD 2018:13 submit your manuscript | www.dovepress. [/fig]
[fig] F: Villar-Álvarez, R Moreno-Zabaleta, JJ Mira-Solves, E Calvo-Corbella, S Díaz-Lobato, González-Torralba, A Hernando-Sanz, S Salgado-Aranda, B Simón-Rodríguez, and IM Navarro-Soler report no conflicts of interest in this work. International Journal of COPD 2018:13 submit your manuscript | www.dovepress. [/fig]
[table] Table 1: Do not discontinue taking inhaled medication because an improvement in clinical symptoms has taken place. Do not use the inhaler incorrectly. [/table]
[table] Table 2: level of evidence and grade of recommendation as indicated in sIgn 24 including bases that justify the "do not do" recommendations [/table]
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https://www.dovepress.com/getfile.php?fileID=40385
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Background To identify practices that do not add value, cause harm, or subject patients with chronic obstructive pulmonary disease (COPD) to a level of risk that outweighs possible benefits (overuse). Methods A qualitative approach was applied. First, a multidisciplinary group of healthcare professionals used the Metaplan technique to draft and rank a list of overused procedures as well as self-care practices in patients with stable and exacerbated COPD. Second, in successive consensus-building rounds, description files were created for each “do not do” (DND) recommendation, consisting of a definition, description, quality of supporting evidence for the recommendation, and the indicator used to measure the degree of overuse. The consensus group comprised 6 pulmonologists, 2 general practitioners, 1 nurse, and 1 physiotherapist. Results In total, 16 DND recommendations were made for patients with COPD: 6 for stable COPD, 6 for exacerbated COPD, and 4 concerning self-care. Conclusion Overuse poses a risk for patients and jeopardizes care quality. These 16 DND recommendations for COPD will lower care risks and improve disease management, facilitate communication between physicians and patients, and bolster patient ability to provide self-care.
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Clinical Practice Guidelines for Liver Transplantation in Saudi Arabia
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Clinical Practice Guidelines for Liver Transplantation in Saudi Arabia
أمراض عبء بارتفاع السعودية العربية اململكة في الكبد زراعة على الطلب ارتبط في املتلقني بني الكبد زراعة مؤشرات وبائيات اجتاهات تغيرت اململكة. في الكبد غير الدهني الكبد التهاب طغى ا. ً
1,005 from deceased donors. [bib_ref] The Saudi Center for Organ Transplantation: An Ideal Model for Arabic Countries..., Shaheen [/bib_ref] However, these numbers are disproportional to the actual need for organ transplant, and drastic strategies and programs need to be refined and developed to meet the high demands for organ donations.
The demand for LT in the KSA is associated with the country's high burden of hepatic disease. The hepatitis B (HBV) epidemic in the early 1980s resulted in a high prevalence rate and a significant proportion of patients needing LT for end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC). However, the HBV vaccination program introduced in 1989 caused a substantial prevalence reduction, decreasing the requirement for HBV-related LT 8 but led to a changing trend in LT indications. [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] Although hepatitis C virus (HCV) is still the primary indication for LTs in KSA, [bib_ref] SASLT guidelines: Update in treatment of Hepatitis C virus infection, Alghamdi [/bib_ref] the indications for LT are changing from viral-induced hepatic disease to non-alcoholic fatty liver-related cirrhosis. [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] Risk factors that are common in KSA, like type 2 diabetes mellitus (T2DM), obesity, and hyperlipidemia, are becoming a significant concern and a leading indication for LT in the KSA due to nonalcoholic steatohepatitis (NASH)-related liver disease. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] There is also a significantly increased prevalence and incidence of genetic adult familial liver diseases in KSA. [bib_ref] Genetic profiling of children with advanced cholestatic liver disease, Shagrani [/bib_ref] The advent of new immunosuppressants and preservation solutions, improved surgical procedures, and the early disease recognition and management of manifestations have increased the success rate of LT outcome, but concerns about the side effects of immunosuppressive therapy can jeopardise long-term survival outcomes. [bib_ref] Current and Future Trends in Liver Transplantation in Europe, Dutkowski [/bib_ref] [bib_ref] Challenges to liver transplantation and strategies to improve outcomes, Dutkowski [/bib_ref] Despite this, indications for LT continue to increase, resulting in ongoing challenges to increase the number of potential donors and curtail waiting-list mortality.
Presently, KSA has 4 LT centers: 3 in the country capital, Riyadh, and one in the Eastern Province (Dammam). [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] Over 50% of the total LT in 2017 was conducted at the King Faisal Specialist Hospital and Research Centre (KFSHRC) in Riyadh, with results comparable with international standards. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] In fact, the 2017 annual report of the Saudi Center for Organ Transplantation (SCOT) states that a total of 147 LDLT were performed, of which 131 (89%) LTs were from living-related donors and 16 (11%) from livingunrelated liver donors. Out of these 147 LDLTs, 110 (69%) were performed at KFSHRC.The SCOT is the national agency for organ donation and transplantation. The center carries many roles, from rendering necessary support for organ procurement allocation and transplantation in KSA to authorizing all programs for LT [bib_ref] The Saudi Center for Organ Transplantation: An Ideal Model for Arabic Countries..., Shaheen [/bib_ref] and providing the required criteria for establishing LT Centers in KSA.The most recent data on LT has been extracted from the International Registry in Organ Donation and Transplantation (IRODaT) [fig_ref] Table 1 -: Registered liver transplantation in the Kingdom of Saudi Arabia between 2018 and... [/fig_ref].
These Clinical Practice Guidelines (CPG) aim to help physicians and other healthcare providers evaluate candidates for LT and correctly manage LT patients in KSA. It generates evidence and recommendations according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. [bib_ref] GRADE: An emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] The principles of the GRADE system reflect the quality of underlying data. There are 2 grades of recommendations: strong and weak. If the evidence quality is higher, a strong recommendation is necessary; if the inconsistency in values or ambiguity is more, then a weaker recommendation is granted. [fig_ref] Table 2 -: Grading of Recommendations Assessment Development and Evaluation [/fig_ref] shows the grading used in this CPG.
## Organ donation
Introduction. Currently, the KSA represents one of the leading countries in the Middle Eastern region in the field of LT, [bib_ref] Experience with 122 consecutive liver transplant procedures at King Faisal Specialist Hospital..., Al-Sebayel [/bib_ref] but the supply of organ donation is still far from the requirements for LT. Indeed, the KSA possesses a wide supply-demand gap in transplants, assessed to be 2 to 4 per million population (pmp). [bib_ref] How informed are the Saudi public about the value of organ donation:..., Alnasyan [/bib_ref] This creates a major shortage crisis in organs and a worsening waiting list of critically ill patients registered for transplantation. [bib_ref] Organ donation after brain-death: experience over five-years in a tertiary hospital, Aldawood [/bib_ref] In the KSA, both deceased donor LT (DDLT) and LDLT are encouraged. However, donation after brain function loss and death is currently the only option available for DDLT in KSA, and for years, religious and ethical concerns have constrained the LT program from progressing. These concerns were mainly due to initial Islamic scholar opinions (Fatwa) advising against donation from brain dead individuals, which have negatively affected the perception of the local community. As a result, a study reported that from 162 patients diagnosed with brain death between 2001-2005, only 17% of patients consented to organ donation, and a majority of these were non-Saudis. [bib_ref] Organ donation after brain-death: experience over five-years in a tertiary hospital, Aldawood [/bib_ref] Since expatriate workers form the largest pool of deceased donors in KSA, ethical apprehensions arise on the financial compensation by the government, through SCOT, to the donor's next of kin. However, SCOT clarified that such monetary compensation is nothing but showing deep gratitude to the donor's family, as they are responsible for making the donation decision. [bib_ref] Organ donation after brain-death: experience over five-years in a tertiary hospital, Aldawood [/bib_ref] Organ shortage crisis. The main challenge continues to be organ shortage. Although the lack of transplantable organs is a worldwide phenomenon, it is particularly evident in countries like KSA due to significant barriers, such as public awareness based on social, religious, and organizational values. [bib_ref] Organ donation after brain-death: experience over five-years in a tertiary hospital, Aldawood [/bib_ref] Constraints related to understanding the concept of brain death and inadequate public awareness of the importance of donating organs for transplantation in many countries of the region have a negative impact on deceased organ donation. [bib_ref] How to improve organ donation in the MESOT Countries, Shaheen [/bib_ref] The results of a survey conducted in 2018 of 500 respondents in KSA demonstrated that less than half of the respondents (44%) agreed with the statement that upon their death, they would allow their organs to be removed to help others in need, 26% neither agreed nor disagreed, and 30% disagreed. [bib_ref] Organ Donation and Transplantation in the Kingdom of Saudi Arabia, Statista Research Department [/bib_ref] Another concern is that organ allocation in KSA for livers is center-dependant, that is, a center gets an organ irrespective of the need of patients. This situation creates disparities that impact organ donation. This procedure has been followed since early 1990s, leading to the unbalanced organ dispersal among patients within the KSA. [bib_ref] Organ donor allocation system for liver transplantation in the Kingdom of Saudi..., Sebayel [/bib_ref] An equitable allocation system needs to be enforced to improve the LT program in the KSA.
Despite all efforts, there is an excessive discarding of livers. About half of the donated livers are rejected because of low standards of managing donors. Besides, the brain death protocol is finished in approximately 60% of patients. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] There were 629 donors in 2016; however, surprisingly, only 399 (63%) correctly finalized the required protocol-based documentation procedures. Only 101 were consenting donors (25%), while 64 were DDLTs; thus, the liver donor conversion rate was merely 10%. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] This severe organ shortage crisis has led to investments in LDLT in the 4 LT centers in the KSA. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] Reporting and documentation. The current reporting system for organ donation in KSA mandates all hospitals to comply with the Ministry of Health (MoH) regulation to report all cases of confirmed brain death donors to SCOT. Laws of enforcement, however, are not in place yet. It is suspected that only a quarter of the brain death cases is being reported to SCOT. [bib_ref] The efficiency in the utilization of potential donors for organ transplantation in..., Al-Sebayel [/bib_ref] Appropriate policies are being introduced to enable procedures to confirm brain death and initiate the required process to manage deceased donor candidates. Saudi Centre for Organ Transplantation publicly provides the necessary documentation for declaring brain death.Specific laws and regulations have been recently enforced including individual declaration of willingness to donate upon death for all Saudi citizens and foreigners living in Saudi Arabia. Declaration will be mandatory through the Ministry of Interior's electronic web services. This will hopefully result in limiting the loss of potential deceased organs. Recently, SCOT has implemented policies that include close monitoring and reporting of survival outcomes from all centers. Feedback will then be discussed in the National Liver Transplant Committee governed by SCOT. Donation cascade. The Spanish organ donation system is one of the most efficient, with the highest number of donors pmp. Approximately 5.4% of all the LTs are performed in Spain, with a rate of 22.9 pmp. [bib_ref] Limits for adult liver donation in Spain, Briceño [/bib_ref] The National Transplant Organization of Spain has published good practice guidelines in the process of organ donation, which entails a series of recommendations to improve the effectiveness of their LT program.The Spanish system is an organized and aggressive approach that optimizes the donation process component within their healthcare system, yet to be fully replicated in other countries.
In KSA, it is feasible to adjust some of the Spanish model components for our healthcare system. In fact, the SCOT has already adopted the sequence of procedures for organ donation after death, which is publicly available. 36
Deceased organ donation. With the steep rise in the requirement of transplantation came the realization that living-related donation was not an answer to the problem. Therefore, by the late 1980s, the need for an active DDLT program within the KSA became obvious. [bib_ref] Cadaveric organ donation in Saudi Arabia, Nicholls [/bib_ref] In 1985, the setup for an active deceased organ donation and transplantation initiative was started. The National Kidney Foundation was first formed as the KSA organ donor referral center, to which all institutes were required to report any suitable donors. [bib_ref] Cadaveric organ donation in Saudi Arabia, Nicholls [/bib_ref] This center was renamed as SCOT in 1993. [bib_ref] Saudi center for organ transplantation: activities and achievements, Shaheen [/bib_ref] Media campaigns were used to educate the population and increase public and medical personnel awareness about the concept of brain death and the importance of transplantation program for various organs; addressing religious, social, and medical aspects of the program.In 1990, the first DDLT was performed, and nowadays, the KSA is one of the leading countries in the Middle Eastern region in the field of DDLT. [bib_ref] Experience with 122 consecutive liver transplant procedures at King Faisal Specialist Hospital..., Al-Sebayel [/bib_ref] Despite the various social, religious, and organizational challenges, LT in KSA has increased substantially in the last 30 years with comparable outcomes to other well-recognized international centers. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] Still today, many factors can affect the availability of deceased organ donors, such as the potential of clinically appropriate donors, governmental regulations, health care investment, public awareness and perceptions, tradition, and faith.In 2017, 79 deceased livers were transplanted in KSA. Of these, 69 (87%) livers were transplanted to adult recipients and 10 (13%) to pediatric recipients. These cases were distributed between the 3 LT centers.Not only is there a limited supply of organs for LTs, but the quality of available organs is also not uniform. An association between organ quality and quality of life after LT has been reported. [bib_ref] Organ quality and quality of life after liver transplantation, Volk [/bib_ref] [bib_ref] Should a lower quality organ go to the least sick patient? Model..., Croome [/bib_ref] In 2017, the MoH introduced a 3-year joint program with the Donation Transplantation Institute and SCOT. This project aimed to improve the donation and transplantation rates as well as communication with donor hospitals, by introducing a quality management system developed with inputs from popular prototypes in organ donation that amalgamate evidence-supported practices from Europe and USA, including the Organ Donation European Quality System. [bib_ref] Implementation of a quality management system on organ donation in the Kingdom..., Arredondo [/bib_ref] Saudi Centre for Organ Transplantation has more comprehensive geographical coverage in KSA regions, by setting up an electronic alert system-based organ donation coordination through intensive care units (ICUs) of donating hospitals. [bib_ref] Organ Transplantation in Saudi Arabia, Shaheen [/bib_ref] The ultimate goal of this project was to increase the donation rate up to 10 pmp.According to data from the IRODaT, in 2019, the actual LT from deceased donors for KSA was 2.33 pmp, while the LT from living donors was 7.22 pmp. 7 Donor maintenance. The donors are primarily heart-functional, brain-dead, and deceased. Many have major physiologic deficiencies, that are exaggerated post brain death. Prompt rectification of such defects is crucial to maintain proper post-transplant organ functioning. Hence, appropriate donor maintenance is vital to achieving good functioning of the graft for a long duration. [bib_ref] Organ donor maintenance and procurement : Current opinion in organ transplantation, Szmalc [/bib_ref] Per the American Association of Neurology, brain death involves 3 cardinal signs, i) termination of brain functions, including the brainstem, ii) coma or unresponsiveness, and iii) breath cessation. [bib_ref] Evidence-based guideline update: Determining brain death in adults: Report of the quality..., Wijdicks [/bib_ref] Improvement in the quality of donated graft can be achieved by providing appropriate attention to the parameters that help assess the blood flow in donor and pulmonary-protective ventilator tactics. Use of thyroxine, antidiuretic hormone, corticosteroid, and insulin as a supplementary hormone therapy has been reported to provide improved outcomes post-surgery. [bib_ref] Brain death and care of the organ donor, Kumar [/bib_ref] As an essential component of the donation process, the care of the donors should be standardized. [bib_ref] Proposed Treatment Guidelines for Donor Care, Powner [/bib_ref] Currently, the maintenance of brain death donors is mainly performed by intensivists in the referring hospital who communicate directly with the coordinators and doctors in SCOT. On-site care of donors by SCOT personnel is occasionally done. However, the donation system in KSA lacks well-trained coordinators who can optimize donor care. [bib_ref] Organ donation after brain-death: experience over five-years in a tertiary hospital, Aldawood [/bib_ref] The transplant center determines the suitability of the donor or liver for harvesting or transplantation. The decision is based on the donor and organ status. 4
## Extended criteria donors (ecds). the increasing
need for LT is expected to surge even more in the years to come, necessitating exploration of ways to strengthen donor pool.
Organ shortage requires increasing number of potential donors and increased use of ECDs, also called marginal donors.These represent a wide range of donors with adverse characteristics. Extended criteria donors liver grafts represent a higher primary graft https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] Besides, cold ischemia time and locality where the donor resides are regarded with respect to where the recipient is living.Liver steatosis is not taken into account in DRI, which is a crucial limitation.BAR score. The BAR score recognizes a few significant predictors of recipient survival after transplantation and a study confirmed the superiority of the BAR score as compared to the other scoring systems. [bib_ref] Are There Better Guidelines for Allocation in Liver Transplantation?, Dutkowski [/bib_ref] Partial LTs (split and living donor LT), donation after circulatory death (DCD), and combined LTs are not considered. These predictors are: MELD score and age of recipient, age of donor, cold ischemia time, earlier transplantation, and pre-transplant life assistance dependency.
Rise in BAR scores implies reduced patient survival. Balance of risk score has a threshold, after which the mortality increases exponentially at BAR,while it stays stable below 16.The BAR score is suitable to explain the threshold when there is increased LT risk. This is especially advantageous when allocating ECD livers to sick patients, which is a common occurrence in KSA.
Disorders in liver donors. Liver steatosis. The frequency of steatosis in donors for LT is increasing over time. The prevalence of this condition in the Saudi population is predicted to be 25%. [bib_ref] Nonalcoholic fatty liver disease burden -Saudi Arabia and United Arab Emirates, Alswat [/bib_ref] Still, the SCOT statistics show that steatosis is the primary cause of unrecovered extinct livers of qualified donors agreed for donating between 1994 and 2017 (45.6%).The rise in demand to increase the donor liver graft availability results in the possible inclusion of steatotic livers as donors. Although related to poor post-LT outcomes, the inclusion of steatotic livers has conflicting results in the literature, and further investigation is needed. [bib_ref] Donor hepatic steatosis and outcome after liver transplantation: A systematic review, Chu [/bib_ref] In spite of poor outcomes than that of nonsteatotic donor livers, steatotic are the most common marginal donor livers presented in the recent 2 decades because of the scarcity of donor organs. Liver steatosis is not against cadaveric LT all the times. [bib_ref] Hepatic steatosis is not always a contraindication for cadaveric liver transplantation, Deroose [/bib_ref] Mild steatotic donor livers in LT could not substantially raise the risk for unfortunate outcomes after LT. [bib_ref] Short-term and long-term outcomes of liver transplantation using moderately and severely steatotic..., Wu [/bib_ref] Metabolic syndrome especially obesity and diabetes negatively affected the number of living donors. [bib_ref] The impact of metabolic syndrome and prevalent liver disease on living donor..., Al-Hamoudi [/bib_ref] Increasing the donor pool needs proper introduction of novel approaches, including the use of living non-related liver donors under strict policies.
The classification of steatosis can range from mild (10-30%), moderate (30 to 60%), and severe (>60%), based on the proportion of hepatocytes that contain cytoplasmic fat droplets. [bib_ref] Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat..., Veteläinen [/bib_ref] Moderate and severe steatotic donor livers can be considered for recipients in comparatively better clinical status but having an failure than standard-criteria donor grafts. [bib_ref] Expanded criteria donor grafts for deceased donor liver transplantation under the MELD..., Amin [/bib_ref] However, with an ECD, the waiting time may become shorter. Although ECD livers are not considered to be ideal and highly challenging for the transplant team, they can significantly shorten the waiting time to transplantation. [bib_ref] Extended criteria donors in liver transplantation, Vodkin [/bib_ref] Per the Eurotransplant definition, concerning the various classes of graft dysfunction, these criteria are used for ECDs:- Donor above 65 years of age - Hospitalization in the ICU under ventilation support for more than 7 days - Body mass index (BMI) >30 kg/m 2 - Serum sodium level more than 165 mmol/L - Serum bilirubin level above 3 mg/dl - Aspartate aminotransferase above 90 U/L - Alanine aminotransferase level above 105 U/L Graft failure in extended criteria donors. Anticipated risks. In the past 2 decades, many quality models for donor, recipient, or combining both have been developed. To estimate post-LT outcomes, the survival outcomes following LT, [bib_ref] Survival Outcomes Following Liver Transplantation (SOFT) score: A novel method to predict..., Rana [/bib_ref] Delta model of end-stage liver disease (D-MELD), [bib_ref] D-MELD, a simple predictor of post liver transplant mortality for optimization of..., Halldorson [/bib_ref] and balance of risk (BAR) scores [bib_ref] Are There Better Guidelines for Allocation in Liver Transplantation?, Dutkowski [/bib_ref] established. Such models integrate features of donor and recipient, along with LT characteristics; the donor risk index (DRI) [bib_ref] Characteristics associated with liver graft failure: The concept of a donor risk..., Feng [/bib_ref] includes only donor and LT features to assess the quality of donor and organ.
Donor risk index. The overall survival after LT has steadily improved over the last 20 years. [bib_ref] Evolution of indications and results of liver transplantation in Europe. A report..., Adam [/bib_ref] Nevertheless, the increasing demand for organ availability causes augmented use of high-risk or ECD organs. During procurement and LT, donor-recipient matching occurs, and an extensive process is involved in choosing and finalizing an organ for LT. [bib_ref] Organ allocation for chronic liver disease: Model for end-stage liver disease and..., Asrani [/bib_ref] [bib_ref] Development of organ-specific donor risk indices, Akkina [/bib_ref] Thus, identifying the donor-related factors that may derive from poor post-LT outcomes is extremely important. Furthermore, different regions have different donor characteristics and differences in medical management across organ procurement institutions, which have the potential to affect the post-LT results. [bib_ref] Development of organ-specific donor risk indices, Akkina [/bib_ref] Organ-specific DRI are introduced to estimate graft survival among different donor and recipient features. The use of livers with high DRI associates with amplified healthcare expenses that are risk-independent to patients. [bib_ref] Development of organ-specific donor risk indices, Akkina [/bib_ref] Graft failure risk can be substantially increased due to: - recipient's age (more than 40 years) - racial group (African versus White) - death reason (cardiovascular [CV] injuries) - type of graft (partial or split LDLT) - height (by means of 10 cm reduction) desperate requirement for LT. Moderately and severely steatotic donor livers used for LT were reported to cause higher occurrence of primary non-function and a drift to rise 1-month recipient death rate. Still, the outcomes over on a more extended period were comparatively similar. This outcome led to the suggestion that recipients with good health might endure weak graft function in the beginning or severe post-LT difficulties and further supports the use of moderate and severe steatotic donors for LT. [bib_ref] Short-term and long-term outcomes of liver transplantation using moderately and severely steatotic..., Wu [/bib_ref] Furthermore, it has been shown that microvesicular steatosis of donor livers has no adverse effect on the postoperative outcome after LT. [bib_ref] Grade of donor liver microvesicular steatosis does not affect the postoperative outcome..., Andert [/bib_ref] The results from a study that combined the 2 major LT databases (United States and Europe) into one complete model to foresee outcome after LT, which focused on the effect of the existence of graft steatosis, showed that hepatic steatosis can be included in modern liver allocation models. Using the BAR score, microsteatosis or less than 30% of macrosteatotic grafts are safer to use until BAR score <18, while grafts with >30% macrosteatosis need to be used for BAR score of 9 or inferior. [bib_ref] The use of fatty liver grafts in modern allocation systems: risk assessment..., Dutkowski [/bib_ref] These results are helpful, considering the current high prevalence of steatosis in LT donors in KSA.
Use of anti-HBc positive donors. Hepatic grafts from donors positive for anti-HBc antibody are frequently associated with HBV infection transmission to recipients, even in the absence of serological markers of active infection. [bib_ref] Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation, Holt [/bib_ref] De novo HBV infection is mainly caused by transplanting anti-HBc positive grafts, and care must be taken by the LT centers when using these organs.
Studies have shown that use of hepatitis B immunoglobulin (HBIg) during the surgery along with the use of nucleos(t)ide analogs (NUCs) therapy for longer duration, like lamivudine, can prevent HBV infection in those who received hepatic allografts from those having anti-HBc positivity. [bib_ref] Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation, Holt [/bib_ref] [bib_ref] Prevention of hepatitis B virus infection from hepatitis B core antibody-positive donor..., Suehiro [/bib_ref] De novo HBV infection developed in 19% of recipients with hepatitis B surface antigen (HBsAg)positivity is not common in anti-HBc/hepatitis B surface antibody (anti-HBs) positive recipients (15%) than HBV naïve non-prophylactic patients (48%). Anti-HBV prophylaxis decreased the rates of such infections in anti-HBc/anti-HBs positive and HBV naïve recipients (3% and 12%). Liver grafts from that donors having anti-HBc positivity are safer to use, especially in recipients with HBsAg or anti-HBc/ anti-HBs positivity. Recipients with HBsAg negativity must get lamivudine prophylaxis, similar to recipients with anti-HBc and anti-HBs positivity.In an international, European, multicenter retrospective analysis to measure the rates of HBV recurrence in LT recipients with HBV, it was shown that fewer recurrence incidents were reported when patients received HBIg and NUC as prophylaxis (4.3%) in the long-term of 7 years. The HBV-HCC recurrence rate was 9.5%. [bib_ref] Recurrence of Hepatitis B Infection in Liver Transplant Patients Receiving Long-Term Hepatitis..., Beckebaum [/bib_ref] However, lifelong HBIg use is both burdensome and costly, whereas sustained use of lamivudine for a longer time induces resistance formation. Lately, to bring in HBIg-free therapy regimens, highly efficacious NUCs, such as entecavir or tenofovir, were investigated either as a single-drug regimen or together with HBIg in a lower dosage with better outcomes. [bib_ref] Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and..., Chauhan [/bib_ref] The use of HbsAg donors is increasingly done in clinical practice and could help in expanding our local donor pool. [bib_ref] Long term follow-up and outcome of liver transplantation from hepatitis B surface..., Ballarin [/bib_ref] Hepatitis C virus positive donors. These donors have varying (mild to severe) forms of infection. However, choosing viremic donors and those with seropositivity are crucial to LT for an uninfected recipient. A viremic donor may pose a 100% transmission risk through LT. Nevertheless, an aviremic but seropositive-only donor possesses lesser threat in terms of HCV transmission (up to 16% risk). [bib_ref] Expanding the donor pool: Hepatitis C, hepatitis B and human immunodeficiency virus-positive..., Crismale [/bib_ref] Direct-acting antiviral therapy has proven to be highly effective in treating HCV infection. Its almost 100% cure rates suggest that organs with HCV positivity are safer to waitlisted patients who do not have HCV infection. [bib_ref] Should organs from hepatitis C-positive donors be used in hepatitis C-negative recipients..., Selzner [/bib_ref] Excellent outcomes of antiviral agents against viral hepatitis have rendered the LT fraternity with the advent to utilize organs from donors with viral hepatitis that require simple treatment post-LT. [bib_ref] Expanding the donor pool: Hepatitis C, hepatitis B and human immunodeficiency virus-positive..., Crismale [/bib_ref] However, ethical concerns should be considered and require a rigorous process of obtaining informed consent from potential recipients. [bib_ref] Should organs from hepatitis C-positive donors be used in hepatitis C-negative recipients..., Selzner [/bib_ref] Grafts from donors with viral hepatitis. During transplantation, stored fresh tissue grafts from donors, who are infected with HBV and HCV, are utilized for vascular reconstruction. This is how the recipients get infected and pose a risk of disease transmission.To avoid these constraints, it is not advisable to store these arterial and venous tissues for use in patients other than relevant organ.Present/past cancer in donors. Malignancy transferring from donor to recipient due to LT is often a severe complication in patients with less immunity and is challenging for both transplant experts and recipients.The tumor transmission risk to the recipient of DDLT from donors affected by central nervous system (CNS) cancer is less common. Because cancers of the https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] CNS less frequently spread and affect outside the brain, marginal grafts can be used to increase the potential organ availability for LT. A recent study has shown that median survival of 40 months was attained in patients who received grafts from donors having a CNS cancer, and no donor-related cancer transformation has been found. [bib_ref] Deceased donor liver transplantation from donors with central nervous system malignancy: Inonu..., Ince [/bib_ref] However, the available literature remains incomplete. Further investigation is needed to understand the actual tumor transmission risk, possible risk factors, and readiness to treat recipients in case of a transmission. For donors with various primary brain tumor groups, the considerations are as follows: [bib_ref] Patients with primary brain tumors as organ donors, Orlic [/bib_ref] - Group I: organ donation is not contraindicated.
- Group II: organ donation can be considered when there are no risk factors present. - Group III: organ donation is contraindicated, unless in cases of life-challenging emergency LT, in which the waiting-list death risk is higher compared to the risk of transmitting after the surgery.
The ultimate decision regarding LT from donors with primary brain tumor is with the specialists and other team members involved in the transplanting process, who should ponder the tumor transmission risk with the death risk during the waiting list period. [bib_ref] Patients with primary brain tumors as organ donors, Orlic [/bib_ref] Careful risk and benefit assessments of using organs from those having a present or past history of cancer require cautious evaluation before performing LT. [bib_ref] Liver transplantation from donors with a history of malignancy, Benkö [/bib_ref] Individuals with glioblastoma multiforme, colorectal carcinoma (>T3), melanoma, choriocarcinoma, breast cancer (>T1c), and lung carcinoma are not suitable as LT donors.Use of organs from infected donors. The risk of microbial infections can occur following LT. The European Association for the Study of the Liver (EASL) Guidelines used a risk classification to assess the safety and suitability of donors based on infection type 12 and considers as absolute contraindications or unacceptable risk: positive donors for HIV-1 and HIV-2, multidrugresistant (MDR) infections caused by bacteria, or West Nile virus (WNV), encephalitis, tuberculosis (TB), or others; for such patients, a concrete treatment strategy is unavailable.
In contrast to the US Centers for Disease Control and Prevention policy principle of "zero" risk donor to recipient transmission, the European guidelines take a more practical and pragmatic approach in which the clinical context is considered.This seems to be more suitable for the KSA population [fig_ref] Table 3 -: Risk stratification of microbial transmission from donor to recipient in liver transplantation [/fig_ref].
## Consent and ethical issues.
The ideal organ donation model requires a significant capability to attain all available organs while upholding ethical morals. The ethical underpinning of the Western model is a combination of quality and deontology, concentrating on individual independence and advantage. The moral premise of this model is a "gift metaphor."
The donation system in KSA is incentive-based, which is not altruistic nor forcible since it preserves the individual autonomy and privacy with respect to accepting or rejecting incentives when attempting to increase usage, that practically builds a win-win state for the transplant recipients and the familial members of the deceased donor, as a minimum from a financial viewpoint. This model is not in contradiction with Saudi society values, which are based on non-secular religious underpinning. [bib_ref] The Saudi Center for Organ Transplantation: An Ideal Model for Arabic Countries..., Shaheen [/bib_ref] The incentives of this model are state-regulated. Although ideally, they are not mentioned when soliciting consent, the family members of the deceased are mostly aware, especially those of expatriates. The consent is usually obtained by an administrative coordinator from SCOT and occasionally by an in-house intensivist. A religious committee in each hospital is available to support the administrative coordinator.
Many challenges have been associated with society and the medical community regarding organ donation. Social and moral values, death taboo, ignorance, and procrastination may influence the organ donation system. [bib_ref] Ethical, socio-cultural and religious issues in organ donation, Cotrau [/bib_ref] The ethical rules that underlie live donation are different from those that concern deceased donors. However, the more careful consideration of organ donation by ethicists, religious scholars, and healthcare fraternity is common to both donors. Organ donations within the circle of a family are very welcomed and respected. Altruistic donations are also acceptable. However, an organ donation carried out with a financial motive is strictly unethical. [bib_ref] Challenges in organ transplantation, Beyar [/bib_ref] Since the 1990s, one of the main issues in the KSA relates to not properly using organs from the available cadaveric donors. Strategies have been placed to raise awareness about organ donation and raise positive consents.
In the KSA, the current system used to get consent for cadaveric donation is an "opting-in" system. [bib_ref] Organ donation: Opting in or opting out?, Rudge [/bib_ref] This procedure requires explicit donor consent before he/ she dies or endorsement by a suitable family member during the donor's death.
This system contrasts with an "opting-out" model. Donatable organs are taken out from brain dead cadavers, albeit no clear consent is given except when the deceased has earlier expressed any wish against donating. [bib_ref] Organ donation: Opting in or opting out?, Rudge [/bib_ref] Allocation and waiting-list death. Despite the widespread usage of living donors in the transplant centers in KSA, death on the waiting list has been substantial. Approximately one-third of the patients die before receiving a deceased organ. More alarming is the fact that two-thirds of the patients who need an emergency re-transplant die while waiting for an organ, and as mentioned, allocation favors centers rather than those patients in urgent need.Globally, the patient-oriented allocation (based on MELD score) has been favored over center-based allocation. Though in some European countries, notably Spain, the allocation is center-based. It is agreeable by all world centers, including KSA, that priority is given for 2 conditions: fulminant hepatic failure and re-transplant within 7 days of the first transplant. The center-based allocation in KSA has been built around zonal distribution with the core idea of supporting the transplant center receiving the donation in the respective zone. This, however, has not resulted in a major success, except for the period between 2006 and 2012, when a Mobile Donor Action Team (MDAT) operated in the Riyadh region supported by one of the transplant centers and yielded a triple number of donors immediately after its implementation by addressing logistical obstacles. [bib_ref] The Saudi Center for Organ Transplantation: An Ideal Model for Arabic Countries..., Shaheen [/bib_ref] A major review of the allocation system needs to be urgently pursued to make the best use of all potential organs.
The proposal for a new organ distribution scheme should be based on the following assumptions:
- The transplant community (mainly SCOT and the four transplant centers) is responsible for stewarding donor organs and must avoid futility at all costsloss of one graft translates into death on the waiting list. - Each program is assumed to have transparent, reasonable, responsible approaches to list, care, and educate patients, including listing and allocation policy criteria. - Programs should not have low survival rates based on listing practices, such as listing patients who have a poor chance of survival. - Though a 5 or even 10-year survival is a better estimate of program performance, a shorter year survival may be chosen at the beginning of implementing new policies. - All centers will observe and provide wait-list deaths and drop-outs (by following Scientific Registry of Transplant Recipients [SRTR] explanations) and coordinated by SCOT. Emphasis must be put on the outcome rather than numbers.
Utility concerns. The decision to prioritize high-risk patients results in lower post-LT survival (as the patient already has a high death risk), better resource utilization, and uneven transplantation rates for various indications.
Comprehensive data collection is important. The following data needs to be collected by centers and reported regularly: Summary of organ donation. The SCOT oversees multifaceted logistics-related activities during the entire organ donation procedure, such as identifying the suitable donor, reporting, diagnosing, managing, documenting, and getting the required donor consent. [bib_ref] Experience with 122 consecutive liver transplant procedures at King Faisal Specialist Hospital..., Al-Sebayel [/bib_ref] [bib_ref] The status of cadaveric organ donation for liver transplantation in Saudi Arabia, Al-Sebayel [/bib_ref] They firmly believe that continuous efforts are needed to increase public and medical community awareness on the importance of donation and transplantation of organs, to rise the count of transplantations. Clear guidelines are needed to inform the population and health care professionals. Guidelines regarding the diagnosis of brain death and subsequently to the removal of life support in such donors are required. Additionally, guidelines related to organ donation and increased public awareness about brain death are a priority and should be considered as a medical condition. [bib_ref] Understanding the concept of brain death in the Middle East, Al-Hashim [/bib_ref] Also, the knowledge and attitude of health care providers towards organ donation are concerning, and educational programs, especially for nursing and medical students, have been implemented. [bib_ref] Saudi nursing and medical student's knowledge and attitude toward organ donation-A comparative..., Majeed [/bib_ref] National legislative, governing, and monitoring bodies, in order to ensure quality, health equity, and transparency in LT are needed nationwide to support SCOTs efforts.
[formula] - [/formula]
## Evaluation of an adult for liver transplant
Indications for liver transplantation. Liver transplantation is indicated for patients with ESLD who would benefit from the procedure to extend life expectancy and/or improve quality of life. End-stage liver disease can have many etiologies and includes decompensated cirrhosis, HCC, and acute liver failure. Hepatitis B virus-related hepatic disease. Even though decompensated HBV cirrhosis is lessening globally because of extensive vaccination campaigns and the introduction of direct-acting antivirals, it is still considered a major cause of ESLD in KSA, with HCC being the third leading indication for LT. [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] The HBV status of the recipient needs to be assessed. If HBV DNA is detectable, regardless of the level, antiviral treatment with NUCs should be started because interferon (IFN) is not to be used in those having decompensated cirrhosis. Entecavir or tenofovir are the drugs of choice (Grade II-2), [bib_ref] Guideline Committee of the Korean Association for the Study of the Liver)...., Lee [/bib_ref] and they act by improving liver function and decreasing the risk of HBV recurrence after LT. They are efficacious and safe in patients with advanced liver disease. [bib_ref] Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic..., Liaw [/bib_ref] [bib_ref] Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients..., Liaw [/bib_ref] [bib_ref] Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis, Shim [/bib_ref] The dose of NUCs should be modified in those with poor creatinine clearance.It is essential to note that a significant proportion of decompensated patients who initiate NUCs therapy show improved hepatic function, that may, at times, result in delisting from LT waitlist (Grade II-2). 82,83 A recent study from KSA revealed HBV/HDV coinfection rate of 24%; however, this did not negatively impact LT outcomes. [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] On the other hand, one-third of patients may die within half a year due to hepatic function loss, irrespective of giving effective antiviral treatment,and a precise prognosis is not available to predict patients who will not require LT for recovering and those who will succumb with no LT.
Hepatitis C virus-related hepatic disease. Hepatitis C virus infection is the leading LT indication. Hepatitis C virus genotype 4 (HCV-G4) is the most prevalent genotype in the Middle Eastern region. [bib_ref] Global distribution and prevalence of hepatitis C virus genotypes, Messina [/bib_ref] [bib_ref] HCV genotypes among 1013 Saudi nationals: A multicenter study, Traif [/bib_ref] In KSA, HCV forms approximately 29% of LT indications; of them, approximately 60% are related to HCV-G4.Liver transplantation candidates need pre-LT antiviral agents to lessen the post-LT HCV recurrence (Grade I). Interferon-based regimens are not recommended due to issues with safety and tolerability. [bib_ref] Systematic review of the treatment of established recurrent hepatitis C with pegylated..., Berenguer [/bib_ref] [bib_ref] Viral hepatitis in liver transplantation, Crespo [/bib_ref] Treatment with IFN-free antiviral drugs has shown improved liver function, with some patients being delisted (Grade II). [bib_ref] Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients..., Charlton [/bib_ref] [bib_ref] The efficacy of direct anti-HCV drugs improves early post-liver transplant survival and..., Crespo [/bib_ref] Treatment with sofosbuvir and ribavirin (RBV) for a few weeks before LT in patients with HCV genotype-1 (HCV-G1) or HCV-G4, compensated cirrhosis, and HCC prevented graft infection in the most patients 91 (Grade II). Sofosbuvir/ledipasvir given along with RBV for 12 or 24 weeks was evaluated in patients with HCV-G1 or HCV-G4 and compensated or decompensated cirrhosis. The rates of sustained viral response (SVR) at 12 weeks (SVR12) were above 95% and 85% in individuals with compensated and decompensated cirrhosis, respectively (Grade II). [bib_ref] Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients..., Charlton [/bib_ref] The same study showed improvement in MELD scores by 1-8 points in about 66% of patients with decompensated cirrhosis. Sustained viral response at 12 weeks rates of ~95% was obtained with the use of the combined drugs of ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir with RBV in compensated cirrhotic cases with HCV-G1 infection. [bib_ref] ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis, Poordad [/bib_ref] Efficacy in those with compensated cirrhosis of all genotypes is obtained using the combined use of sofosbuvir, daclatasvir, and RBV (Grade II). [bib_ref] Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection, Sulkowski [/bib_ref] A report on patients infected with HCV-G4 concluded that the combination of ledipasvir and sofosbuvir, without RBV, is potent and safe in treating these patients, either in a pre-or post-LT setting. [bib_ref] Treatment of patients with hepatitis C virus infection with ledipasvir-sofosbuvir in the..., Abaalkhail [/bib_ref] Alcoholic liver disease (ALD). It is most frequent in Western countries, where it is a common LT indication,and LT for alcoholic cirrhosis has a favorable outcome. [bib_ref] Liver transplantation for alcoholic liver disease in Europe: A study from the..., Burra [/bib_ref] A period of 6-month alcohol abstinence before LT is recommended (Grade II-3). This recommendation can result in improved liver function and delisting of the patient and is a good predictor of patient compliance.
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Due to epidemic levels of obesity and T2DM, NAFLD and NASH prevalence are emerging as serious health concerns in KSA. [bib_ref] Nonalcoholic fatty liver disease burden -Saudi Arabia and United Arab Emirates, Alswat [/bib_ref] Patients with NAFLD/NASH may progress to ESLD and require LT. The presence of metabolic syndrome is linked to many comorbidities, which increases the risk of complications related to surgery [bib_ref] Evolving aspects of liver transplantation for nonalcoholic steatohepatitis, Charlton [/bib_ref] and needs to be carefully evaluated. Conditions, such as obesity, hypertension, T2DM, and dyslipidemia require rigorous workup in the screening phase, and they may exacerbate in the post-LT phase (Grade III). [bib_ref] Additive effect of pretransplant obesity, diabetes, and cardiovascular risk factors on outcomes..., Dare [/bib_ref] Primary biliary cholangitis. Survival of primary biliary cholangitis (PBC) patients hugely increased well with the extensive use of ursodeoxycholic acid. Nevertheless, approximately 33% of patients show treatment failure and continue to develop cirrhosis, necessitating LT as the final option. [bib_ref] Primary biliary cirrhosis and liver transplantation, Akamatsu [/bib_ref] Indications for LT in individuals with PBC do not differ from those in patients with other liver diseases; those with decompensated hepatic disease, portal hypertension of advanced, complex stage, and non-controllable and non-tolerable pruritus are indicated for LT 12 (Grade II-3). The optimal timing for LT in PBC is when the total serum bilirubin reaches around 10 mg/dL. [bib_ref] Optimal timing of liver transplantation for patients with primary biliary cirrhosis: Use..., Christensen [/bib_ref] Primary sclerosing cholangitis (PSC). In PSC cases, decompensated hepatic disease, complicated portal hypertension, and recurring occurrences of cholangitis must be indicated for LT (Grade II-3).The cholangiocarcinoma risk rises approximately 10-15% post a 10-year PSC course, [bib_ref] Primary sclerosing cholangitis and malignancy, Boberg [/bib_ref] and this bile duct cancer should be left out using pre-LT radiological and biological markers (Grade III). Colon cancer should be monitored by annual colonoscopy in patients with PSC and ulcerative colitis (Grade II-3).
Autoimmune hepatitis (AIH). Autoimmune hepatitis affects more females than males, with the percentage of female patients in the KSA ranging from 60.8% in the central region to 75.7% in the Western region. [bib_ref] The saudi association for the study of liver diseases and transplantation clinical..., Aljumah [/bib_ref] The prevalence of AIH among LT patients from KSA is estimated to be approximately 14.3%, based on a single-center report. [bib_ref] Liver transplantation for autoimmune hepatitis: a single-center experience, Khalaf [/bib_ref] Liver transplantation is indicated for AIH in those with ESLD, or with acute hepatic failure during ineffective immunosuppressant therapy (Grade II-3). [bib_ref] Usefulness of corticosteroids for the treatment of severe and fulminant forms of..., Ichai [/bib_ref] The outcomes of LT for AIH patients are extremely good, with 1-(90%) and 5-year (80%) survival rates. [bib_ref] Long-term follow-up after liver transplantation for autoimmune hepatitis: Evidence of recurrence of..., Ratziu [/bib_ref] Wilson's disease (WD). Wilson's disease is a rare autosomal recessive disease affecting copper metabolism. Only a few studies on WD patients of a small sample size have been conducted in KSA, mainly in regions where consanguineous marriages exceed 50%. [bib_ref] Wilson disease in 71 patients followed for over two decades in a..., Fadda [/bib_ref] Wilson's disease can manifest as acute, subacute, or even chronic hepatic failure, leading to ESLD. Acute stage (Grade III) or ESLD development may require LT, and candidates with neuropsychiatric symptoms need neuropsychiatric examination.Hereditary hemochromatosis (HH). Hereditary hemochromatosis is an autosomal recessive disorder featured by iron overload. It is caused by a mutation in the HFE gene, the most common being p.C282Y and p.H63D. In the Saudi population, the frequency of p.C282Y is extremely low (<0.001), but the p.H63D mutation is relatively common. [bib_ref] Frequency of common HFE variants in the Saudi population: A high throughput..., Alsmadi [/bib_ref] Few HH patients (1%) transplant due to ESLD, 12 but they pose a higher risk of HCC than those affected by other cirrhosis causes. [bib_ref] Survival and causes of death in cirrhotic and in noncirrhotic patients with..., Niederau [/bib_ref] Therapeutic phlebotomy is the generally recommended therapy for HH. [bib_ref] Hemochromatosis: The impact of early diagnosis and therapy, Powell [/bib_ref] Iron overload mainly poses hepatic implications; nevertheless, it has the potential to develop multiple organ damage. The post-LT outcome for HH is favorable, with 1-(80.7%) and 5-year (74%) survival rates (Grade III). [bib_ref] Survival After Liver Transplantation in Patients With Hepatic Iron Overload: The National..., Kowdley [/bib_ref] Primary hyperoxaluria type 1 (PHT1). This disease develops due to shortage of alanine:glyoxylate aminotransferase. It results in the accumulation of insoluble calcium oxalate salts in the kidney and other organs. [bib_ref] The primary hyperoxalurias, Bobrowski [/bib_ref] Hemodialysis is inadequate for oxalate clearance, requiring LT and kidney transplantation (KT) to rectify the metabolic irregularity. [bib_ref] Liver-kidney transplantation in primary hyperoxaluria type-1: case report and literature review, Siegal [/bib_ref] Isolated KT reinstates oxalate excretion but is linked to increased recurrence. Pre-emptive LT before end-stage kidney disease is thus a recommended strategy, as LT improves the metabolic defect and averts renal failure . Hepatocellular carcinoma. Hepatocellular carcinoma is the most frequent hepatic cancer. In the KSA, HCC comprises 87.6% of all hepatic malignancies, and the median ages at cancer recognition are 65 and 60 years for males and females, respectively. [bib_ref] Saudi gastroenterology association guidelines for the diagnosis and management of hepatocellular carcinoma:..., Abdo [/bib_ref] This HCC incidence in KSA is a consequence of the increased occurrences of 2 major risk factors, namely HBV and HCV infection. Indications for LT in HCC patients are liver cirrhosis, Milan criteria (one lesion <5 cm or <3 lesions <3 cm each), no proof of portal vein (PV) invasion or extrahepatic spread, and no contraindications for LT 112 (Grade I). When these criteria are applied, 5-year survival rate exceeding 70% can be predictable. [bib_ref] Liver transplantation for the treatment of small hepatocellular carcinomas in patients with..., Mazzaferro [/bib_ref] To avert the patient from falling out of these criteria when on waiting list, local ablative treatment or chemoembolization can be given to resist cancer growth. https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] University of California San Francisco (UCSF) criteria have shown that the patients with the following measures possess a recurrence-less survival not substantially varied from those within the Milan principles: one nodule of <6.5 cm or many nodules with the hugest being <4.5 cm and the sum being <8 cm. [bib_ref] Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B:..., Schiff [/bib_ref] Nonetheless, the Milan criteria serve as the yardstick for choosing HCC patients to undergo LT and the source for appraising new suggested criteria. A 5-year survival is to be attained after downstaging post-LT as similar as the HCC patients who fit the norms for LT with no need of downstaging. [bib_ref] HCV genotypes among 1013 Saudi nationals: A multicenter study, Traif [/bib_ref] Another criteria includes the alpha-fetoprotein (AFP) levels above 500 ng/ml or a hike of 15 ng/ml per month which are poor prognosis criteria. [bib_ref] Beneficial effects of lamivudine in hepatitis b virus-related decompensated cirrhosis, Kapoor [/bib_ref] Like the AFP model, other measures have been used, that consider the nodule counts and sizes along with the AFP level. [bib_ref] Global distribution and prevalence of hepatitis C virus genotypes, Messina [/bib_ref] Cancer progression, downstaging, and bridging therapy make all patients estimated to wait for LT more than 6 months. [bib_ref] Systematic review of the treatment of established recurrent hepatitis C with pegylated..., Berenguer [/bib_ref] Non-cirrhotic patients with non-resectable HCC, who have a resection and an intrahepatic HCC recurrence, are regarded as suitable LT candidates when the non-existence of macrovascular invasion and extrahepatic spread has been confirmed. [bib_ref] Viral hepatitis in liver transplantation, Crespo [/bib_ref] Cholangiocarcinoma. It is the second most common hepatic neoplasia. A study on cancer incidence using data from the KFSHRC Tumor Registry program showed that 11% of cancer malignancies were due to cholangiocarcinoma. [bib_ref] Trends and patterns of primary hepatic carcinoma in Saudi Arabia, Hussain [/bib_ref] Cholangiocarcinoma often features a poor prognosis and is separated into intrahepatic, hilar, and distal. Liver transplantation in such cases is contentious as the disease may recur. [bib_ref] Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma, Bridgewater [/bib_ref] For unresectable hilar cholangiocarcinoma, neoadjuvant
## Recommendations for indication of liver transplantation:
- Entecavir or tenofovir is the recommended antiviral treatment for hepatitis B virus (HBV)-related liver disease prior to liver transplant (Grade II-2) as they improve hepatic function and reduce post-liver transplantation (LT) HBV recurrence risk. - Antiviral drugs should be given if possible before LT (Grade I) to lessen post-LT hepatitis C virus (HCV) recurrence.
Treatment with interferon (IFN)-free antiviral drugs can improve liver function, with some patients being delisted (Grade II). - Treatment with sofosbuvir and ribavirin is recommended for a few weeks before LT in patients with HCV-G1 or HCV-G4, compensated cirrhosis, and hepatocellular carcinoma (HCC) to prevent graft infection in the majority of patients (Grade II). The combination of sofosbuvir, daclatasvir, and RBV is also useful in patients with compensated cirrhosis and with all genotypes (Grade II). - A period of 6-month alcohol abstinence before LT is recommended (Grade II-3) - In the setting of cirrhosis, conditions such as obesity, hypertension, type 2 diabetes mellitus (T2DM), and dyslipidemia should go through rigorous workup in the pre-transplant screening phase, to prevent exacerbation in the post-LT phase (Grade III). - Patients with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) should be considered for LT if they present with decompensated hepatic disease, portal hypertension of difficult complex stage, recurrent cholangitis, and non-controllable and non-tolerable pruritus (Grade II-3). - Cholangiocarcinoma, the bile duct cancer, needs to be left out by radiological and biological indicators using pre-LT in PSC patients (Grade III). Colon cancer should be monitored by annual colonoscopy in patients with PSC and ulcerative colitis (Grade II-3). - LT is indicated for autoimmune hepatitis (AIH) patients with end-stage liver disease (ESLD), or acute hepatic failure during ineffective immunosuppressant therapy (Grade II-3). - Wilson's disease can manifest as acute, subacute, or chronic hepatic failure, leading to ESLD. Acute stage or ESLD development may require LT. - Pre-emptive LT before end-stage kidney disease is a recommended strategy, as LT improves the metabolic defect and averts renal failure (Grade III). - Patients with HCC and present with liver cirrhosis, Milan criteria (a single lesion less than 5 cm or less than 3 lesions smaller than 3 cm each), no evidence of portal vein invasion or extrahepatic spread, and no contraindications for LT should be considered for LT (Grade I chemoradiation and LT are considered a therapy strategy [bib_ref] Liver transplantation for cholangiocarcinoma, Rosen [/bib_ref] [fig_ref] Table 3 -: Risk stratification of microbial transmission from donor to recipient in liver transplantation [/fig_ref] , assisting in achieving lesser recurrences and more remarkable long-term survival than other available therapy strategies. [bib_ref] Liver transplantation for cholangiocarcinoma, Rosen [/bib_ref] Surgical removal is regarded as a suitable therapeutical option for extrahepatic cholangiocarcinoma. Other hepatic malignancies. Liver transplantation can help treat other hepatic malignancies that do not feature extrahepatic metastatic spread, including fibrolamellar cancer and epithelioid hemangioendothelioma. Remarkable disease-free survival rates: 90% (one year), 82% (5 years), and 64% (10 years) (Grade II-3). [bib_ref] The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma:..., Lerut [/bib_ref] Workup process. Management of pre-LT patients should aim at not only eliminating surgery risks but also managing contraindications of long-term immunosuppression following LT. Assessing a LT candidate needs the collaboration of a multidisciplinary team (MDT) of specialists to check for all related comorbidities 118 (Grade III).
## Management of medical comorbidities
Obesity. Overweight and obese patients have significantly increased morbidity in terms of infections after LT and, consequently, more prolonged hospitalizations. [bib_ref] Increased morbidity in overweight and obese liver transplant recipients: A single-center experience..., Hakeem [/bib_ref] In obese patients (BMI >35), MDT discussion involving a diet specialist, psychology expert, hepatologist, anesthetic expert, and surgeon is needed. On the other hand, malnutrition is another major concern in cirrhotic patients; therefore, nutritional assessment and management of malnutrition are mandatory in the pretransplant setting. [bib_ref] Nutritional assessment and therapy in patients requiring liver transplantation, Lowell [/bib_ref] Older age. Though LT does not have any specific age requirement, patients above 65 years need a MDT discussion to evaluate comorbidities (Grade III). Elderly patients (>70 years) having several comorbid conditions are regarded as relatively contraindicated LT by all 4 LT centers in KSA. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] However, 5-year death rate and graft loss in recipients above 70 years are similar to those in younger patients, signifying that patients need not be excluded based only on age, but these recipients develop a higher CV complications risk. [bib_ref] Outcomes after liver transplant in patients aged 70 years or older compared..., Aduen [/bib_ref] The impact of old donor age is more pronounced in younger recipients, and age-matching between the donor and the recipient should be incorporated into allocation policies with a multistep approach. [bib_ref] Age and liver transplantation, Durand [/bib_ref] Cardiovascular disease. Checking of CV function is essential in the assessment process. Traditional CV risk factors are associated with coronary artery disease (CAD) in candidates with hepatic disease, which are to be considered as indicators for cautious pre-LT assessment of coronary risk. [bib_ref] Prevalence and prediction of coronary artery disease in patients with liver cirrhosis:..., An [/bib_ref] Electrocardiogram and transthoracic echocardiography need to be conducted in LT candidates to differentiate the pre-existing cardiac disease. To uncover asymptomatic ischemic heart disease, a cardiopulmonary exercise test is required if the candidate has several CV risk factors and is above 50 years (Grade II-3). In candidates with increased CV risk, a cardiology consultation is required for executing a coronary angiography when CAD is suspected. If the candidates received effective pre-LT CAD treatment, post-LT survival is not expressively varied between those having and not having obstructive CAD. [bib_ref] Liver transplantation outcome in patients with angiographically proven coronary artery disease: A..., Wray [/bib_ref] Respiratory diseases. All LT candidates may require pulmonary function tests and chest X-ray (Grade II-3). Hepatopulmonary syndrome (HPS) is found in up to 17% of cirrhotic patients resulting from intrapulmonary vascular dilatations and hypoxemia and is recognized by measuring the alveolar-arterial oxygen gradient and conducting contrast echocardiography. [bib_ref] Hepatopulmonary syndrome, Koch [/bib_ref] Hepatopulmonary syndrome can be treated only by LT (Grade II-2/3). Severe HPS patients with <50 mmHg oxygen partial pressure without 100% reversibility pose a hazard of permanent pulmonary failure post-LT and high-risk perioperative death. [bib_ref] Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary..., Arguedas [/bib_ref] Hepatopulmonary syndrome betterment and reversibility may take months after surgery. [bib_ref] Therapy insight: hepatopulmonary syndrome and orthotopic liver transplantation, Pastor [/bib_ref] Portopulmonary hypertension (PPHTN) happens in 2% to 8% of cirrhotic patients. A disparity between vasodilators and vasoconstrictors may cause erroneous angiogenesis and pulmonary hypertension. [bib_ref] The impact of treatment of portopulmonary hypertension on survival following liver transplantation, Ashfaq [/bib_ref] Portopulmonary hypertension is doubted when systolic pulmonary artery pressure is >30 mmHg on echocardiography, which needs to be established by right heart catheterization. Moderate (mean pulmonary artery pressure [MPAP] less than 35 mmHg) and severe PPHTN (less than 45 mmHg) are related to high post-LT death rates. [bib_ref] Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups, Swanson [/bib_ref] Managing PPHTN patients before surgery needs early disease detection and treatment using respiratory vasodilators epoprostenol (prostacycline) or endothelin receptor antagonist, or phosphodiesterase inhibitor type 5 (sildenafil), could support maintaining respiratory hemodynamics and had shown satisfactory results; though, long-term outcomes are yet to be known. [bib_ref] Portopulmonary hypertension and hepatopulmonary syndrome, Hoeper [/bib_ref] Hence, LT could be the treatment option in moderate PPHTN patients who show good response to clinical therapy and respiratory vasodilators and with moderate MPAP less than 35 mmHg (Grade II-2/3) under anesthetic consultation. [bib_ref] Long-term follow-up of portopulmonary hypertension: Effect of treatment with epoprostenol, Fix [/bib_ref] Renal disease. Assessing kidney physiology is crucial for a LT candidate. Cirrhotic patients who suffer kidney https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] impairment pose a 7-fold high mortality risk post-LT, with half of them dying within a month. [bib_ref] Renal failure and cirrhosis: A systematic review of mortality and prognosis, Fede [/bib_ref] The hepatorenal syndrome, a reversible cause of kidney impairment, is defined as an acute decline in renal physiology manifested by increased serum creatinine (>0.3 mg/dl) to a percentage rise of 50% (1.5-fold) from baseline, caused due to pre-LT reasons other than those of acute kidney injury (AKI), including sepsis, decrease in blood volume, and parenchymal kidney disease.
Chronic kidney disease (CKD) is defined as a projected glomerular filtration rate (GFR) of less than 60 ml/min for more than 3 months. [bib_ref] Working Party proposal for a revised classification system of renal dysfunction in..., Wong [/bib_ref] Patients with ESLD having 1) GFR <30 ml/min, 2) hepatorenal syndrome wanting kidney replacement treatment over 8 to 12 weeks, and 3) kidney biopsy exposing >30% fibrosis and glomerulosclerosis, would be advantageous from getting both liver and renal grafts.However, the requirement of combined LT-KT in those with creatinine clearance of 30-60 ml/min. The risk of deterioration of kidney function post LT alone needs to be balanced as a significance of LT and medication side effects, and the scarcity of renal grafts (Grade II-2).
## Infection screening. cirrhotic patients are
immunosuppressed and at risk of severe infections. [bib_ref] Severe sepsis in cirrhosis, Gustot [/bib_ref] All patients waiting for LT need to be assessed for any latent infections to avoid an exacerbation of infections after LT, especially with the use of immunosuppressive therapy [bib_ref] Management of infections pre-and post-liver transplantation: report of an AISF consensus conference, Fagiuoli [/bib_ref].
Screening of infections in LT recipients needs to be progressed in various stages, such as:
A) Level 1: for all LT candidates. B) Level 2: only in proposed LT recipient at the time of listing. C) Level 3: in high-risk patients or those from high-risk endemic infection localities.
Level 1 includes tests for HIV 1 and 2 antibodies, HBV serology, HCV antibodies, hepatitis A virus (HAV) antibodies, cytomegalovirus (CMV), and chest X-ray. Level 2 comprises tests for Mycobacterium tuberculosis (history + purified protein derivative [PPD]-Mantoux + IFN-gamma release assays), Epstein-Barr virus (EBV), human herpesvirus 8, varicella-zoster virus, herpes simplex virus (HSV)-1, HSV-2, urine culture, parasitological exam and stool culture (Strongyloidiasis stercoralis serology, Toxoplasma gondii IgG, Treponema pallidum serology), with venereal disease research laboratory test, Staphylococcus aureus nasal/axillary swab, and dental review. Level 3 of screening needs to be carried out in subgroup of patients based on medical history, comorbidities, endemic diseases, and local epidemiologic conditions. The candidates should have been vaccinated to counter HAV and HBV, varicella, Pneumococcus, influenza, and tetanus. [bib_ref] Management of infections pre-and post-liver transplantation: report of an AISF consensus conference, Fagiuoli [/bib_ref] Infected patients need to be monitored, similarly to dust exposure for aspergillosis, and those residing in WNV endemic localities for WNV serology and PCR. A chest radiograph is necessary to check for any lung infection, predominantly active or old TB. Purified protein derivative and TB quantiferon testing is also recommended, especially in older populations, as many KSA patients live in endemic areas for TB. Those testing positive with evidence of an active infection require prophylactic treatment with isoniazid under the care of an infectious disease specialist.
Both Gram-positive (Staphylococcus aureus, Streptococci) and Gram-negative bacteria (Klebsiella spp.) cause soft tissue infections, which comprise 11% of the infections. This increased risk is secondary to chronic edema of soft tissue and bacterial translocation. Cellulitis, the most common skin infection in those with cirrhosis, possesses 20% recurrence possibility. [bib_ref] Risk factors for the outcome of cirrhotic patients with soft tissue infections, Liu [/bib_ref] [bib_ref] The risk of cellulitis in cirrhotic patients: A nationwide population-based study in..., Lin [/bib_ref] Bacteremia can develop spontaneously or due to skin, respiratory, or urinary tract infections. Despite transitory bacteremia, associated with invasive treatment measures, including transarterial chemoembolization (TACE) is comparatively feasible, the threat of a pertinent medical influence does not deserve prophylaxis using antibiotics. [bib_ref] Bacterial infections, sepsis, and multiorgan failure in cirrhosis, Tandon [/bib_ref] [bib_ref] Dental health status of liver transplant candidates, Guggenheimer [/bib_ref] A prerequisite dental evaluation is recommended for potential liver transplant candidates. Untreated dental disease may pose a risk for infection and sepsis following liver transplantation. [bib_ref] Dental health status of liver transplant candidates, Guggenheimer [/bib_ref] Pneumonia, the third foremost source of infections in cirrhotic patients, has a higher bacteremia risk than healthy people. Community-acquired infection is usually due to Streptococcus pneumonia and H. influenza. Immunization using pneumococcal vaccination is suggested in cirrhotic patients. [bib_ref] A prospective study of bacterial infections in patients with cirrhosis, Caly [/bib_ref] [bib_ref] Guidelines for the management of adults with community-acquired pneumonia diagnosis, assessment of..., Niederman [/bib_ref] Human immunodeficiency virus infection was regarded as not suitable for LT before the availability of antiretroviral treatment options. The reason being the low spontaneous HIV prognosis. The arrival of highly vigorous antiretroviral agents has been a beneficial revolution, resulted in improved prognosis. [bib_ref] Are HIV-infected patients candidates for liver transplantation?, Samuel [/bib_ref] The development of chronic hepatitis (HBV and HCV) appears quicker in patients with HIV coinfection, and many patients will form more dangerous hepatic cirrhosis. Patients with a controlled HIV disease, without any relevant event, and CD4 >100 to 150/mm 3 can be considered for LT. [bib_ref] Transplantation in HIV: Multi-Site Study Investigators. Outcomes of liver transplant recipients with..., Terrault [/bib_ref] Candidemia characterizes a familiar infection in chronic hepatic disease patients and those with PSC recognized in over 40% of bile samples, more specifically in those having dominant strictures. [bib_ref] Prevalence, associations, and trends of biliary-tract candidiasis: a prospective observational study, Lenz [/bib_ref] Infection of invasive fungus aspergillosis is contraindicated to LT, and the treatment needs to be continued until the infection is clear radiographically, clinically, and microbiologically. [bib_ref] Biliary candida infections in primary sclerosing cholangitis, Kulaksiz [/bib_ref] Screening for neoplastic lesions. Treated cancers should not be the reason for the removal of LT candidates (Grade III). The long-term survival and recurrence at 1, 5, and 10 years under an immunosuppressant therapy need to be calculated, individually, with a consultation by cancer specialist. Generally, <10% recurrence risk is regarded as the cut-off for LT consideration. Recurrencefree period of about 5 years is often required (Grade III), which usually differs with cancer type. [bib_ref] Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion..., Al-Adra [/bib_ref] Different risk factors, such as age, gender, alcohol drinking, and smoking habit of the candidate should be assessed cautiously.
In terms of the type of malignancy, for individuals aged over 50 years, checking for colorectal cancer is obligatory. A colonoscopy would be the preferred screening method; however, CT colonography can be an alternative.The screening for lung neoplasia, otorhinolaryngology examination, esophageal and bladder cancers should be carried out, particularly in smokers and alcoholics 118 (Grade II-3). Upper gastrointestinal endoscopy is a general procedure carried out in all candidates, for both malignancy screening and to check esophageal and gastric varices, if present.All the female candidates should have a regular gynecological examination, comprising Pap smear and mammogram when required. Checking for prostate cancer needs to be carried out in all males over 40 years.Besides, skin evaluation is imperative, as nonmelanotic skin malignancies contraindicate LT.
Then, another dedicated screening for liver cancer, based on preoperative standard metastatic examination, comprising a bone scan and chest CT, is required. A positron emission tomography scan may be used to diagnose otherwise undetected neoplastic lesions. [bib_ref] 18 F] fludeoxyglucose positron emission tomography and computed tomography as a prognostic..., Asman [/bib_ref] Anatomical evaluation. The assessment of arterial, venous, and biliary systems is crucial for LT (Grade II-3). In the past, patients were not regarded as eligible for LT if they had PV thrombosis (PVT). Still, with clinical, surgical, and radiological advancements, PVT by itself can denote a LT indication [bib_ref] Portal vein thrombosis, cirrhosis, and liver transplantation, Francoz [/bib_ref] [fig_ref] Table 3 -: Risk stratification of microbial transmission from donor to recipient in liver transplantation [/fig_ref].
Several studies have shown that surgical thrombectomy, thromboendovenectomy with venous reconstruction, interposition of vein graft, portocaval hemitransposition, and radiological endovascular interventions may help remove venous obstruction in LT patients. Notably, 1-and 5-years survival after LT are same in PVT patients. Isolated PVT does not stop a surgery; anticoagulant does avert thrombus extension; nevertheless, in certain patients, entire portal system thrombosis (such as PV, superior mesenteric vein, splenic vein) may not favor a LT.
## Recommendations
- Assessing a liver transplantation (LT) candidate needs the collaboration of a multidisciplinary team (MDT) of specialists to check for all related comorbidities (Grade III). - Though LT does not have any specific age requirement, patients above 65 years need a MDT discussion to evaluate comorbidities (Grade III). - To uncover asymptomatic ischemic heart disease, a cardiopulmonary exercise test is required if the candidate has several cardiovascular (CV) risk factors and is above 50 years (Grade II-3). - All LT candidates may require pulmonary function tests and chest x-ray (Grade II-3). Biliary tree anatomy assessment is crucial in LDLT recipients, and non-invasive procedures including MRI, magnetic resonance cholangiography (MRCP), or endoscopic retrograde cholangiopancreatography (ERCP) are helpful in achieving it.
## Social condition, psychiatric status and addiction.
It is essential to evaluate the social situation, psychiatric condition, and habit-forming history of LT recipients to evaluate the appropriateness of the candidate for transplantation 150 (Grade III).
In patients with hepatic encephalopathy (HE), neuropsychological testing, CT brain scan or electroencephalography (EEG) are considered useful in identifying the reversibility of neuropsychiatric status. Active substance addiction or alcohol dependence is not favorable to LT due to the risk of recidivism, non-compliance, and graft injury. [bib_ref] Polysubstance abuse in liver transplant patients and its impact on survival outcome, Nickels [/bib_ref] All patients with previous alcohol-intake should follow an addiction rehabilitation program, with a careful assessment to ensure a low risk of recidivism before being listed for transplantation. [bib_ref] Smoking-related morbidity and mortality following liver transplantation, Leithead [/bib_ref] Liver transplantation in patients with active drug abuse may result in 27% recidivism, although this may not influence post-LT survival. [bib_ref] Cigarette smoking is associated with an increased incidence of vascular complications after..., Pungpapong [/bib_ref] 3. Scoring system used to list patients for liver transplantation and managing patient complications while on the waitlist Adoption of Child-Turcotte-Pugh (CTP) Scoring System. In 1997, OPTN/UNOS, for the first time in solid organ transplantation, the CTP score was adopted as a medical scoring system to evaluate severity of illness. Per UNOS classification, LT candidates were grouped into 4 classes for organ allocation: Status 1, 2A, 2B, and 3 (in descending order of LT importance). [bib_ref] Homotransplantation of the liver in humans, Starzl [/bib_ref] Unfortunately, from the first year of implementation, the CTP score new policy got a lot of criticism because it did not lead to equitable allocation and proper prioritization, namely, waiting time was still more important than the rule that sicker patients should go first, and also it did not address the geographic difference in time to LT. Between 1998 and 1999, application of the Final Rule to prioritize organ allocation based on necessity, irrespective of geography, and lessening the waiting time to get LT. 157 The MELD score substituted the CTP-based organ-sharing system. Delta model of end-stage liver disease scores ranging between 6 and 40 replaced waiting lists time favoring the rule of "the sickest first."
## Replacement of ctp scoring system by meld
Following this system, dramatic changes occurred since its first year of implementation in 2003, namely a 12% decrease in the new LT candidate registration pool in the UNOS database, primarily with MELD score <10, a 10.2% rise in the rate of cadaveric LT, a reduction by >200 days of the time to LT and almost a 3.5% decline of waiting list death rates, compared to the pre-MELD era. [bib_ref] Results of the first year of the new liver allocation plan, Freeman [/bib_ref] Adding "Share Policy 15" then 35 to address geographic disparity of organ distribution. The MELD allocation system enhanced the liver graft allocation rate to the much-required patients, but there were still disparities in DDLT by location. For this reason, in 2005, the "Share 15" policy was adopted. Under this initiative, regional DDLT candidates with MELD scores ≥15 were allocated liver grafts before local DDLT candidates with MELD scores below 15. Then, in 2013 "Share 15" policy was changed to "Share 35," which prioritized local and regional DDLT candidates with MELD scores ≥35 before local DDLT candidates with MELD scores <35.
One year after adaptation and use of the "Share 35" policy, candidates with MELD scores ≥35 were found more likely to undergo DDLT. Regional sharing of liver grafts raised from 18.9% to 30.4%. There was a significant decrease in waitlist mortality for DDLT candidates with MELD scores >30, reduced discarding of liver grafts and increased overall DDLT volume. [bib_ref] Early changes in liver distribution following implementation of Share 35, Massie [/bib_ref] Addition of sodium into the MELD score calculation. Over time, several research reports have shown that low serum sodium associates with the intensity of portal hypertension, and it is correlated with ascites and hepatorenal syndrome (HRS). [bib_ref] The association between the serum sodium level and the severity of complications..., Jong [/bib_ref] Serum sodium (Na+) <126 during listing is related to poor outcomes, with significant hazard ratios of 7.8 and 6.3, respectively, and independent of MELD. [bib_ref] Serum sodium and survival benefit of liver transplantation HHS public access, Sharma [/bib_ref] In January 2016, OPTN/UNOS permitted the inclusion of Na into the MELD score estimation, with the help of a revised version of the MELD-Na formula for any patient with an initial MELD >11. This formula increases the MELD score for patients with serum sodium <137 mEq/dL; however, patients with sodium <125 mEq/dL do not get any additional MELD increase. [bib_ref] Impact of meld sodium on liver transplantation waiting list, Freitas Act [/bib_ref] MELD exceptions. The MELD system is based on equity and the idea that LT should be performed faster for the sickest patients with high short-term mortality. However, the MELD score does not have a 100% sensitivity: it does not address those with low MELD scores but has high mortality without transplantation, such as patients with HCC. For this reason, 2 types of MELD exceptions were adopted: standardized exceptions, which are conditions with sufficient data, such as HCC, HPS, or amyloid neuropathy; and nonstandardized MELD exceptions, which are conditions associated with a poor quality of life, such as recurrent encephalopathy or refractory pruritus, or rare diseases with a high risk of mortality. [bib_ref] Model for end-stage liver disease (MELD) exception guidelines: results and recommendations from..., Freeman [/bib_ref] Hepatocellular carcinoma. Initially, in 2002, a MELD exception was given based on Milan criteria, which included either one lesion <5 cm in maximum diameter or up to 3 lesions with a maximum diameter of any lesion of 3 cm. Stage I tumors (<2 cm size) and stage II lesions were granted a MELD score of 24 and 29, respectively, with an increase in MELD every 3 months, provided the tumor remains within Milan criteria for LT. [bib_ref] Liver transplantation for the treatment of small hepatocellular carcinomas in patients with..., Mazzaferro [/bib_ref] Due to an inequitable increase in DDLT for HCC candidates compared to non-HCC patients, along with discrepancies in diagnosis and new drop-out rate data, several modifications to the original MELD score exception assigned to HCC patients were issued to reduce this advantage.
In 2003, OPTN/UNOS reduced the initial MELD scores except 20 for stage I HCC, and 24 for stage II HCC. [bib_ref] Allocation policy for hepatocellular carcinoma in the MELD era: room for improvement?, Roayaie [/bib_ref] In 2004, the MELD exception priority for stage I lesions was eliminated. [bib_ref] Report of a national conference on liver allocation in patients with hepatocellular..., Pomfret [/bib_ref] Then, in 2005, the initial MELD exception score for stage II HCC was reduced from 24 to 22. Patients continued to receive a 10% increase in exception points every 3 months, provided they remained within Milan criteria. [bib_ref] Changing prioritization for transplantation: MELD-Na, hepatocellular carcinoma exceptions, and more, Kalra [/bib_ref] In 2015 ("Delay and Cap HCC" policy), a patient listed with an actual MELD score like without HCC in the first 6 months was then given a MELD score of 28. Every 3 months, extensions are applied to increase the MELD score to 30, 32, and 34 as the maximum.In 2017, it was allowed standard exception points to be granted to patients who were down-staged as per criteria set by the UCSF (up to 5 tumors with the largest being 4.5 cm and
## Non-infectious complication
## Clinical outcome recommendations
Variceal bleeding - 20% initial risk of death - Primary and secondary variceal hemorrhage prophylaxis is the standard of care for prevention.
- Primary prophylaxis depends on the MELD score
- Carvedilol leads to a greater hemodynamic response than NSBB because of its alpha-adrenergic blockade, but this can worsen fluid accumulation - Hyponatremia should be avoided in high MELD patients.
- NSBB will be a better option, but it should be avoided in patients with refractory ascites after SBP development, and those who require variceal band ligation - Secondary prophylaxis with endoscopic banding to obliteration and NSBB/ carvedilol, both modalities, if tolerated, are standard of care
Renal failure - Renal dysfunction typically implies a substantially increased risk of mortality, commonly precipitated by a bacterial infection, then hypovolemia.
- Other etiologies include HRS and parenchymal nephropathy.
- Identify and treat infection with antibiotic therapy.
- Appropriate prophylactic antibiotic therapy should be used in variceal hemorrhage or SBP prophylaxis.
- Antibiotic therapy administration should be used when an infection is suspected, and hypovolemia is treated.
- Avoid overdosing lactulose, intravenous albumin administration when SBP occurs.
- Withdraw diuretics and nephrotoxic drugs.
- Vasoconstrictor medications are used to correct peripheral vasodilatation if HRS is suspected.
- Midodrine, in combination with octreotide or terlipressin, is suggested, which does not require ICU monitoring
## Refractory ascites and hh
- Ascites is the most common complication of cirrhosis that leads to hospital admission.
- 50% of patients with compensated cirrhosis develop ascites over ten years, and 15% and 44% of patients will die in one and five years, respectively.
- HH is a complication seen in approximately 5-16% of patients with cirrhosis, usually with ascites.
- Initial management, both with diuretics and sodium restriction, should be effective in 10-20% of cases.
- Predictors of response are mild or moderate ascites/HH, especially with urine Na + excretion >78 mEq/day. - Spironolactone-based diuretics can be used and then add lop diuretics e.g. furosemide (1:4 ratio to preserve potassium).
- In an intractable/recurrent ascites/HH, paracentesis and thoracentesis are often needed to optimize ventilator management and to help treat or prevent pneumonia during hospitalization.
- TIPS is a good option in low MELD patients, but contraindicated in high MELD patients Hepatic encephalopathy
- Precipitated by infection, dehydration, gastrointestinal bleeding, worsening hepatic function, TIPS placement, hypokalemia, hyponatremia, and numerous medications - HE is prevented by avoiding dehydration and electrolyte optimization, specifically potassium repletion to avoid increased renal ammonia-genesis in the presence of hypokalemia, and avoidance of starvation.
- Treatment options include: lactulose, rifaximin, sodium benzoate and polyethylene glycol - Replacement of benzodiazepine-derived sleep-aids with diphenhydramine, melatonin, or trazodone can also work.
- Patients with TIPS who continue to experience refractory encephalopathy may need their TIPS downsized.
## Hyponatremia
- Low serum Na levels reflect the intensity of portal hypertension, and is associated with ascites and HRS. Serum Na + <126 mEq/L at the time of listing is associated with poor outcomes.
- The need for intervention in dilutional hyponatremia is dictated by the absolute serum Na level, the rapidity of decrease, and the presence or absence of symptoms.
- In asymptomatic patients, fluid restriction and limiting diuretic use are considered first-line interventions.
- In symptomatic patients, serum Na should be corrected slowly; a correction of <10 mEq/L to 12 mEq/L in 24 hours and <18 mEq/L in 48 hours is recommended. the sum of tumors being <8 cm), within Milan criteria, and restriction on standardized exception points for HCC patients with AFP levels >1000 ng/mL that do not decrease to <500 ng/mL with treatment. [bib_ref] Alpha-fetoprotein level >1000 ng/mL as an exclusion criterion for liver transplantation in..., Hameed [/bib_ref] [bib_ref] Downstaging of hepatocellular cancer before liver transplant: Long-term outcome compared to tumors..., Yao [/bib_ref] Pulmonary complication of cirrhosis. Both HPS and portopulmonary hypertension (POPH), granted MELD score of 22 with an increase in MELD points equivalent to a 10% increase in mortality every 3 months, provided PaO 2 remains less than 60 mmHg, for patients with HPS and MPAP remains less than 35 mm Hg and pulmonary vascular resistance less than 400 dyn/s/cm for patients with POPH.Management and follow-up of liver transplant listed patients. Although the current allocation system allows timely access to donor organs for the sickest patients, a substantial percentage of patients are still removed from the transplant list for death or clinical deterioration due to infection-related removal or death related to ESLD complications. [bib_ref] Regional variability in liver waiting list removals causes false ascertainment of waiting..., Voigt [/bib_ref] The most common complications are either infectious or non-infectious complications, 172-181 many of which are described and recommendations for treatment in [fig_ref] Table 4 -: Management of infectious complications in liver transplantation [/fig_ref].
## Pediatric liver transplantation
Pediatric LT has been a major success and is now an established therapeutic entity. [bib_ref] Outcomes in pediatric solid-organ transplantation, Larosa [/bib_ref] The use of innovative surgical techniques has allowed for the application of LT even to very young infants with excellent results. [bib_ref] Liver transplantation for small babies, Karakayali [/bib_ref] However, a gap between the number of patients suitable for LT and the number of donated human livers remains, and related LDLT has emerged as an alternative to DDLT. [bib_ref] One hundred nine living donor liver transplants in adults and children: a..., Miller [/bib_ref] The innovative techniques of reduced size and split LT relieved this shortage to some extent, allowing children greater access to transplants. Raia et al [bib_ref] Liver transplantation in children from living related donors: Surgical techniques and results, Raia [/bib_ref] and Broelsch et al 186 extended these techniques to resect left lateral segments from living adults for transplantation into children.
Pediatric LDLT with left lateral segment grafts (segments 2 and 3) has nearly eliminated waiting list deaths among children and improved graft and patient survival rates (Grade III). [bib_ref] Impact of segmental grafts on pediatric liver transplantation--a review of the United..., Sindhi [/bib_ref] [bib_ref] Living donor for liver transplantation, Broelsch [/bib_ref] The success of LT to treat advanced liver disorders has also opened it up to new indications, such as liver tumors and metabolic disorders, [bib_ref] Pediatric liver transplantation, Rawal [/bib_ref] with excellent short-and long-term patient and graft survival and significant improvements in the quality of life. [bib_ref] Liver transplantation in children, Pham [/bib_ref] The most common diagnoses driving pediatric LT in KSA are genetic familial liver diseases, metabolic disorders, and biliary atresia (Grade II-3). [bib_ref] Genetic profiling of children with advanced cholestatic liver disease, Shagrani [/bib_ref] Indications for Pediatric LT. Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers in the KSA. [bib_ref] Genetic profiling of children with advanced cholestatic liver disease, Shagrani [/bib_ref] Recent advances in the genetic classification of this group of disorders promise highly personalized management, although genetic heterogeneity also poses a diagnostic challenge. Children-specific LT indications are summarized in [fig_ref] Table 6 -: Indications for pediatric liver transplantation [/fig_ref].
Progressive familial intrahepatic cholestasis (PFIC). Progressive familial intrahepatic cholestasis is a group of autosomal recessive cholestatic disorders that presents intrahepatic cholestasis in children or early adulthood and often requires LT early in life. Our pediatric community in KSA is a leading referral for LT in children (Grade II-3). [bib_ref] Genetic profiling of children with advanced cholestatic liver disease, Shagrani [/bib_ref] Progressive familial intrahepatic cholestasis includes 3 major diseases characterized by failed secretion of bile acids (BAs) or phospholipids into the bile canaliculus to complete micelle formation. [bib_ref] Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred, Clayton [/bib_ref] Three types of PFIC have been identified, PFIC1, PFIC2, and PFIC3, with an estimated incidence of 1/50,000 -100,000. [bib_ref] Monogenic diseases that can be cured by liver transplantation, Fagiuoli [/bib_ref] Progressive familial intrahepatic cholestasis 1 and PFIC2 are caused by impaired secretion of bile salt [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] or conjugated primary BAs into the canaliculi due, respectively, to defects in ATP8B1 gene encoding the FIC1 protein, and in ABCB11 gene encoding the bile salt export pump protein (BSEP). They are characterized by infantile presentation with jaundice, pruritus, and failure to thrive but low or normal gamma-glutamyl transferase (GGT) activity. ABCB4 gene encodes MDR3 protein, a phospholipid transporter involved in biliary phospholipid excretion. Reduced phospholipid level causes inefficient inactivation of detergent bile salts and epithelial injury of cholangiocytes resulting in high GGT cholestasis, the classical features of PFIC3. In addition to causing PFIC3 (symptoms ranging from neonatal cholestasis to biliary cirrhosis in adult), ABCB4 mutations can also cause intrahepatic cholestasis of pregnancy and low phospholipid-associated cholelithiasis syndrome, and predispose an individual to medicine-induced cholestasis. [bib_ref] The Multiple Facets of ABCB4 (MDR3) Deficiency, Sundaram [/bib_ref] Indication for LT in PFIC includes liver decompensation, failure to thrive, portal hypertension, or intractable itching not responding to medical therapy. [bib_ref] Prognostic factors for pediatric living donor liver transplantation: Impact of zero-mortality transplant..., Yagi [/bib_ref]
## Tight junction protein 2 (tjp2) & ba coenzyme a: amino acid n-acyltransferase (baat). tight
Junction Protein 2 & BAAT mutation-positive cases present with normal GGT cholestasis, high serum BA, and progressive cholestasis to ESLD. The primary role of TJP2 is to avert the back diffusion of bile salts from the canaliculi to the blood circulation at the paracellular level, explaining the reason behind presence of normal GGT, high serum BA, and fat malabsorption in children. However, it is still unclear why they also have progressive cholestasis with high liver enzymes and bilirubin progressing to ESLD. [bib_ref] Mutations in TJP2, encoding zona occludens 2, and liver disease, Sambrotta [/bib_ref] Indications for LT include liver failure and severe failure to thrive.
Bile acid synthesis defects (BASD). Inborn errors of primary BA synthesis are rare inherited autosomal recessive disorders. The most frequent defects are the 3β-Δ5-hydroxy-C27-steroid oxidoreductase (3β-HSD) deficiency (OMIM 607765), which is due to mutations in HSD3B7; and to a lesser extent, the Δ4-3-oxosteroid-5β-reductase (Δ4-3-oxo-R) deficiency, due to mutations in AKR1D1. [bib_ref] Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and..., Clayton [/bib_ref] These defects in enzymes catalyzing key reactions in the formation of the primary BAs, namely cholic acid (CA) and chenodeoxycholic acid in humans, lead to an inadequate synthesis of primary BAs that are critical for bile formation and to the production and the accumulation of atypical and hepatotoxic BA intermediates. These deficiencies commonly manifest in neonates or infants as cholestasis and can progress to early cirrhosis and liver failure unless treated early with CA. [bib_ref] Disorders of bile acid synthesis, Clayton [/bib_ref] Alagille syndrome (ALGS). Alagille syndrome, a multiorgan disorder, having a variety of changes in clinical complications, observed even between patients of a single family. Most common characteristics include bile duct paucity on liver biopsy, cholestasis, congenital cardiac imperfections (chiefly concerning pulmonary arteries), butterfly vertebrae, ophthalmologic irregularities (mainly posterior embryotoxon), and characteristic facial features. Abnormalities in kidney function, growth failure, developmental delays, splenomegaly, and vascular anomalies are also reported. Disease diagnosis is recognized in a proband who fulfills the required criteria and/or possesses a heterozygous pathogenic variant in JAG1 or NOTCH2 as diagnosed by molecular genetic testing. The primary indication for LT in ALGS is ESLD secondary to progressive cholestasis, followed by growth failure as the next indication. Some other primary indications are intractable pruritus, portal hypertension, and fractures (Grade III). [bib_ref] Outcomes of liver transplantation for patients with Alagille syndrome: the studies of..., Kamath [/bib_ref] High disease burden of autosomal recessive cholestatic liver disease in KSA. Comparable with the local experience with other autosomal recessive disorders, most mutations were private young mutations that were rendered homozygous through the consanguinity loop (68%). [bib_ref] Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden, Abouelhoda [/bib_ref] However, the rest (32%) were founders based on their detection in apparently unrelated individuals, and the cumulative carrier frequency was 0.0115 . This translates into a minimum disease burden of cholestatic liver disease in KSA of 1:7246, a really high estimate even compared with countries with a high burden in children, such as Japan. [bib_ref] Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next-generation sequencing, Togawa [/bib_ref] Biliary atresia. Biliary atresia is a fibroinflammatory disease of the intrahepatic and extrahepatic biliary tree. Surgical hepatic portoenterostomy may restore bile drainage, but the intrahepatic disease progression results in complications of portal hypertension and advanced cirrhosis in most children, [bib_ref] Biliary atresia: Clinical and research challenges for the twenty-first century, Bezerra [/bib_ref] becoming one among the most common LT indications in children. Although improvements in biliary atresia surgical treatments, a majority of children require LT (Grade II-3). [bib_ref] Biliary atresia and liver transplantation: results and thoughts for primary liver transplantation..., Superina [/bib_ref] Indications for LT in biliary atresia include failed Kasai portoenterostomy, significant and recalcitrant malnutrition, recurrent cholangitis, and the progressive manifestations of portal hypertension. Extrahepatic complications of this disease, such as HPS and PPHTN, are also indications for LT. [bib_ref] Biliary atresia: Indications and timing of liver transplantation and optimization of pretransplant..., Sundaram [/bib_ref] Urea cycle disorders (UCDs). These are a cluster of monogenic inborn faults of liver metabolism that cause life-threatening hyperammonemia. Flaws in the urea cycle pathway cause a propensity for hyperammonemia
## Recommendations
- Pediatric LDLT with left lateral segment grafts (segments 2 and 3) is a recommended procedure that can reduce waiting list deaths among children and improve graft and patient survival rates (Grade III). - In KSA, genetic familial liver diseases, metabolic disorders, and biliary atresia (Grade II-3) are the most common pediatric diagnoses and LT should be considered. - The primary indication for LT in ALGS patients should be ESLD secondary to progressive cholestasis, followed by growth failure, then intractable pruritus, portal hypertension, and fractures (Grade-III). and resultant neurological injury. Ornithine transcarbamylase (OTC) insufficiency is utmost familiar among the UCDs; others include argininosuccinate lyase insufficiency (argininosuccinic aciduria) and argininosuccinate synthetase deficiency (citrullinemia). All UCDs, except OTC deficiency, are autosomal recessive in inheritance. Quick and intrusive therapy is needed for survival. However, the prognosis is not strong relating to survival and neurological outcomes correlated with the number, severity, and duration of hyperammonemic episodes. The only known "cure" for UCDs is LT, which carries some significant morbidity and mortality (Grade III). [bib_ref] Early liver transplantation in neonatal-onset and moderate urea cycle disorders may lead..., Kido [/bib_ref] Glycogen storage disorders (GSDs). GSDs are inherited disorders in which the concentration and/ or structure of glycogen in body tissues is abnormal. Essentially, all known enzymes involved in the synthesis or degradation of glycogen and glucose have been discovered to cause some type of GSD. [bib_ref] Pathophysiology and dietary treatment of the glycogen storage diseases, Moses [/bib_ref] Glycogen storage disorders types I, III, and IV can be associated with severe liver disease. The indications for LT in GSD I are either multiple liver adenomas bearing the risk of malignant transformation and/or poor metabolic controls. [bib_ref] Hepatic adenomata in type Ia glycogen storage disease, Coire [/bib_ref] In GSD III, the LT indication is liver failure and HCC. In GSD IV LT, the indication is progressive liver cirrhosis with portal hypertension. [bib_ref] Liver transplantation for glycogen storage disease types I, III, and IV, Matern [/bib_ref] Tyrosinemia type 1. Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long-term risks for HCC. [bib_ref] Liver transplant for children with hepatocellular carcinoma and hereditary tyrosinemia type 1, Bahador [/bib_ref] The indications of LT in early life is liver failure that is not responded to medical therapy of NTBC [2-(2-nitro-4-trifluoromethylbenzoil)-1,3 cyclohxanedione]. After the age of 2 years, the indications are HCC and progressive liver disease with portal hypertension.
## Liver transplantation -surgical aspects in adults and pediatrics
Exceptional results have been achieved in LT through the standardization of surgical procedures, surgical innovations, such as LDLT and split LT (SLT), 186 improvements in pre-, intra-, and postoperative management with the adoption of an MDT approach to patient care, as well as improvements in immunosuppressive medications. Despite improved results, many challenges remain, emphasizing the importance of expertise and specialization. Some unique differences between adult and pediatric LT from a surgical perspective are highlighted.
In the Western world, the most common type of LT is the so-called "conventional" or "standard," where a whole liver is grafted. [bib_ref] Pediatric liver transplantation: A surgical perspective and new concepts, Emre [/bib_ref] However, in the KSA, due to the severe shortage of organs, LDLT is common and to a lesser extent SLT. 3
## Timing of liver transplantation. performing lt in
a timely fashion is key to achieve successful outcomes. The decision on transplant timing is a dynamic balance between avoiding early unnecessary morbidity and mortality of the transplant versus late with the poor outcome due to disease progression. In patients with acute liver failure, urgent evaluation and emergency transplantation are indicated. In children, the timing of LT in metabolic liver diseases differs as synthetic liver functions are normal. Nevertheless, some of these patients are at risk of serious neurologic complications. The decision and timing to proceed with LT are aided by consultation with the pediatric genetic specialist. [bib_ref] AASLD Practice Guideline: Evaluation of the Pediatric Patient for Liver Transplantation, Squires [/bib_ref] Donor/recipient matching. Currently, due to the extreme shortage of deceased donor organ availability in KSA, the main source of organs is living donors. Matching recipient body size and donor liver size are https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] key factors for LT success in adults and more so in children, especially in low-weight recipients. [bib_ref] Adult living donor liver transplantation: The hepatologist's perspective, Schiano [/bib_ref] In adults LDLT, a graft/recipient weight ratio (GRWR) of 1% is ideal, while in children, a ratio of up to 4% can bring about a successful outcome. [bib_ref] Effect of graft weight to recipient body weight ratio on hemodynamic and..., Ersoy [/bib_ref] Cases of LT with GRWR >4 can present significant early graft dysfunction, [bib_ref] Impact of graft size mismatching on graft prognosis in liver transplantation from..., Kiuchi [/bib_ref] which is less likely in adults. Furthermore, primary closure of the abdomen would be impossible and may result in vascular complications and graft failure. [bib_ref] Effect of graft size matching on pediatric living-donor liver transplantation in Japan, Kasahara [/bib_ref] Various techniques have been described to reduce graft size, including mono-segmental, reduced, and hyper-reduced grafts. [bib_ref] Liver transplantation for small babies, Karakayali [/bib_ref] [bib_ref] Minimum graft size for successful living donor liver transplantation, Lo [/bib_ref] Despite best efforts, closure of the abdomen occasionally needs to be staged with temporary closure with a mesh sheet to avoid compression of the graft.
## Different types of liver transplantation.
## Conventional or standard liver transplantation.
Whole-liver grafts are used and implanted in the position where the unhealthy liver in the right upper quadrant is located earlier. In many European nations, the piggy-back procedure is considered, preserving the patient's inferior vena cava (IVC). The donor's suprahepatic IVC is anastomosed to the recipient's 3 hepatic veins (HVs), and the PV, hepatic artery (HA), and biliary tree are reconstructed by duct-to-duct anastomosis between the chief biliary tracts of donor and recipient 12 (Grade II-3). If the recipient's IVC cannot be preserved or in some cases of malignancy, the surgery involves vascular reconstruction with end-to-end anastomoses between the donor's IVC and the recipient's infra-and suprahepatic IVC. Standard LT is classified depending on the donor type (brain dead or cardiac death), but in KSA, only brain dead donations are available.
Domino liver transplantation. The most common domino LT indication is familial amyloidotic polyneuropathy (FAP) (Grade II-3). The patient with FAP gives liver to another while getting a deceased organ. [bib_ref] Liver transplantation for familial amyloidotic polyneuropathy (FAP): A single-center experience over 16..., Yamamoto [/bib_ref] The FAP liver recipient should be above 55 years to reduce the risk of emerging FAP.A graft with 3 distinct suprahepatic veins involving bench surgery for reconstruction is required in FAP patient to preserve IVC. The entire hepatectomy in the FAP donor is conducted because the blood circulation is preserved; however, complications are less if there is no portal hypertension. [bib_ref] A new technical option for domino liver transplantation, Pacheco-Moreira [/bib_ref] Partial graft transplantation. It is performed when there is a requirement for partial support to manage a specific or complete metabolic insufficiency. The graft volume should be enough to withstand the post-LT life of the patient. The ratio of patient's weight to the graft must be a minimum of 0.8%, indicating that an 80-kg patient may require a 640g graft at least.This might cause an issue in adult living donors, and it is usually addressed using the right lobe for LT. [bib_ref] Safety of small-for-size grafts in adult-to-adult living donor liver transplantation using the..., Moon [/bib_ref] Auxiliary liver transplantation. It can be performed orthotopically or heterotopically and is used in 2 types of situations: 1) patients with acute hepatic failure with the partial graft supporting the unhealthy liver while recovering, the graft is removed, and immunosuppression is reserved, [bib_ref] Emergency subtotal hepatectomy: A new concept for acetaminophen-induced acute liver failure: Temporary..., Lodge [/bib_ref] and 2) patients with functional congenital or metabolic disorders disturbing the otherwise healthy liver (Grade II-3). Curing metabolic disorder to evade a full LT may require implanting a partial liver graft while maintaining the function of native liver. [bib_ref] Auxiliary partial orthotopic liver transplantation for Crigler-Najjar syndrome type 1, Rela [/bib_ref] Decent outcomes are observed in young patients with acute hepatic failure (mostly viral or autoimmune), [bib_ref] Fulminant hepatic failure: Outcome after listing for highly urgent liver transplantation -12..., Brandsoeter [/bib_ref] but inferior results are seen with Budd-Chiari syndrome and WD. [bib_ref] Role of liver transplantation in acute liver failure, Liou [/bib_ref] Acute HBV infection remains a debatable indication due to the danger of graft reinfection. [bib_ref] Auxiliary versus orthotopic liver transplantation for acute liver failure. EURALT Study Group...., Van Hoek [/bib_ref] Split liver transplantation. Split liver transplantation involves splitting the liver into 2 parts, and how this division is made depends on who the recipients will be. If the liver is intended for one adult and one pediatric patient, it will be separated into a right lobe that also contains segment IV and a partial left lobe that comprises segments II and III [bib_ref] Split liver transplantation, Broering [/bib_ref] (Grade II-2). If the liver is intended for 2 adult patients, it will be separated into the right lobe (segments V-VIII) and left lobe (segments I-IV). Usually, the left lobe has a size of around 450g, which only allows it to be implanted in low-weight (50-55 kg) patients [bib_ref] Outcomes with split liver transplantation in 106 recipients: The University of California, Vagefi [/bib_ref] [bib_ref] Feasibility of split liver transplantation for 2 adults in the model of..., Lee [/bib_ref] (Grade II-2). Split liver transplantation is technically demanding and may increase perioperative complications; therefore, critical evaluation of donor livers suitable for splitting and careful screening of recipients is extremely important. [bib_ref] Split liver transplantation: Current developments, Hackl [/bib_ref] Living donor liver transplantation. Living donor liver transplantation was first introduced to address the scarcity of pediatric sized cadaver donor livers, which bring about an inadmissibly increased rate of pediatric deaths on the waitlist. Pediatric LDLT became an alternative in these cases, where the living adult donor's segments II and III are relocated into a child. [bib_ref] Ethics of Liver Transplantation with Living Donors, Singer [/bib_ref] In Asia, including the KSA, because of the lack of deceased donors, the usage of LDLT slowly extended, terminating with the technique of adult recipients getting entire right lobe grafts (segments V-VIII) from living donors. [bib_ref] Liver transplantation in the Kingdom of Saudi Arabia, Sebayel [/bib_ref] [bib_ref] Living donor liver transplantation: Eastern experiences, Tanaka [/bib_ref] Right hepatectomy is considered safe for the donor [bib_ref] Liver transplantation using a right lobe graft from a living related donor, Yamaoka [/bib_ref] and needs careful dissection in which the right HA, right PV, right bile duct, and right suprahepatic vein are separated.Graft/recipient weight ratio must be of at least 0.8% to ensure viability 222 (Grade III). The recipient process is perplexing because of the anastomoses' size. Nevertheless, the outcomes are good and identical to patients who received whole grafts from deceased donors. [bib_ref] Evolution of indications and results of liver transplantation in Europe. A report..., Adam [/bib_ref] However, the main challenge is the significant morbidity in 38% of donors and causing death in 0.18%. [bib_ref] Evolution of indications and results of liver transplantation in Europe. A report..., Adam [/bib_ref] One-third of donors experience complications; most have type I or II on the Clavien-Dindo classification system. [bib_ref] Classification of surgical complications: A new proposal with evaluation in a cohort..., Dindo [/bib_ref] The most common complications are biliary fistulas, which are generally treated conservatively; however, a few require hospitalization and surgery again. [bib_ref] Lessons learned from 1,000 living donor liver transplantations in a single center:..., Hwang [/bib_ref] [bib_ref] Complications of living donor hepatic lobectomy-A comprehensive report, Abecassis [/bib_ref] Complication in the right lobe donors is more than that of donors of the opposite lobe, with the latter also showing more rapid normalization of serum bilirubin levels and prothrombin time. 240
## Surgical complications. vascular complications
Arterial complications. The incidence of hepatic artery thrombosis (HAT) is approximately 3% in adults and as high as 8% in children; 241 graft dysfunction is the most common feature.This can dramatically alter the graft survival time lowering up to 27.4% at 5 years, in contrast with 76.4% for non-HAT patients. [bib_ref] Etiology and management of hepatic artery thrombosis after adult liver transplantation, Mourad [/bib_ref] Reintervention and revascularization can be the treatment option for 50% of HAT patients, whereas the other half requires re-LT 243 (Grade III). The most severe long-term complication is the incidence of ischemic biliary lesions or ischemic cholangiopathy (IC), which can require re-LT. [bib_ref] Vascular Complications of Orthotopic Liver Transplantation: Experience in More than 4,200 Patients, Duffy [/bib_ref] Early identification is crucial, particularly in the pediatric population. This can be achieved with serial surveillance with Doppler ultrasound, which has a sensitivity of >90%. [bib_ref] Imaging of the transplant liver, Babyn [/bib_ref] Permissive hemodilution (hematocrit 20-25%), anticoagulation, and antiplatelets are non-standardized preventive measures practiced variably by transplant centers for the pediatric population. [bib_ref] Perioperative anticoagulation practices for pediatric liver transplantation, Voulgarelis [/bib_ref] Hepatic artery stenosis (HAS) can be a precursor to HAT, with an incidence in children of 2.8%. [bib_ref] Segmental grafts in adult and pediatric liver transplantation: Improving outcomes by minimizing..., Rodriguez-Davalos [/bib_ref] It is diagnosed by Doppler ultrasound imaging, and the gold standard is angiography and is best managed by angioplasty and endovascular interventions. [bib_ref] Hepatic artery stenosis in liver transplant recipients: Primary treatment with percutaneous transluminal..., Saad [/bib_ref] Venous complications. Stenosis or occlusion of the IVC is an uncommon but serious problem, with 1-6% incidence and, mostly, concerning intimal hyperplasia or fibrosis at the place of anastomosis. [bib_ref] Long-term efficacy of stent placement for treating inferior vena cava stenosis following..., Lee [/bib_ref] The piggy-back technique (preservation of the IVC) may reduce the rate of complications arising due to anastomotic stenosis, [bib_ref] Long-term efficacy of stent placement for treating inferior vena cava stenosis following..., Lee [/bib_ref] and endovascular techniques are the therapy of choice [bib_ref] Stent migration complicating treatment of inferior vena cava stenosis after orthotopic liver..., Guimarães [/bib_ref] (Grade II-3).
The use of the piggy-back technique, with the resultant requirement for anastomosis of the 3 HVs result in outflow problems affecting 30% of recipients.This complication is now very rare due to the performance of anastomosis between the combination of the 3 HVs of the recipient and the IVC of the donor. [bib_ref] Four hundred and twenty-three consecutive adults piggy-back liver transplantations with the three..., Audet [/bib_ref] Patients receiving LDLT/SLT grafts are at particular risk, and graft positioning at the time of the transplantation is critical to minimize the incidence. HV obstruction clinically bears similarity to Budd-Chiari syndrome. Hepatic veins outflow obstruction is common terminology used to reflect HV obstruction instigated by compression or twisting of the anastomosis due to graft regeneration or intimal hyperplasia and fibrosis at the sites of anastomosis. Management by interventional radiology dilation with or without stenting resolves the obstruction. [bib_ref] Interventional radiological treatment of perihepatic vascular stenosis or occlusion in pediatric patients..., Uller [/bib_ref] Clinical problems, such as ascites, renal failure, lower limb edema, and splenomegaly, can resolve after endovascular interventions.
Portal vein thrombosis has an incidence of 2.1-26% in patients undergoing LT, 253 mainly due to complications such as smaller PV diameter, technical, size mismatch between the donor's and recipient's PV, and atretic or hypoplastic recipient PV in biliary atresia. [bib_ref] Risk factors for portal vein complications after pediatric living donor liver transplantation..., Moon [/bib_ref] In patients with previous PVT, LT is associated with higher surgical complexity, and surgical alternatives include portocaval transposition, renoportal anastomosis, mesentericoportal anastomosis, and multi-visceral transplantation.These, however, are associated with higher morbidity and mortality, with the rate of re-thrombosis reaching 13%, and short-term anticoagulation is therefore recommended. [bib_ref] Caval inflow to the graft for liver transplantation in patients with diffuse..., Bhangui [/bib_ref] Early PVT presents with graft dysfunction, bleeding, and ascites, and it is managed by thrombectomy, while late PVT showing symptoms of portal hypertension and can be managed by Meso-Rex or selective portosystemic shunts. Alternatively, it can be managed with interventional radiology. Symptomatic PV stenosis is best managed by interventional radiology. In up to half of the PV, stenosis requires more than one dilatation. [bib_ref] Risk factors for portal vein complications after pediatric living donor liver transplantation..., Moon [/bib_ref] Biliary tract complications. Biliary complications remain the Achilles heel of LT, with a reported incidence of up to 30% and include biliary leaks and biliary strictures. Biliary leaks can be anastomotic or, in cases of LDLT/SLT, from the cut edge of the liver. Leaks occur as an early postoperative complication and increase morbidity and mortality after LT. Presentation can be with peritonitis, irritability, vomiting, fever, bilious output from drains, and elevated liver enzymes. The cause can be technical or secondary to HA complications and timely surgical or radiologic intervention is advised to prevent septic complications.
The incidence of biliary leakage is approximately 5%. [bib_ref] Management of biliary complications after orthotopic liver transplantation: The role of endoscopy, Londoño [/bib_ref] Depending on its cause, it may have a https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] comparatively convenient option that includes ERCP procedure and sphincterotomy, temporarily placing a prosthesis, and many more solutions [fig_ref] Table 3 -: Risk stratification of microbial transmission from donor to recipient in liver transplantation [/fig_ref]. For partial graft, the leak is occasionally located on the superficial split liver and is produced by tubules with a gradually decreasing flow. Very infrequently, tubular embolization or re-surgery is needed. [bib_ref] Las complicaciones biliares en el trasplante hepático de donante vivo no afectan..., Sánchez Cabús [/bib_ref] Ischemic bile duct injuries. These may have various etiologies, such as ABO incompatibility, artery thrombosis, ischemia/reperfusion injury, among others,and are among the most common complications (15-37%) in patients who received livers from DCD donors. [bib_ref] Utilization, outcomes, and retransplantation of liver allografts from donation after cardiac death:..., Selck [/bib_ref] Additional cause is the reappearance of PSC (20-30%). [bib_ref] Recurrence of primary sclerosing cholangitis following liver transplantation, Graziadei [/bib_ref] [bib_ref] Recurrence and rejection in liver transplantation for primary sclerosing cholangitis, Fosby [/bib_ref] These injuries are presented by intrahepatic strictures chiefly disturbing their confluence, making a beaded appearance, with stenosis and dilatation of the entire biliary tract; cholestasis with intractable pruritus and recurrent cholangitis of liver abscesses are the chief manifestations.Re-LT is suggested in these patients (Grade II-3). [bib_ref] Intrahepatic biliary strictures after liver transplantation, Nishida [/bib_ref] Anastomotic stenosis. Anastomotic stenosis occurs 261 in few adults (4-9%), while in children, it can be as high as 25%. [bib_ref] Biliary strictures in pediatric liver transplant recipients -Early diagnosis and treatment results..., Anderson [/bib_ref] [bib_ref] Biliary reconstruction in pediatric live donor liver transplantation: Duct-to-duct or Roux-en-Y hepaticojejunostomy, Tanaka [/bib_ref] The pre-existing reasons for anastomotic strictures are related to suboptimal operation procedures or biliary leak, and their majority presents in the post-LT year, albeit it rises gradually later. [bib_ref] Anastomotic biliary strictures after liver transplantation: Causes and consequences, Verdonk [/bib_ref] Late biliary strictures generally appear as a result of graft ischemia; a radiological examination differentiates HAT. Ischemic biliary strictures usually occur more than one time and upset the entire biliary tree. However, solitary biliary strictures are generally related to surgical anastomosis. The earliest indications are 5 to 10 times increased alkaline phosphatase and GGT levels. [bib_ref] Long-term medical management of the pediatric patient after liver transplantation: 2013 practice..., Kelly [/bib_ref] Biliary dilatation is often absent in ultrasound, but diagnosis can be made by MRCP, with a sensitivity and specificity nearing 90%, [bib_ref] Magnetic resonance cholangiography in the diagnosis of biliary complications after orthotopic liver..., Linhares [/bib_ref] but the treatment ability is not sufficient. The regular treatment strategy involves endoscopic procedure with balloon dilatation and applying a stent, showing a better success rate (70-100%). [bib_ref] Biliary strictures following liver transplantation: Past, present and preventive strategies, Sharma [/bib_ref] [bib_ref] Long-term results of percutaneous bilioenteric anastomotic stricture treatment in livertransplanted children, Moreira [/bib_ref] Percutaneous transhepatic cholangiogram is kept for patients who did not benefit from endoscopic therapy or those with complicated hepatico-jejunostomies and possesses a lesser success rate (50-75%). [bib_ref] Long-term follow-up of percutaneous transhepatic balloon cholangioplasty in the management of biliary..., Sung [/bib_ref] When patients do not respond to either therapy, a hepatico-jejunostomy needs to be conducted (Grade II-3).Complications associated with partial grafts. The most common complication associated with partial grafts is anastomotic stenosis. An important related factor is the presence of bile leak, [bib_ref] Biliary strictures in 130 consecutive right lobe living donor liver transplant recipients:..., Shah [/bib_ref] and even though the underlying process is unknown, it may be associated with the local bile inflammatory effect or with weak local vascularity.Some research reports relate duct-toduct anastomosis size with the presence of stenosis. [bib_ref] Long-term incidence, risk factors, and management of biliary complications after adult living..., Hwang [/bib_ref] The incidence of anastomotic stenosis can affect half of partial liver graft recipients, and although it may not disturb long-term survival, the quality of life may be impacted. [bib_ref] Biliary strictures following liver transplantation: Past, present and preventive strategies, Sharma [/bib_ref] The success rate of endoscopic treatment (60-75%) is lesser compared to anastomotic stenosis after whole-LT. [bib_ref] Biliary complications after duct-to-duct biliary reconstruction in living-donor liver transplantation: Causes and..., Tashiro [/bib_ref] Interventional radiology serves as a good therapy option through dilatation or stent insertion.Around half of the cases need re-surgery, and the duct-to-duct anastomosis becomes a hepaticojejunostomy (Grade III). [bib_ref] Las complicaciones biliares en el trasplante hepático de donante vivo no afectan..., Sánchez Cabús [/bib_ref] Bowel perforation. Bowel perforation is a potentially devastating complication after LT in the pediatric population. Post-Kasai procedure recipients are particularly at risk, while other risk factors include high-dose steroid therapy, CMV infection, prolonged procedure, and re-operation for postoperative bleeding.
## Recommendations
- Domino LT procedure is the preferred option for familial amyloidotic polyneuropathy (Grade II-3) - Auxiliary LT should be used in two types of situations: 1) patients with acute hepatic failure with the partial graft supporting the unhealthy liver while recovering, and 2) patients with functional congenital or metabolic disorders disturbing the otherwise healthy liver (Grade II-3). - In split LT (SLT), if the liver is intended for one adult and one pediatric patient, it should be separated into a right lobe that also contains segment IV and a partial left lobe that comprises segments II and III (Grade II-2). If the liver is intended for two adults, it should be split into the right lobe (segments V-VIII) and left lobe (segments I-IV). Usually, the left lobe has a size of around 450g, which only allows it to be implanted in low-weight (50-55 kg) patients (Grade II-2). - Graft/recipient weight ratio needs to be minimum 0.8% to ensure viability (Grade III). - Re-intervention and revascularization can be the treatment option for 50% of hepatic artery thrombosis, whereas the other half requires re-LT (Grade III). - Monitoring for biliary leakage is recommended as its incidence is around 5%. Depending on its cause, it may have a comparatively convenient option, that included an endoscopic retrograde cholangiopancreatography (ERCP) procedure and sphincterotomy, temporarily placing a prosthesis, and many more solutions (Grade II-3). - Re-LT is the recommended treatment for ischemic bile duct injuries (Grade II-3).
- Hepatico-jejunostomy should be performed for anastomotic stenosis in cases of no response to other therapies (Grade II-3).
- About 7% to -10% of adult patients loose liver graft post-LT, and re-LT is the ideal treatment (Grade II-2).
The diagnosis can be challenging in this age group, with abdominal distention being the only symptom presenting. The incidence is reported to be 10-20%. [bib_ref] Risk and prognostic factors of gut perforation after orthotopic liver transplantation for..., Soubrane [/bib_ref] [bib_ref] Gastrointestinal perforation after pediatric orthotopic liver transplantation, Beierle [/bib_ref] Emergency laparotomy, washout, and repair are indicated.
Re-liver transplantation. Approximately 7-10% of adult patients lose transplanted grafts, [bib_ref] Retransplantation of the liver: Review of current literature for decision making and..., Yoo [/bib_ref] and re-LT is the only suitable therapy for these patients (Grade II-2). [bib_ref] Trends and experiences in liver retransplantation over 15 years, Pfitzmann [/bib_ref] The main causes of graft loss can be divided into early (HAT or main graft not functioning) and late-onset (IC, chronic rejection, or reappearance of the primary liver disease).The re-LT rate in KSA is 3.7%, lower than worldwide rates, which vary between 5-22%, [bib_ref] An analysis of outcomes of liver retransplant in adults: 12-year's single-center experience, Abdelfattah [/bib_ref] and this can be attributed to the severe shortage of deceased donor grafts. Small-for-size syndrome is the leading indication for re-LT in KSA, followed by HAT, recurrence of the original disease, chronic rejection, and late vascular complications. [bib_ref] An analysis of outcomes of liver retransplant in adults: 12-year's single-center experience, Abdelfattah [/bib_ref] The timing of re-LT is a crucial time for patient and graft survival. Those with a re-LT time of fewer than 30 days have lower survival times than those with later re-LT, [bib_ref] An analysis of outcomes of liver retransplant in adults: 12-year's single-center experience, Abdelfattah [/bib_ref] [bib_ref] A Single-center experience of retransplantation for liver transplant recipients with a failing..., Chen [/bib_ref] and re-LT has higher morbidity and mortality compared with LT. [bib_ref] Retransplantation of the liver: Review of current literature for decision making and..., Yoo [/bib_ref] Currently, there is no consensus for defining specific survival outcomes in which re-LT should be avoided, and only the MELD score provides an objective stratification for re-LT candidates.Re-LT recipients having MELD score >25 showed a reduced short-term survival (<60%), while those with MELD score >30 had a 20-40% survival rate. [bib_ref] Poor survival after liver retransplantation: Is hepatitis C to blame?, Watt [/bib_ref] The key parameter in establishing treatment success of re-LT is allograft quality, with aged donors and lengthy cold ischemia time are regarded as crucial aspects.Hepatitis C virus was regarded as an independent risk factor for re-LT. However, several studies show that re-LT can give an optimal survival time, with no significant differences in survival time between HCV positive, cryptogenic, cholestatic, or ALD patients when attuned to MELD scores and age (Grade II-3). [bib_ref] Improving Outcomes of Liver Retransplantation: An Analysis of Trends and the Impact..., Ghabril [/bib_ref] [bib_ref] Prediction of survival after liver retransplantation for late graft failure based on..., Yao [/bib_ref] [bib_ref] A model to predict survival following liver retransplantation, Rosen [/bib_ref] The selection of recipients for re-LT needs to be integrated with disease severity, time since first LT, and graft quality, which are imperative than the cause of re-LT.
## Post-transplant care
Survival after LT has improved over time with fine-tuned immunosuppression protocols, postoperative care, and prevention and treatment of infections. [bib_ref] Care of the liver transplant patient, Bhat [/bib_ref] There are several causes of death post-LT. A year after surgery, infections and operation-related complications may form the reason for the deaths or graft losses in 60% of cases. After this period, cancers, renal failure, and cardiovascular manifestations are the most important causes of mortality. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Immunosuppression. Post-LT patients require lifelong immunosuppression, which is key for graft survival. The sustained immunosuppressant usage may induce unavoidable consequences, like high infection risk, metabolic complications such as hypertension, T2DM); hyperlipidemia, obesity, and gout; and de novo cancers (including post-LT lymphoproliferative disorder [PTLD]). [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] The specific immunosuppression regimen should consider minimizing these side effects that may affect patient survival. Immunosuppression medication is maximized gradually during the first week of postoperative care, aiming to reduce the risk of acute cellular rejection.Most LT centers in the KSA use 3 agents to prevent rejection in the immediate postoperative period. These include a glucocorticoid, such as prednisone, a calcineurin inhibitor (CNI), such as tacrolimus or cyclosporine, and a third agent, such as mycophenolate mofetil (MMF). After 6 months, with the stability of the graft function, most patients require only a single immunosuppressive agent, which is the main drug for long-term immunosuppression, typically a CNI.
## Immunosuppressive drugs
Calcineurin inhibitor. Tacrolimus is the medicine of choice and main CNI in post-LT patients. A metaanalysis comparing tacrolimus with cyclosporin has shown that tacrolimus is better than cyclosporin in terms of improving survival and avoiding graft loss or rejection. However, no difference in renal function has been found. [bib_ref] Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: A metaanalysis, Mcalister [/bib_ref] [bib_ref] Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation:..., O'grady [/bib_ref] The main side effects of CNI therapy are renal impairment, infections, gout, hypertension, hypercholesterolemia, glucose intolerance, hypomagnesemia, hyperkalemia, and tremor. [bib_ref] Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation:..., O'grady [/bib_ref] Calcineurin inhibitor neurotoxicity post-LT is a rare but serious event, especially associated with posterior reversible encephalopathy syndrome (PRES) due to endothelial dysfunction secondary to CNIs. In a retrospective cohort of 1923 adult LT recipients, PRES was diagnosed radiologically in 19 patients (1%), with most cases occurring early post-LT. [bib_ref] Posterior reversible encephalopathy syndrome in liver transplant patients: Clinical presentation, risk factors..., Cruz [/bib_ref] A sustainedrelease formulation of tacrolimus was introduced, which offers a once-daily dosing option, but showing efficacy and safety identical to the twice-daily dosing regimen. [bib_ref] Conversion from twice daily tacrolimus to once daily tacrolimus in long-term stable..., Dumortier [/bib_ref] [bib_ref] Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation, Trunečka [/bib_ref] Such a formulation may help achieve patient medication adherence. [bib_ref] Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from..., Beckebaum [/bib_ref] Azathioprine (AZA) and mycophenolate mofetil. In LT, both the antimetabolites, AZA and MMF, are widely used. These drugs reduce purine synthesis, https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref]
## Recommendations
- Calcineurin inhibitors (CNI)-based regimen has shown better long-term graft and patient survival in liver transplantation (LT) recipients and can thus be considered as the primary immunosuppressive treatment; tacrolimus has better performance than cyclosporin A, even in hepatitis C virus (HCV) patients (Grade I). - Treatment of mycophenolate mofetil (MMF) alone may induce acute cellular rejection and has not to be considered (Grade I).
However, MMF along with MMF reduced CNI (minimum 50%) results in better advancement kidney function and possesses a lesser risk of acute rejection (Grade I). - Safer conversion to Sirolimus (SRL) may offer adequate immunosuppression with no rise in rejection, graft loss, or infection in LT recipients (Grade I). - Post-LT renal function can be improved using early EVR-based CNI-free immunosuppressive agents; however, care must be taken as it may increases the chance of acute rejection (Grade I) impacting T and B lymphocyte proliferation, and they are used in combination with a CNI for preventing graft rejection. The use of these drugs has increased in the last 2 decades as they serve the purpose of decreasing the CNI's dose, especially in patients with kidney impairment, minimizing the effect of CNI nephrotoxicity. Mycophenolate mofetil has increasingly become the highly utilized antimetabolite drug, albeit no differences were observed with AZA regarding patient and graft survival. [bib_ref] Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion..., Al-Adra [/bib_ref] [bib_ref] A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination..., Wiesner [/bib_ref] [bib_ref] Improvement in gastrointestinal and health-related quality of life outcomes after conversion from..., Sterneck [/bib_ref] Major side effects of MMF include diarrhea, leucopenia and bone marrow suppression. The enteric-coated formulation of mycophenolate sodium (EC-MPS) reduces the gastrointestinal side effects, but the LT data is limited. [bib_ref] Enteric-Coated Mycophenolate Sodium Experience in Liver Transplant Patients, Cantisani [/bib_ref] [bib_ref] Clinical evolution in the first 3 months of patients after liver transplantation..., Miras [/bib_ref] A small size single-arm study in LT showed that the conversion from MMF to EC-MPS was related to substantial progress in gastrointestinal symptoms, [bib_ref] Improvement in gastrointestinal and health-related quality of life outcomes after conversion from..., Sterneck [/bib_ref] but no high-level evidence is existing as such.
## Sirolimus (srl) and everolimus (evr).
Sirolimus and EVR inhibit the mammalian target of rapamycin (mTORi), blocking interleukin (IL)-2 and IL-15 induced proliferation of T and B lymphocytes. The main side effects of mTORi are thrombocytopenia, leucopenia, impaired wound healing, hyperlipidemia, proteinuria, possible increased risk of HAT. [bib_ref] Clinical Practice Guidelines for the management of patients with decompensated cirrhosis, Angeli [/bib_ref] The use of EVR in combination with reduced tacrolimus dose prevents renal impairment post-LT. [bib_ref] Everolimus with early withdrawal or reduced-dose calcineurin inhibitors improves renal function in..., Lin [/bib_ref] It reduces the HCC recurrence rate in one year, as shown in a randomized multicenter study of LDLT. [bib_ref] Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant..., Jeng [/bib_ref] Basiliximab. Basiliximab is an induction agent, IL-2 receptor (CD25) monoclonal antibody used to decrease the side effects of immunosuppressants by diminishing or delaying the use of CNIs. This agent is used especially when the recipient has renal impairment prior to transplant, although studies have not found differences in patient and graft survival. A meta-analysis of 18 studies showed that LT patients receiving IL-2R antagonists had lesser acute rejection, steroid-resistant acute rejection, and no functioning of kidneys when related to decreased or late CNI use. [bib_ref] Interleukin 2 receptor antagonists for liver transplant recipients: A systematic review and..., Goralczyk [/bib_ref] Corticosteroids. Corticosteroids are part of the standard immunosuppression regimen with CNI and antimetabolite agents, starting with the induction in the immediate operative phase and then continuing with taper protocols. Steroids may be tapered by 2 months in patients at low risk for rejection, uncontrolled diabetes, severe osteoporosis, sepsis, or delayed wound healing. However, low-dose steroids should continue in autoimmune disease to try to prevent disease recurrence. Steroids have many side effects, including infections, hypertension, T2DM, and osteoporosis. Therefore, minimizing the corticosteroids regimen with time is prudent. 298 [fig_ref] Table 6 -: Indications for pediatric liver transplantation [/fig_ref] summarizes the side effects of immunosuppressive drugs.
The choice of immunosuppressive drugs varies between individuals and depends on many factors that include time after transplant, indication for transplant, rejection episodes, risk of cancer, renal impairment, risk of infections, and comorbid diseases. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] [bib_ref] Adult liver transplantation: UK clinical guideline-part 2: Surgery and post-operation, Millson [/bib_ref] In addition, drug-drug interactions must be considered during the use of immunosuppressive agents [fig_ref] Table 7 -: Major drug-drug interactions involving immunosuppressive agents [/fig_ref].
## Medical complications. before and after lt,
medication adherence is imperative in avoiding complications that may affect graft function; otherwise, it may increase costs after the surgery or even patient death.Early post-liver transplantation and long-term follow-up. Most deaths happen in the initial days after LT, and the causes differ based on the time after LT. Almost 60% of deaths are related to infections and intra-and perioperative surgical complications. Graft losses in the initial year post-LT and de novo cancers and cardiovascular manifestations are key mortality causes after this period.Increased, adequate, and safer use of immuno suppressive agents may prevent acute rejections or graft loss, while chronic ductopenic rejection poses a lesser prognosis without re-LT.The increasing prevalence of NAFLD and aged LT recipients, de novo diabetes and metabolic bone disease, are diagnosed after LT. De novo malignancy and PTLD, although less common, are associated with significant mortality in NAFLD recipients. Earlier diagnosis, immunosuppression treatment modification, and rarely re-LT in the context of irreversible graft rejection and KT in end-stage renal disease (ESRD) are important for patient outcomes. 118,300
## Recurrence of disease
## Hepatitis c virus recurrence: management and treatment post-liver transplantation.
It is expected that HCV may recur post-LT in approximately 33% of LT patients who are HCV-infected, increasing the risk of clinical decompensation and graft loss. [bib_ref] Liver transplantation for viral hepatitis in 2015, Ferrarese [/bib_ref] [bib_ref] HCV-related fibrosis progression following liver transplantation: Increase in recent years, Berenguer [/bib_ref] Early antiviral treatment is suggested in these patients. Sustained viral response is related to better patient outcomes. [bib_ref] Viral hepatitis in liver transplantation, Crespo [/bib_ref] (Grade II-1). For genotype 1-and 4-infected LT recipients, such as patients with compensated cirrhosis, an initial treatment regimen with a sofosbuvir-based therapy or a combination of glecaprevir/pibrentasvir for 12 weeks is recommended with high SVR rates. While for decompensated cirrhosis, the treatment will be sofosbuvir-based therapy with RBV for 12 -24 weeks, as per the HCV guidelines: (https://www.hcvguidelines.org).
Preventing and treating hepatitis B virus recurrence. The recurrence of post-LT HBV causes allograft dysfunction, allograft cirrhosis, and graft failure. [bib_ref] Prevention and treatment of recurrent hepatitis B after liver transplantation, Maiwall [/bib_ref] Hepatitis B virus-related cirrhotic patients pose increased graft infection risk (~70%), hepatitis D virus-related cirrhotic patients have moderate (~40%) risk, and those with acute hepatic failure has comparatively lower (<20%) risk. The key cause of HBV recurrence is increased HBV DNA levels during the LT procedure. [bib_ref] Liver transplantation in European patients with the Hepatitis B surface antigen, Samuel [/bib_ref] Liver transplantation for HBV-related cirrhosis currently has exceptional long-term outcomes, with 5-year SVR ≥80%. [bib_ref] Global distribution and prevalence of hepatitis C virus genotypes, Messina [/bib_ref] [bib_ref] Liver transplantation and hepatitis B virus infection: The situation seems to be..., Samuel [/bib_ref] The use of antivirals for patients waiting for LT subdues allograft HBV replication and recurrence. Thus, HBV patients with decompensated cirrhosis must require entecavir or tenofovir prior to LT. [bib_ref] Prevention and treatment of recurrent hepatitis B after liver transplantation, Maiwall [/bib_ref] Currently, >90% of patients with recurrent HBV infections require antiviral agents. [bib_ref] Prevention and treatment of recurrent hepatitis B after liver transplantation, Maiwall [/bib_ref] Hepatitis B virus recurrence can be prevented by a combination of HBIg and antiviral drugs in high-risk patients. However, low dose HBIg, HBIg-free protocols, and monoprophylaxis with high-efficacy antiviral drugs can also be used in low-risk cases. [bib_ref] Prevention and treatment of recurrent hepatitis B after liver transplantation, Maiwall [/bib_ref] Because of the increased expenses related to HBIg therapy, many research projects have evaluated the efficacy of HBIg in reduced doses or even withdrawal in chosen patients. These approaches, along with NUCs, have successfully prohibited HBV recurrence and seem to be a possible strategy for HBeAg-negative in LT candidates with nondetectable HBV DNA traces. Besides, these regimens dramatically reduce costs when compared to high-dose intravenous HBIg regimens.Five years after receiving intramuscular injections of HBIg (400 IU to 800 IU per month) along with lamivudine, the recurrence was merely 4%. [bib_ref] Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following..., Gane [/bib_ref] A randomized study has shown that a small dosage regimen of HBIg along with lamivudine, trailed by lamivudine monotherapy, has yielded good results in patients with undetectable HBV DNA levels during LT. 314 Although recent studies have questioned the need for HBIg since NUCs have become more efficient, data is not consistent concerning HBV graft infection and HBV recurrence. [bib_ref] Editorial: Prophylaxis in hbv-infected liver transplant patients: End of the HBIG era?, Terrault [/bib_ref] Patients who got liver transplantation from anti-hepatitis C virus positive donors. The impact of anti-HBc positive liver grafts on survival and de novo HBV infection risk post-LT continue to be debatable. [bib_ref] Liver transplantation using hepatitis B core positive grafts with antiviral monotherapy prophylaxis, Wong [/bib_ref] Liver transplantation patients who received transplant from an anti-HBc positive donor must receive antiviral therapy soon after LT (Grade II-2). [bib_ref] Liver grafts from anti-hepatitis B core positive donors: A systematic review, Cholongitas [/bib_ref] In terms of cost-effective treatment, lamivudine monotherapy is the best option. A recent study comparing lamivudine and entecavir monotherapy prophylaxis in HBsAg negative recipients that received anti-HBc positive grafts showed that de novo HBV was exceptionally infrequent, particularly with entecavir prophylaxis. [bib_ref] Liver transplantation using hepatitis B core positive grafts with antiviral monotherapy prophylaxis, Wong [/bib_ref] Hepatitis B immune globulin must not be given in HBsAg negative patients who received LT from an anti-HBc positive donor (Grade II-2).Managing patients transplanted for alcoholic liver disease. Liver transplantation candidates with ALD have a similar survival rate compared to those without ALD, but the post-LT death rate is high in patients with comorbid ALD. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Post-LT alcohol relapse in ALD patients varies a lot (10%-90%), and patients with an earlier disease detection of ALD must be advised to avoid alcohol at all (Grade II-2) and undergo psychiatric treatment or consultation if they start back alcohol consumption in the post-LT period (Grade II-3). [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Advice on smoking cessation must be considered. The risk of cardiovascular disease and associated manifestations or new-onset malignancies of the airway, pulmonary tract, or upper digestive tract, particularly in cigarette smokers, requires caution. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Recurrence of NAFLD. Both NAFLD and NASH, recurrent and de novo, are common after LT. [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] Pre-and post-LT BMI, T2DM, arterial hypertension, and hyperlipidemia are the major risk factors for post-LT NAFLD/NASH. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] [bib_ref] Nonalcoholic steatohepatitis recurrence after liver transplant, Taneja [/bib_ref] Liver biopsy is required to confirm recurrent or de novo NAFLD/NASH, recognize fibrosis, and exclude alternate causes of altered liver chemistry tests (Grade III). Avoiding extreme weight gains and keeping hypertension, dyslipidemia, and T2DM in control are recommended (Grade III). [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Recurrence of cholestatic hepatic disease. Autoimmune hepatitis, PBC, and PSC recurrence differ from 10% to 50% and must be confirmed by liver biopsy and/or cholangiography (PSC) (Grade II-3).Primary sclerosing cholangitis recurrence is common and leads to graft failure after LT for PSC. Keeping an inactive inflammatory bowel disease status may guard against PSC recurrence. [bib_ref] Long-term prognosis and recurrence of primary sclerosing cholangitis after liver transplantation, Ueda [/bib_ref] There is no convincing data to support the ursodeoxycholic acid prophylaxis in patients who underwent LT for PBC and PSC (Grade III).Managing hepatocellular carcinoma recurrence. The risk of HCC recurrence following LT affects between 15% and 20% of the cases. It is generally observed during a couple of years initially after LT, with a median survival lesser than a year. [bib_ref] Liver transplantation for hepatocellular carcinoma: A model including α-fetoprotein improves the performance..., Duvoux [/bib_ref] [bib_ref] Recommendations for liver transplantation for hepatocellular carcinoma: An international consensus conference report, Clavien [/bib_ref] The recurrence risk depends on numerous factors related to the tumor, patient, and treatment. [bib_ref] Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation, Filgueira [/bib_ref] Factors such as the histopathological characteristics of the tumor, AFP levels, and waiting time are well established. However, other biological factors related to tumor behavior and treatment must be identified since they can be used to refine selection criteria of transplant candidates to reduce recurrence. [bib_ref] Hepatocellular carcinoma recurrence after liver transplantation: Risk factors, screening and clinical presentation, Filgueira [/bib_ref] In patients who developed hepatic cirrhosis due to HCC recurrence, de novo HCC may progress, similar treatment protocol used for immunocompetent patients needs to be adhered, that may include hepatic resection, radiofrequency ablation or TACE (when possible) and, when indicated, re-LT.Surveillance for de novo HCC needs to be carried out with radiological investigation of the abdomen every 6 months to one year. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Currently, there is no supporting data suggesting that long-term (>5 years) recurrence-free survival is achieved using SRL (Grade I); however, it seems to be effective in 3-5 years, time in HCC patients within Milan criteria (Grade I). Therefore, an immunosuppressant treatment plan that comprises SRL starting many weeks post-LT must be used for patients who are affected due to HCC. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Several studies have attempted to demonstrate that sorafenib, a multikinase inhibitor, might be associated with benefits in survival and safety profiles; however, based on the current data, a recommendation for its use cannot be established. [bib_ref] Sorafenib in advanced hepatocellular carcinoma, Llovet [/bib_ref] [bib_ref] Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma..., Sposito [/bib_ref] [bib_ref] Sorafenib for recurrent hepatocellular carcinoma after liver transplantation, Kim [/bib_ref] Thus, it is recommended that therapy for HCC recurrence post-LT be personalized, and there is no evidence to utilize sorafenib in patients with disseminated recurrence (Grade III).Managing kidney dysfunction. Most LT recipients, who survive the initial 6 months, develop CKD. [bib_ref] Chronic renal failure after transplantation of a nonrenal organ, Ojo [/bib_ref] The causes of CKD in LT patients [fig_ref] Table 8 -: Prevalence of cardiovascular risk factors and CKD in LT recipients beyond the... [/fig_ref] depend on many factors that include long-time use of CNIs: hypertension, T2DM, obesity, atherosclerosis, hyperlipidemia, chronic HCV infection, pretransplant renal dysfunction, and perioperative AKI. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Immediately after LT, incessant observing of kidney function is mandatory for detecting and managing CKD, including treating possible risk factors (Grade II-2).Quantifying urinary protein by means of protein to creatinine concentration ratio is required a minimum once a year post-LT. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Reducing or completely withdrawing CNI-associated immunosuppression or using CNI-free treatment regimens is an appropriate regimen in LT recipients with abnormal kidney function (Grade I). [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Kidney transplantation is helpful in improving survival and can be regarded as the ideal therapeutic option for LT patients with ESRD (Grade II-3). [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Preventing and treating infections. Infections are a serious concern following LT, as around two-thirds of the LT patients get them postoperatively. Therefore, preventing infections and using aggressive disease recognizing approaches are essential depending on the time after LT 12 [fig_ref] Table 8 -: Prevalence of cardiovascular risk factors and CKD in LT recipients beyond the... [/fig_ref].
Infections may highly occur during 2-6 months post-LT with opportunistic agents, such as herpesviruses (especially CMV, herpes zoster and simplex, and EBV), fungi (Aspergillus and Cryptococcus), and more not-common bacterial infections (Nocardia, Listeria, and Mycobacteria). Therefore, assessing infections following LT should consider implementing prophylactic antimicrobials, avoid high-risk exposures, and minimize immunosuppression therapy. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Following the 3 months after LT, with the reduction of immunosuppression regimens, the risk of infection becomes lower. After this period, infections in intraabdominal, lower respiratory tract, or by communityacquired pathogens, such as enteric Gram-negative infections, S. pneumonia, and respiratory viruses, are quite common. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] Bacterial pathogens cause most infections post-LT, particularly Gram-negative bacteria, including Escherichia coli and Enterobacter, Pseudomonas.Surgical site, abdominal cavity, urinary tract, and bloodstream are the common locations. Intra-abdominal infections are related to graft loss and increased mortality. [bib_ref] Infected bilomas in liver transplant recipients: Clinical features, optimal management, and risk..., Safdar [/bib_ref] Cytomegalovirus, infection is the most common opportunistic infection in LT recipients. Although satisfactory prophylaxis has been shown to expressively lessen its incidence, it still involves pertinent illness. The most common syndromes are viremia, bone marrow suppression, colitis, and hepatitis. [bib_ref] Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation, Kotton [/bib_ref] For at least 3 months post-LT, CMV prophylaxis should be given to patients who have high CMV infection risk (Grade II-2).
Postulate lymphoproliferative disorder must be doubted in LT patients, particularly in patients who show seropositivity to EBV before LT or are treated with anti-lymphocyte globulin, an aggressive immunosuppressive agent, as they are at an increased risk of progressing PTLD (Grade III). [bib_ref] Occurrence of post-transplant lymphoproliferative disorders among over thousand adult recipients: Any role..., Burra [/bib_ref] Treatment for PTLD needs reducing immunosuppressants. Further treatments include rituximab, chemotherapy, radiation, and surgery if no response is received by immunosuppressant reduction.Fungal infections have been reported over the last 2 decades, with a substantial reduction in invasive candidiasis and an insignificant rise in invasive aspergillosis in LT recipients. [bib_ref] Trends in invasive fungal infections in liver transplant recipients: Correlation with evolution..., Singh [/bib_ref] Risk factors associated with invasive fungal infections are decreased length of LT surgery, transfusion needs during LT, cold ischemic time, usage of roux-en-Y biliary anastomosis, PVT, biopsy-proven rejection episodes, re-LT, and kidney replacement treatment. [bib_ref] Trends in invasive fungal infections in liver transplant recipients: Correlation with evolution..., Singh [/bib_ref] [bib_ref] Risk factors of invasive Candida and non-Candida fungal infections after liver transplantation, Patel [/bib_ref] [bib_ref] Risk factors for invasive aspergillosis in living donor liver transplant recipients, Osawa [/bib_ref] Therapy protocol consists of reducing immunosuppressive therapy and using antifungal agents. Oral prophylaxis to counter Candida species is recommended in the initial months, as it lessens death rates resulting from fungal infection (Grade II-3). Prophylaxis for countering aspergillus is only endorsed in high-risk scenarios (Grade II-3).Pneumocystis jirovecci, the agent that causes pneumocystis pneumonia, is infrequent during trimethoprim-sulphamethoxazole (TMP-SMX) prophylaxis. However, TMP-SMX might cause kidney toxicity, and corticosteroids are helpful as an adjunctive treatment to decrease respiratory inflammation and fibrosis occurring after infection (Grade II-3).Prophylaxis to counter Pneumocystis jirovecci with TMP-SMX is required in LT patients for 6 months to one year (Grade II-2).Liver transplantation patients may experience active TB (0.47-2.3%), particularly in the first year after surgery. [bib_ref] Tuberculosis after Solid-Organ Transplant: Incidence, Risk Factors, and Clinical Characteristics in the..., Torre-Cisneros [/bib_ref] [bib_ref] Mycobacterium tuberculosis Infection in Recipients of Solid Organ Transplants, Munoz [/bib_ref] This infection has a high mortality rate, and treatment for latent TB is relevant. Isoniazid https://smj.org.sa Saudi Med J 2021; Vol. 42 [bib_ref] Liver transplantation for hepatitis B virus: Decreasing indication and changing trends, Al-Hamoudi [/bib_ref] regimen for 9 months (along with vitamin B6) is the typical treatment option. It needs to be indicated in the following scenarios: PPD positive skin test, history of untreated TB, or chest radiography findings suggesting TB.Treating active TB in LT recipients is complicated due to drug interactions between anti-TB and immunosuppressants, plus the liver toxicity related to the first-line TB treatment. Patients on anti-TB therapy should be observed for possible side effects relevant to liver and acute rejection (Grade II-3). Treatment of non-severe TB must include isoniazid and ethambutol, and no rifamycins. Levofloxacin can be chosen instead of isoniazid. Severe form of TB must consist of treatment with rifamycin in the earlier and maintenance stages. 12 outlines the prophylactic strategies underlying the common microorganisms that affect LT recipients.
## Recommendations
- In most LT HBV-infected patients, a combination of HBIg and NUCs should be used as an effective strategy to prevent HBV recurrence (Grade I) - Patients with undetectable HBV DNA during LT, without any prior resistance to NUCs can be benefited from HBIg in a lower dose or for a shorter duration up to 3 months, supported later by NUC monotherapy (Grade I) - Entecavir or tenofovir monotherapy is efficient in controlling the recurrence of infection, but is not be adequate to evade HBV graft infection (Grade II-2) - HBV recurrence needs to be treated with entecavir or tenofovir, with prompt initiation (Grade II-3) - LT recipients who get from an anti-HBc positive donor must be given effective antiviral drugs soon after LT (Grade II-2) - In HBsAg-negative LT recipients transplanted from an anti-HBc-positive donor, HBIg must not be used (Grade II-2) - Patients with a prior ALD diagnosis must be advised to avoid alcohol at all (Grade II-2) and undergo psychiatric treatment or consultation if they start back alcohol consumption in the post-LT period (Grade II-3) - Liver biopsy is required to confirm recurrent or de novo NAFLD/NASH, recognition of fibrosis, and exclusion of alternate causes of altered liver chemistry tests (Grade III). Avoid extreme weight gains and keeping hypertension, dyslipidemia, and T2DM in control are recommended (Grade III) - AIH, PBC, and PSC recurrence differ from 10% to 50% and must be confirmed by liver biopsy and/or cholangiography (PSC) (Grade II-3) - There is no convincing data to support the prophylactic use of ursodeoxycholic acid in patients who underwent LT for PBC and PSC (Grade III) - Currently, there is no data suggesting that long-term (over 5 years) recurrence-free survival is achieved using SRL (Grade I); however, it seems to be effective in 3-5 years, time in HCC patients within Milan criteria (Grade I). - It is recommended that therapy for HCC recurrence post-LT needs to be personalized, and there is no evidence to utilize sorafenib in patients with disseminated recurrence (Grade III). - Immediately after LT, incessant observing of kidney function is mandatory for detecting and managing CKD, including treating possible risk factors (Grade II-2) - Reducting or completely withdrawing CNI-associated immunosuppression or using CNI-free treatment regimens is an appropriate regimen in LT recipients with abnormal kidney function (Grade I) - Kidney transplantation is helpful in improving survival and can be regarded as the ideal therapy for LT patients with ESRD (Grade II-3) - For at least 3 months, CMV prophylaxis must be used in those at an increased risk of developing CMV infection (Grade II-2). - PTLD must be doubted in LT patients, particularly those patients that show seropositivity to EBV before LT or that are treated with anti-lymphocyte globulin, an aggressive immunosuppressive agent, as they are at increased risk of progressing PTLD (Grade III) - Oral prophylaxis to counter Candida species is recommended in the initial months, as it lessens death rates resulting from fungal infection (Grade II-3). Prophylaxis for countering aspergillus is only endorsed in high-risk scenarios (Grade II-3) - TMP-SMX might cause kidney toxicity, and corticosteroids are helpful as adjunctive treatment to decrease respiratory inflammation and fibrosis occurring after infection (Grade II-3) - Prophylaxis to counter P. jirovecii with TMP-SMX is required in LT patients for a period of half to one year (Grade II-2) - Patients on anti-tuberculosis should be observed for possible side effects relevant to liver and acute rejection (Grade II-3). -Timeline of infectious complications following LT.
## First month after lt 2-6 months after lt > 6 months after lt
Nosocomial infections related to surgery and postoperative care
## Opportunistic infections reactivation of latent infections community-acquired infections
Managing metabolic syndrome. One year following LT, complications associated with cardiovascular risks and metabolic syndrome become increasingly relevant. [bib_ref] Adult liver transplantation: UK clinical guideline-part 2: Surgery and post-operation, Millson [/bib_ref] The number of LT recipients with underlying metabolic syndrome rises as the population's median BMI grows. [bib_ref] Metabolic syndrome in liver transplant recipients: Prevalence, risk factors, and association with..., Laish [/bib_ref] The clinical characteristics of metabolic syndrome, namely insulin-resistant (type 2) diabetes mellitus, obesity, dyslipidemia, and arterial hypertension, aid in delayed morbidity and mortality. It is estimated that the occurrence of metabolic syndrome in the LT population is between 50-60%. [bib_ref] Metabolic syndrome and liver transplantation: A review and guide to management, Watt [/bib_ref] Liver transplantation recipients have a higher risk of cardiovascular disease, representing almost one-fourth of mortality in the post-LT, long-term follow-up. [bib_ref] Cardiovascular risk factors following orthotopic liver transplantation: Predisposing factors, incidence and management, Desai [/bib_ref] [bib_ref] Long-term probability of and mortality from de novo malignancy after liver transplantation, Watt [/bib_ref] Data has shown that the immunosuppressant treatment protocols exacerbate underlying systemic and metabolic disorders and de novo arterial hypertension after surgery, hyperlipidemia, T2DM, and obesity. [bib_ref] Cardiovascular risk factors following orthotopic liver transplantation: Predisposing factors, incidence and management, Desai [/bib_ref] Hence, adequate therapy for modifiable risk factors by means of lifestyle and behavioral modifications, drug treatments, and changes to the immunosuppressive drugs are essential to prevent serious cardiovascular manifestations (Grade III).Drug treatments in parallel with a balanced diet and routine physical exercise need to be implemented earlier to control arterial hypertension, hyperlipidemia, T2DM, and obesity (Grade II-3). Balanced diet and physical exercise initiatives can effectively help (Grade III).Bone disease. Bone loss increases in the first 6 months following LT and is related to higher fracture risk inducing obvious morbidity and poor quality of life. [bib_ref] Fractures and avascular necrosis before and after orthotopic liver transplantation: Long-term follow-up..., Guichelaar [/bib_ref] Following the initial 6-12 months post-LT, bone loss reverses, and bone density increases. Annual examination of bone mineral density is advisable for patients with underlying osteoporosis and osteopenia. Similar examination is suggested every 2-3 years in those with normal values. After that, checking relies on how bone mineral density and associated risk factors change over time (Grade II-3).When the diagnosis of osteopenic bone disease is established or atraumatic fractures surge, associated risk factors for bone disease need to be evaluated. Particularly, calcium intake and 25-hydroxy-vitamin D need to be assessed. Gonadal and thyroid function evaluation, along with thoracolumbar radiography, need to be carried out. Besides, a complete medication history needs to be checked. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] For the osteopenic LT recipient, regular weightbearing exercises in combination with calcium and vitamin D supplements should be performed (Grade II-3). Bisphosphonate must be used in LT recipients with osteoporosis or recent fractures (Grade II-2). [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] De novo malignancies. The incidence of de novo cancers is higher in the LT population than a control population (age-and sex-matched non-LT) [fig_ref] Table 1 -: Registered liver transplantation in the Kingdom of Saudi Arabia between 2018 and... [/fig_ref]. The incidence of de novo cancer following LT may increase up to 34% at 15 years after LT. [bib_ref] Long-term probability of and mortality from de novo malignancy after liver transplantation, Watt [/bib_ref] [bib_ref] Spectrum of cancer risk among US solid organ transplant recipients, Engels [/bib_ref] [bib_ref] Extensive surveillance promotes early diagnosis and improved survival of de novo malignancies..., Finkenstedt [/bib_ref] The increased incidence of de novo malignancies is because of the loss of immunovigilance induced by immunosuppressants and other associated risk factors, such as viral infections with oncogenic capability (namely, EBV, human papillomavirus), PSC, cigarette smoking, and alcohol consumption.Post-LT malignancy screening protocols are required, especially in patients at high risk to notice de novo malignancies at an initial and possibly curative phase (Grade II-2). Several risk factors associated with de novo cancers cannot be altered, such as age or pre-existing hepatic disease. Thus, routine oncology surveillance initiatives have been suggested, although the optimal surveillance protocol still needs to be defined.The most common de novo malignancy in LT patients is skin malignancy. The most frequent are non-melanoma cancers, such as squamous and basal cell carcinoma. [bib_ref] Posttransplantation de novo tumors in liver allograft recipients, Penn [/bib_ref] Besides having a higher frequency, they tend to be more aggressive and metastasize more frequently in LT recipients than in a control population. [bib_ref] Nonmelanoma skin cancer after liver transplantation. Study of risk factors, Herrero [/bib_ref] Many risk factors aid in the progression of non-melanoma skin malignancies post-LT and include advanced age, prolonged sun exposure, sunburn, fair skin, and skin malignancy history. [bib_ref] Nonmelanoma skin cancer after liver transplantation. Study of risk factors, Herrero [/bib_ref] After surgery, LT recipients must attain dermatology consultation to evaluate cutaneous lesions with yearly assessments after five years or more post-LT (Grade I-1).
Malignancy in the upper gastrointestinal oropharyngeal-laryngeal and pulmonary cancers are particularly increasing in patients with alcoholic cirrhosis. These recipients should be subjected to a comprehensive surveillance strategy for identifying these malignancies (Grade II-3). [bib_ref] Long-term probability of and mortality from de novo malignancy after liver transplantation, Watt [/bib_ref] Pre-and post-LT history of smoking additionally raises the risk of head/ neck and pulmonary de novo malignancies, stressing the significance of quitting smoking by LT patients. [bib_ref] Risk factors of lung, head and neck, esophageal, and kidney and urinary..., Herrero [/bib_ref] Post-LT lymphoproliferative disorder is frequent in LT recipients and should be suspected when patients present with fever, weight loss, and night sweats, even without lymphadenopathy.Epstein-Barr virusassociated PTLD was observed to be the most frequently Reserve for high-risk individuals (pretransplant fungal colonization, renal replacement therapy, massive transfusion, choledochojejunostomy, re-operation, retransplantation, or hepatic iron overload).
## P. jirovecii (p. carinii)
Trimethoprim sulfamethoxazole (single strength daily or double strength 3 times per week), dapsone (100 mg daily), or atovaquone (1500 mg daily)
## 6-12 months (adjust duration)
A longer duration of therapy should be considered for patients on augmented immunosuppression. Lifelong therapy should be considered for HIV-infected recipients.
## Tb (latent infection)
Isoniazid (300 mg daily) 9 months Monitor for hepatotoxicity
## Recommendations
- Adequate therapy for modifiable risk factors by means of lifestyle and behavioral modifications, drug treatments, and changes to the immunosuppressive drugs are essential to prevent serious cardiovascular manifestations post-LT (Grade III). Drug treatments in parallel with a balanced diet and routine physical exercise need to be implemented early to control arterial hypertension, hyperlipidemia, T2DM, and obesity (Grade II-3). Balanced diet and physical exercise initiatives can effectively help (Grade III) - Annual examination of bone mineral density screening is advisable for patients with underlying osteoporosis and osteopenia. Similar examination is suggested every 2-3 years in those with normal values. After that, checking relies on how bone mineral density and associated risk factors change over time (Grade II-3) - For the osteopenic LT recipient, regular weight-bearing exercises in combination with calcium and vitamin D supplements should be performed (Grade II-3). Bisphosphonate must be used in LT recipients with osteoporosis or recent fractures (Grade II-2) - Post-LT malignancy screening protocols are required, especially in patients at high risk to notice de novo malignancies at an initial and possibly curative phase (Grade II-2). - LT recipients must attain dermatology consultation after surgery to evaluate cutaneous lesions with yearly assessments after five years or more post-LT (Grade I-1). - Malignancy in the upper gastrointestinal oropharyngeal-laryngeal, and pulmonary cancers, are particularly increasing in patients with alcoholic cirrhosis, and these recipients should be subjected to a comprehensive surveillance strategy for identifying these malignancies (Grade II-3) - Patients who underwent LT for PSC with related bowel disease require colonoscopy every year, with biopsies for colorectal cancer checking and detection (Grade II-3)
Patients who underwent LT for PSC with related bowel disease must take colonoscopy with biopsies every year to check and detect colorectal cancer (Grade II-3). [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref] If dysplasia is diagnosed in a colonic biopsy, colectomy, including continence-preserving pouch procedures, must be tried. [bib_ref] Long-term management of the successful adult liver transplant: 2012 practice guideline by..., Lucey [/bib_ref]
[table] Table 1 -: Registered liver transplantation in the Kingdom of Saudi Arabia between 2018 and 2019. [/table]
[table] Table 2 -: Grading of Recommendations Assessment Development and Evaluation (GRADE) system used in the Clinical Practice Guidelines for Liver Transplantation in Saudi Arabia. [/table]
[table] Table 3 -: Risk stratification of microbial transmission from donor to recipient in liver transplantation (LT). [/table]
[table] Table 4 -: Management of infectious complications in liver transplantation (LT) listed patients. [/table]
[table] Table 5 -: Management of non-infectious complications in LT listed patients. [/table]
[table] Table 6 -: Indications for pediatric liver transplantation (LT). [/table]
[table] Table 7 -: Major drug-drug interactions involving immunosuppressive agents.https://smj.org.sa Saudi Med J 2021; Vol. 42(9) [/table]
[table] Table 8 -: Prevalence of cardiovascular risk factors and CKD in LT recipients beyond the first post-transplant year. Any 3 of the following: hypertension, obesity, dyslipidemia, and diabetes mellitus. † Estimated glomerular filtration rate = 15 to <60 mL/minute/1.73 m 2 . [/table]
[table] Table 10 -: Prophylactic strategies for common microorganisms that affect LT recipients.Valganciclovir is not FDA-approved for LT. Prolonged-duration regimens are effective in kidney transplantation. Valganciclovir is not FDA-approved for LT. [/table]
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https://smj.org.sa/content/smj/42/9/927.full.pdf
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The demand for liver transplantation in the Kingdom of Saudi Arabia (KSA) is associated with the country’s high burden of liver disease. Trends in the epidemiology of liver transplantation indications among recipients in KSA have changed over 20 years. Non-alcoholic steatohepatitis has eclipsed the hepatitis C virus in the country due to the effective treatment strategies for HCV. Risk factors for NASH, like type 2 diabetes mellitus, obesity, and hyperlipidemia, are becoming a major concern and a leading indication for liver transplantation in the KSA. There is also a significantly increased prevalence and incidence of genetic adult familial liver diseases in KSA. New immunosuppressive agents and preservation solutions, improved surgical capabilities, and early disease recognition and management have increased the success rate of liver transplant outcome but concerns about the side effects of immunosuppressive therapy can jeopardise long-term survival outcomes. Despite this, indications for liver transplantation continue to increase, resulting in ongoing challenges to maximize the number of potential donors and reduce patient mortality rate while expecting to get transplanted. The Saudi Center of Organ Transplant is the recognized National Organ Donation Agency for transplantation, which renders important support for procurement and allocation of organs. This guidance document aims to help healthcare providers in managing patients in the liver transplant setting.
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pubmed
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The Japanese clinical practice guideline for acute kidney injury 2016
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The Japanese clinical practice guideline for acute kidney injury 2016
Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention is necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.Keywords Acute kidney injury · Atrial natriuretic peptide · Biomarker · Blood purification · Long-term follow-up · Nafamostat mesilate CQ1: What is the concept of AKI, and what are the key elements of its clinical practice?Recommendation: AKI is a syndrome associated with a broad spectrum of diseases and a variety of underlying pathologies. Therefore, differentiation of the causes and elimination of the reversible factors are always required. invasiveness is assumed to lead to sudden renal impairment in patients with relatively few comorbidities. In addition, as ARF is thought to be essentially a reversible disease, there was little awareness of its poor outcomes; greater attention was paid to the differentiation of the causes and to the countermeasures against the complications associated with renal failure than to the need for early detection. However, as medical care progressed, patients such as high-risk elderly subjects who were not deemed to be candidates for invasive therapy came to be treated in intensive care units (ICUs). Eventually, there grew to be widespread awareness of the increase in cases of sudden kidney injury comorbid with sepsis and multiple organ failure, and of the incredibly poor outcomes in these cases. This led kidney injury as a subset of multiple organ failure to be reconsidered as AKI in intensive care medicine. Thus, AKI was proposed as a novel disease concept to emphasize early diagnosis and early intervention for the improvement of prognoses.
Meanwhile, the RIFLE [bib_ref] Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology..., Bellomo [/bib_ref] , AKIN [bib_ref] Acute Kidney Injury Network: report of an initiative to improve outcomes in..., Mehta [/bib_ref] , and KDIGOdiagnostic criteria were introduced in an effort to establish unified international diagnostic criteria. The present guideline recommends the use of the KDIGO diagnostic criteria (see CQ2-1). However, these criteria are based solely on the serum creatinine (sCr) and urine output; they do not take into account the cause or site of the kidney injury, or location and mode of onset of AKI. Thus, as AKI refers to a syndrome with a broad spectrum of diseases and a variety of pathophysiologies, it calls for constant differentiation of the causes and elimination of the reversible factors. The KDIGO Clinical Practice Guideline for AKIalso recommends searching for and assessing the cause of the syndrome whenever possible, particularly in regard to reversible causes (recommendations 2.1.3 and 2.3.1).
## Cq2-1: should the diagnosis of aki be based on the kdigo diagnostic criteria?
Recommendation: The KDIGO criteria are superior to the RIFLE criteria and to the AKIN criteria in predicting survival outcomes; therefore, we suggest using the KDIGO criteria to diagnose AKI. However, it is unknown which criteria should be used to predict the renal outcomes.
## Strength of recommendation: 2
## Quality of evidence: c
## Summary of evidence
We identified 11 observational studies that compared the KDIGO with the AKIN and RIFLE criteria and that assessed death as an outcome. However, they did not assess the initiation of dialysis. In these 11 observational studies, the comparisons of the AKI diagnosis based on the KDIGO criteria versus those based on the RIFLE and AKIN criteria showed that the KDIGO criteria is more precise than, or as precise as, the RIFLE and AKIN criteria in reflecting the-in-hospital mortality.
## Commentary
In the past, acute renal failure (ARF) was diagnosed and classified according to several different criteria. In response to the growing call for unified international diagnostic criteria, the acute dialysis quality initiative (ADQI) published the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria in 2004 [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref] [bib_ref] Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology..., Bellomo [/bib_ref] [bib_ref] Developing a consensus classification system for acute renal failure, Kellum [/bib_ref]. The RIFLE criteria distinguished three degrees of severity (risk, injury, and failure), with the latter defined as an increase in the serum creatinine (sCr), a decline in the glomerular filtration rate (GFR), and a reduction in the urine output; and two types of clinical outcomes (Loss and End-Stage Kidney Disease). In 2004, members of the International Society of Nephrology, the American Society of Nephrology, the National Kidney Foundation (in the United States), and the European Society of Intensive Care Medicine founded the acute kidney injury network (AKIN); as a replacement for the term ARF, the AKIN advocated the concept of acute kidney injury (AKI), which encompasses earlier stages of kidney injury. On the other hand, after the RIFLE criteria were published, a mere 0.3 mg/dl increase in sCr was reported to affect the survival prognosis and the clinical course of AKI [bib_ref] Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery:..., Lassnigg [/bib_ref] [bib_ref] Acute kidney injury, mortality, length of stay, and costs in hospitalized patients, Chertow [/bib_ref].
In 2007, the AKIN proposed the AKIN criteria, which were a revision of the RIFLE criteria [bib_ref] Acute Kidney Injury Network: report of an initiative to improve outcomes in..., Mehta [/bib_ref]. The AKIN criteria included milder increases in sCr (0.3 mg/dl) and added the time course of the sCr increase (within 48 h) to the diagnostic criteria. By contrast, a reduced GFR was removed from the RIFLE criteria. In addition, while both the AKIN criteria and the RIFLE criteria included the urine output, the AKIN criteria specified that when making a diagnosis based on the urine output alone, urinary tract obstructions and easily reversible causes of a reduced urine output were to be excluded, and an adjustment was to be made for the body fluid volume. In addition, the RIFLE criteria's loss and end-stage kidney disease were judged to be outcomes of AKI and were removed from the AKIN criteria's staging system. Furthermore, patients who had started renal replacement therapy (RRT) became classified as stage 3 regardless of their sCr and urine output prior to the RRT initiation.
In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) group assembled all the available evidence into their own clinical practice guideline for AKI and proposed the KDIGO criteria, which integrate the RIFLE and AKIN criteria [fig_ref] Table 3: KDIGO criteria sCr serum creatinine, UO urine output, RRT renal replacement therapy [/fig_ref]. The KDIGO criteria diverge from the AKIN criteria in that the time course for a 1.5-fold increase in sCr from baseline was changed from within 48 h to within 7 days. Thus, as the KDIGO criteria encompass more gradual increases in sCr, they have made the number of patients diagnosed with AKI likely to increase.
As described above, three sets of diagnostic criteria for AKI have been proposed: the RIFLE, AKIN, and KDIGO criteria. The utility of the KDIGO criteria, the most recent of the three sets, has been compared with that of the two older sets. In a prospective, multicenter observational study of 3107 intensive care unit (ICU) patients, Luo et al. reported the percentages of patients diagnosed with AKI according to the RIFLE, AKIN, and KDIGO criteria using both the sCr and urine output, and compared their in-hospital mortality rates [bib_ref] A comparison of different diagnostic criteria of acute kidney injury in critically..., Luo [/bib_ref]. The percentages of patients diagnosed with AKI according to the RIFLE, AKIN, and KDIGO criteria were 46.9, 38.4, and 51.0%, respectively; thus, the number of patients diagnosed with AKI was significantly higher when using the KDIGO criteria than when using either the AKIN or RIFLE criteria. The patients diagnosed with AKI based on the KDIGO criteria had poorer survival outcomes than those diagnosed using the AKIN criteria, although there was no significant difference in the survival outcomes of patients diagnosed using the RIFLE criteria. In a retrospective multicenter study of 1005 adult patients hospitalized for acute heart failure, Li et al. compared the percentages of patients diagnosed with AKI within 7 days of hospitalization using the KDIGO, AKIN, and RIFLE criteria, as well as the patients' in-hospital mortality rates [bib_ref] Identification and predicting short-term prognosis of early cardiorenal syndrome type 1: KDIGO..., Li [/bib_ref]. Using only the sCr criterion, the percentages of patients diagnosed with AKI according to the KDIGO, AKIN, and RIFLE criteria were 38.9, 34.7, and 32.1%, respectively. A total of 110 patients (10.9%) were diagnosed with AKI with the KDIGO criteria but not with the RIFLE or AKIN criteria. A total of 18.4% of the patients who died in the hospital were diagnosed with AKI according to the KDIGO criteria only; this group was at a high risk of in-hospital death. In a study of 1050 patients hospitalized for acute myocardial infarction, Rodrigues et al. compared the percentages of patients diagnosed with AKI according to the RIFLE and KDIGO criteria using the sCr criterion only, as well as their mortality rates [bib_ref] Incidence and mortality of acute kidney injury after myocardial infarction: a comparison..., Rodrigues [/bib_ref]. A total of In other studies of the AKI diagnostic criteria in hospitalized patients [bib_ref] Validation of the Kidney Disease Improving Global Outcomes criteria for AKI and..., Fujii [/bib_ref] [bib_ref] Incidence, outcomes, and comparisons across definitions of AKI in hospitalized individuals, Zeng [/bib_ref] , ICU patients [bib_ref] Comparison of the RIFLE, AKIN and KDIGO criteria to predict mortality in..., Levi [/bib_ref] [bib_ref] Comparison of kidney disease: improving global outcomes and acute kidney injury network..., Shinjo [/bib_ref] [bib_ref] Incidence, risk factors and 90-day mortality of patients with acute kidney injury..., Nisula [/bib_ref] , acute decompensated heart failure [bib_ref] A comparison of traditional and novel definitions (RIFLE, AKIN, and KDIGO) of..., Roy [/bib_ref] , patients after cardiac surgery [bib_ref] Acute kidney injury after cardiac surgery according to risk/ injury/failure/loss/end-stage, acute kidney..., Bastin [/bib_ref] , and sepsis [bib_ref] Epidemiology of acute kidney injury in intensive care septic patients based on..., Peng [/bib_ref] , the KDIGO criteria were reported to be equal or superior to the RIFLE and AKIN criteria in their ability to predict the survival outcomes. Based on the above, the KDIGO criteria are considered to be more useful in their survival outcome prediction ability than the RIFLE or AKIN criteria for the diagnosis of AKI.
## Literature review
PubMed was searched for relevant studies published between January 1990 and July 2015, and papers related to the present CQ were identified from the search results.
## Cq2-2: when diagnosing aki, how should an unknown baseline renal function be estimated?
Recommendation: Whenever possible, the baseline renal function should be determined using multiple methods, and the potential presence of CKD and other comorbidities should be assessed.
## Strength of recommendation: 2
## Quality of evidence: c
## Summary of evidence
Several methods have been suggested to estimate the baseline renal function. However, compared to the use of the known baseline function, all of these methods have been reported to yield a certain rate of false positives or false negatives in their AKI diagnoses and mortality predictions.
## Commentary
The diagnosis of acute kidney injury (AKI) requires the baseline renal function; however, in actual clinical practice, the patient's history of examination and his/her baseline renal function are often unknown. These cases require an estimation of the baseline renal function, and many methods have been proposed [fig_ref] Table 4: Estimation of unknown baseline serum creatinine sCr serum creatinine, GFR glomerular filtration... [/fig_ref].
To compare the estimated baseline renal function with the known baseline renal function, we identified seven observational studies that used the AKI diagnosis as an outcome [bib_ref] New ICA criteria for the diagnosis of acute kidney injury in cirrhotic..., Rosi [/bib_ref] [bib_ref] Use of multiple imputation method to improve estimation of missing baseline serum..., Siew [/bib_ref] [bib_ref] Are surrogate assumptions and use of diuretics associated with diagnosis and staging..., Sims [/bib_ref] [bib_ref] The calculation of baseline serum creatinine overestimates the diagnosis of acute kidney..., Candela-Toha [/bib_ref] [bib_ref] Commonly used surrogates for baseline renal function affect the classification and prognosis..., Siew [/bib_ref] [bib_ref] Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive..., Pickering [/bib_ref] [bib_ref] A comparison of observed versus estimated baseline creatinine for determination of RIFLE..., Bagshaw [/bib_ref] , and two observational studies that used the all-cause mortality as an outcome [bib_ref] Are surrogate assumptions and use of diuretics associated with diagnosis and staging..., Sims [/bib_ref] [bib_ref] Commonly used surrogates for baseline renal function affect the classification and prognosis..., Siew [/bib_ref]. While two of the seven studies included all hospitalized patients [bib_ref] Use of multiple imputation method to improve estimation of missing baseline serum..., Siew [/bib_ref] [bib_ref] Commonly used surrogates for baseline renal function affect the classification and prognosis..., Siew [/bib_ref] , two of them limited the subjects to intensive care unit (ICU) patients [bib_ref] Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive..., Pickering [/bib_ref] [bib_ref] A comparison of observed versus estimated baseline creatinine for determination of RIFLE..., Bagshaw [/bib_ref] , two used only patients undergoing cardiac surgery [bib_ref] Are surrogate assumptions and use of diuretics associated with diagnosis and staging..., Sims [/bib_ref] [bib_ref] The calculation of baseline serum creatinine overestimates the diagnosis of acute kidney..., Candela-Toha [/bib_ref] , and one study only included patients with cirrhosis [bib_ref] New ICA criteria for the diagnosis of acute kidney injury in cirrhotic..., Rosi [/bib_ref]. All these studies assumed the lower limit of the normal renal function to be an estimated glomerular filtration rate (eGFR) of 75 ml/min/1.73 m 2 (as suggested by the KDIGO clinical practice guidelineand examined a way to back-calculate the serum creatinine (sCr) based on the MDRD equation. In the six studies whose subjects included all hospitalized patients, the ICU patients only, and the cardiac surgery patients only, an assumed baseline renal function of eGFR 75 ml/min/1.73 m 2 yielded false positive AKI diagnoses. Four of these studies [bib_ref] Use of multiple imputation method to improve estimation of missing baseline serum..., Siew [/bib_ref] [bib_ref] The calculation of baseline serum creatinine overestimates the diagnosis of acute kidney..., Candela-Toha [/bib_ref] [bib_ref] Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive..., Pickering [/bib_ref] [bib_ref] A comparison of observed versus estimated baseline creatinine for determination of RIFLE..., Bagshaw [/bib_ref] stated that false positives were especially frequent in patients with a known eGFR < 60 ml/min/1.73 m 2 . On the contrary, in the study whose subjects included cirrhosis patients only, an assumed baseline renal function of eGFR 75 ml/min/1.73 m 2 yielded false negative AKI diagnoses. In a study that was not taken into account due to its unsuitable outcome, Zavada et al. indicated that the estimated sCr was higher than the known sCr in young people [bib_ref] A comparison of three methods to estimate baseline creatinine for RIFLE classification, Zavada [/bib_ref]. The two observational studies that used the all-cause mortality as an outcome reported that the mortality rates were reduced by sCr estimation methods that frequently yielded false positive AKI diagnoses, while the mortality rates were increased by estimation methods that frequently yielded false negative diagnoses.
In conclusion, there is currently no specific baseline sCr estimation method on par with a measured baseline sCr. The easy method that involves the calculation of the sCr based on an eGFR of 75 ml/min/1.73 m 2 is tolerable; however, this method often overestimates the sCr in young people and cirrhosis patients, and underestimates it in chronic kidney disease (CKD) patients. Therefore, we suggest that whenever possible, the baseline renal function should be determined using multiple methods, while also confirming whether the CKD and other comorbidities are present based on methods such as image searches to check for renal atrophy.
## Literature review
PubMed was searched for relevant studies published up to July 2015, and papers related to the present CQ were identified from the search results.
## 3
## Cq2-3: should the aki staging with the urine output be included in addition to the serum creatinine for the predictions of the aki outcomes?
Recommendation: In the RIFLE, AKIN, and KDIGO criteria, the inclusion of the urine output along with the serum creatinine to determine the AKI stage yields more accurate reflections of the survival outcomes and the renal outcomes than the determination of the AKI stage based on the serum creatinine alone. Therefore, we suggest that the AKI staging should involve the urine output whenever possible.
## Strength of recommendation: 2
## Quality of evidence: b
## Summary of evidence
We identified seven observational studies that used death as an outcome. In the studies of ICU patients, the inclusion of the urine output as a criterion significantly improved the survival outcome predictions. In one of these studies, the renal outcome prediction was also improved; however, a study of patients after cardiac surgery indicated a potential for overdiagnosis. Because no study of outpatients or general ward patients have been conducted, it is unclear whether the above results can be generalized.
## Commentary
During the 10 years since the concept of AKI was introduced, three sets of diagnostic criteria/classifications have been proposed: the RIFLE, AKIN, and KDIGO. All these criteria sets enable the diagnosis and staging of AKI based on changes in the serum creatinine (sCr) or the urine output [bib_ref] Acute renal failure-definition, outcome measures, animal models, fluid therapy and information technology..., Bellomo [/bib_ref] [bib_ref] Acute Kidney Injury Network: report of an initiative to improve outcomes in..., Mehta [/bib_ref]. In many previous clinical studies, AKI was diagnosed and staged according to the sCr alone, and a slight increase in the sCr was reported to affect the survival outcomes [bib_ref] Acute kidney injury, mortality, length of stay, and costs in hospitalized patients, Chertow [/bib_ref]. However, few clinical studies have used the urine output as a criterion for the diagnosis and staging of AKI. Therefore, we examined whether the urine output reflects the survival outcomes of AKI as accurately as the sCr, and whether the inclusion of the urine output in the determination of the AKI stage reflects the survival outcomes more accurately than determination based on the sCr alone.
To compare the sCr and the urine output, we adopted seven observational studies that used death as an outcome [bib_ref] Relationship between patients' outcomes and the changes in serum creatinine and urine..., Harris [/bib_ref] [bib_ref] Clermont G. Classifying AKI by urine output versus serum creatinine level, Kellum [/bib_ref] [bib_ref] Derivation of urine output thresholds that identify a very high risk of..., Leedahl [/bib_ref] [bib_ref] A comparison of RIFLE with and without urine output criteria for acute..., Wlodzimirow [/bib_ref] [bib_ref] Additional role of urine output criterion in defining acute kidney injury, Han [/bib_ref] [bib_ref] Defining urine output criterion for acute kidney injury in critically ill patients, Macedo [/bib_ref] [bib_ref] Incidence and outcomes of acute kidney injury after cardiac surgery using either..., Lagny [/bib_ref]. All these studies were conducted in intensive care units (ICUs); none of them involved outpatients or patients in general wards. Regarding the AKI diagnostic criteria, three studies used the RIFLE criteria [bib_ref] Relationship between patients' outcomes and the changes in serum creatinine and urine..., Harris [/bib_ref] [bib_ref] Clermont G. Classifying AKI by urine output versus serum creatinine level, Kellum [/bib_ref] [bib_ref] Additional role of urine output criterion in defining acute kidney injury, Han [/bib_ref] , two used the AKIN criteria [bib_ref] Defining urine output criterion for acute kidney injury in critically ill patients, Macedo [/bib_ref] [bib_ref] Incidence and outcomes of acute kidney injury after cardiac surgery using either..., Lagny [/bib_ref] , and two used the KDIGO criteria [bib_ref] Derivation of urine output thresholds that identify a very high risk of..., Leedahl [/bib_ref] [bib_ref] A comparison of RIFLE with and without urine output criteria for acute..., Wlodzimirow [/bib_ref]. In six of these studies, the inclusion of the urine output with the sCr in the AKI diagnosis significantly improved the survival outcome predictions [bib_ref] Clermont G. Classifying AKI by urine output versus serum creatinine level, Kellum [/bib_ref] [bib_ref] Derivation of urine output thresholds that identify a very high risk of..., Leedahl [/bib_ref] [bib_ref] A comparison of RIFLE with and without urine output criteria for acute..., Wlodzimirow [/bib_ref] [bib_ref] Additional role of urine output criterion in defining acute kidney injury, Han [/bib_ref] [bib_ref] Defining urine output criterion for acute kidney injury in critically ill patients, Macedo [/bib_ref] [bib_ref] Incidence and outcomes of acute kidney injury after cardiac surgery using either..., Lagny [/bib_ref] ; furthermore, in one of these six studies, the renal outcome prediction ability was also improved [bib_ref] Clermont G. Classifying AKI by urine output versus serum creatinine level, Kellum [/bib_ref].
In an analysis of 155,624 patients hospitalized in ICUs on an emergency admission, Harris et al. reported that the urine output was a more powerful predictor of the survival outcomes than the sCr [bib_ref] Relationship between patients' outcomes and the changes in serum creatinine and urine..., Harris [/bib_ref]. In a study of 32,045 adult ICU patients classified according to the KDIGO sCr and urine output criteria, Low specificity especially in CKD patients [bib_ref] New ICA criteria for the diagnosis of acute kidney injury in cirrhotic..., Rosi [/bib_ref] [bib_ref] Use of multiple imputation method to improve estimation of missing baseline serum..., Siew [/bib_ref] [bib_ref] Are surrogate assumptions and use of diuretics associated with diagnosis and staging..., Sims [/bib_ref] [bib_ref] The calculation of baseline serum creatinine overestimates the diagnosis of acute kidney..., Candela-Toha [/bib_ref] [bib_ref] Commonly used surrogates for baseline renal function affect the classification and prognosis..., Siew [/bib_ref] [bib_ref] Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive..., Pickering [/bib_ref] [bib_ref] A comparison of observed versus estimated baseline creatinine for determination of RIFLE..., Bagshaw [/bib_ref] An estimated sCr determined by back-calculation using MDRD assuming a GFR of 100 ml/min/1.73 m 2
Very high sensitivity and very low specificity [bib_ref] Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive..., Pickering [/bib_ref] The first admission sCr Low sensitivity [bib_ref] Commonly used surrogates for baseline renal function affect the classification and prognosis..., Siew [/bib_ref] A minimum inpatient sCr during the first 7 days Low specificity [bib_ref] Commonly used surrogates for baseline renal function affect the classification and prognosis..., Siew [/bib_ref] A minimum sCr during the first 7 days in the ICU Low specificity although tendency to underestimate the AKI stage [bib_ref] Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive..., Pickering [/bib_ref] An estimated sCr using multiple imputation methods such as sex, race, comorbidity (CKD, etc), and a minimum inpatient sCr
High specificity [bib_ref] Use of multiple imputation method to improve estimation of missing baseline serum..., Siew [/bib_ref] A minimum inpatient sCr [11] sCr = 1.0 mg/dl (male)/0.8 mg/dl (female) [bib_ref] A comparison of three methods to estimate baseline creatinine for RIFLE classification, Zavada [/bib_ref] 1 3
Kellum et al. demonstrated that patients who fulfilled both the sCr and urine output criteria were at the highest risk of death and the initiation of permanent renal replacement therapy (RRT), while isolated oliguria was associated with a long-term risk of death even when the sCr criterion was not fulfilled [bib_ref] Clermont G. Classifying AKI by urine output versus serum creatinine level, Kellum [/bib_ref]. Similarly, in an analysis of 390 septic shock patients, Leedahl et al. reported that persistent oliguria was a risk factor for death by day 28 [bib_ref] Derivation of urine output thresholds that identify a very high risk of..., Leedahl [/bib_ref]. In a study of 260 ICU patients, Wlodzimirow et al. compared the combined use of the RIFLE's sCr and urine output criteria (RIFLEsCr + urine output) with the use of the sCr criterion (RIFLEsCr) alone; they reported that the RIFLE-sCr was associated with a delayed AKI diagnosis and higher mortality [bib_ref] A comparison of RIFLE with and without urine output criteria for acute..., Wlodzimirow [/bib_ref]. Furthermore, Han et al. [bib_ref] Additional role of urine output criterion in defining acute kidney injury, Han [/bib_ref] and Macedo et al. [bib_ref] Defining urine output criterion for acute kidney injury in critically ill patients, Macedo [/bib_ref] also reported that the addition of the urine output criterion enabled a more accurate AKI diagnosis than the use of the sCr criterion alone. Although some studies have featured different urine output criterion values, overall, the assessment of the urine output has been shown to improve the accuracy of the AKI diagnosis. However, in a comparison of the sCr criterion alone with the urine output criterion alone for the diagnosis of AKI in patients after cardiac surgery, Lagny et al. indicated that the use of the urine output criterion alone could lead to overdiagnosis [bib_ref] Incidence and outcomes of acute kidney injury after cardiac surgery using either..., Lagny [/bib_ref]. In a recent multicenter prospective study that assessed the association between the hourly urine output and mortality, Vaara et al. reported that patients who fulfilled both the sCr and urine output criteria had the highest rate of RRT initiation and the highest 90-day mortality, while isolated oliguria was associated with poor outcomes; these results affirm the importance of measuring the hourly urine output and the need to combine the urine output criterion with the sCr criterion [bib_ref] Association of oliguria with the development of acute kidney injury in the..., Vaara [/bib_ref]. Moreover, in using the urine output criterion in the diagnosis and staging of AKI, there is a concern that the use of diuretics may change the urine output, causing underestimation of the AKI severity. However, in their analysis of the effects of diuretics on the AKI diagnosis, Han et al. reported that the inclusion of the urine output criterion alongside the sCr criterion played an additional role in the diagnosis and staging of AKI regardless of whether diuretics were used [bib_ref] Additional role of urine output criterion in defining acute kidney injury, Han [/bib_ref].
To summarize the above studies, the inclusion of the urine output along with the sCr to determine the AKI stage improves the sensitivity of the AKI diagnosis, and yields more accurate reflections of the survival and renal outcomes than AKI staging based on the sCr alone. Therefore, we suggest that AKI staging should involve the urine output whenever possible.
## Literature review
PubMed was searched for relevant studies published between January 1990 and August 2015, and papers related to the present CQ were identified from the search results.
## Cq3-1: what should be assessed as risk factors for aki development in cardiac surgery?
Recommendation: We suggest that factors such as age, preoperative renal dysfunction and the duration of the cardiopulmonary bypass should be assessed as risk factors.
## Strength of recommendation: 2
Quality of evidence: C
## Summary of evidence
We identified seven papers that assessed the risk of development of AKI in cardiac surgery. All of them were observational studies. Certain observational studies have stated that TAVR and TAVI, which have become more common with the recent aging of society, do not match the same risk of AKI observed in cardiac surgery.
## Commentary
# Background
Acute kidney injury (AKI) is a comorbidity that complicates the perioperative management of body fluid; the risk of AKI development is reported to be particularly high in cardiac surgery [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref]. In Hu et al.'s meta-analysis of 91 studies of cardiac surgery, the incidence of postoperative AKI was 22.3%, while 2.3% of the patients required renal replacement therapy (RRT). Furthermore, the in-hospital mortality of patients who developed AKI following cardiac surgery was 10.7%, and the mortality in long-term observation (1-5 years) was 30.0% [bib_ref] Global incidence and outcomes of adult patients with acute kidney injury after..., Hu [/bib_ref]. Therefore, assessment of the risk of AKI development is crucial for patients scheduled to undergo cardiac surgery. Nearly all the relevant studies have been observational studies, which makes them insufficient to demonstrate strong evidence; nevertheless, they have identified several potential risk factors [fig_ref] Table 5: Risk factors for AKI development in cardiac surgery ○ [/fig_ref].
## Aging
The aging of patients who undergo cardiac surgery may make their perioperative management more difficult. In a prospective observational study, Ozkayanak et al. reported that the risk of development of AKI from cardiac surgery increased with age (odds ratio 1.022, 95% confidence interval: 1.005-1.039) [bib_ref] Time from cardiac catheterization to cardiac surgery: a risk factor for acute..., Ozkaynak [/bib_ref]. Nearly identical results have been demonstrated in retrospective observational studies [bib_ref] Cardiac surgery-associated acute kidney injury: risk factors analysis and comparison of prediction..., Kristovic [/bib_ref] [bib_ref] Association of preoperative uric acid and acute kidney injury following cardiovascular surgery, Joung [/bib_ref]. Regarding coronary artery bypass grafting (CABG), a prospective observational 1 3 study limited to Asian patients showed that AKI developed significantly more frequently in patients aged ≥ 70 years (odds ratio 1.350, 95% confidence interval: 1.085-1.679) [bib_ref] Identification of modifiable risk factors for acute kidney injury after coronary artery..., Ng [/bib_ref]. A retrospective observational study of patients who had undergone cardiac surgery with a cardiopulmonary bypass also reported age as a significant risk factor for AKI development [bib_ref] Risk factors for perioperative acute kidney injury after adult cardiac surgery: role..., Parolari [/bib_ref]. The risk of AKI development should be considered while treating elderly patients undergoing cardiac surgery.
## Preoperative renal impairment
Preoperative renal dysfunction is known as a risk factor for perioperative AKI development. Observational studies of cardiac surgery patients have also reported that pre-AKI renal dysfunction was a potential risk factor for AKI development. Huang et al. reported that CKD stage G3 (odds ratio 1.68, 95% confidence interval: 1.12-2.52) and CKD stage G4 (odds ratio 3.01, 95% confidence interval: 1.57-6.03) were risk factors for AKI development after cardiac surgery [bib_ref] Preoperative proteinuria predicts adverse renal outcomes after coronary artery bypass grafting, Huang [/bib_ref]. In a prospective observational study of CABG patients, Guenancia et al. reported that a higher preoperative estimated glomerular filtration rate (eGFR) was associated with a lower risk of AKI development (odds ratio 0.97, 95% confidence interval: 0.96-0.99) [bib_ref] Pre-operative growth differentiation factor 15 as a novel biomarker of acute kidney..., Guenancia [/bib_ref]. In another prospective observational study of CABG patients, Ng et al. reported that a higher preoperative serum creatinine (sCr) value was associated with an increased risk of AKI development (odds ratio 1.003, 95% confidence interval: 1.001-1.006) [bib_ref] Identification of modifiable risk factors for acute kidney injury after coronary artery..., Ng [/bib_ref].
## Duration of cardiopulmonary bypass
A cardiopulmonary bypass (CPB) creates an extracorporeal environment and a non-physiological state in which a constant blood flow is maintained with a pump, independently from the heartbeat. In typical CPBs, the blood is diluted by 20-50% to reduce the hemoglobin concentration. During CPBs, the renal blood flow is affected by various factors, including hypothermia, blood dilution, hemolysis, microthrombi, and vasoactive drugs; these factors constrict the renal artery and reduce the renal blood flow. In a metaanalysis of 9 studies on the correlation between the duration of CPBs in cardiac surgery and the development of AKI, the CPB duration was reported to be significantly associated with the development of AKI [bib_ref] Association between postoperative acute kidney injury and duration of cardiopulmonary bypass: a..., Kumar [/bib_ref]. Off-pump surgery, which has become more common recently, could make surgery less invasive for elderly heart disease patients in Japan. In a meta-analysis of randomized controlled trials (RCTs) involving CABG patients, reported that compared to on-pump CABG, off-pump CABG significantly inhibited the postoperative AKI onset; however, no significant association was observed with the need for dialysis [bib_ref] Off-pump coronary artery bypass surgery and acute kidney injury: a metaanalysis of..., Seabra [/bib_ref]. In an RCT that observed the long-term renal outcomes, the incidence of AKI development within 30 days after surgery was significantly lower after off-pump CABG (17.5% vs 20.8%, 95% confidence interval: 0.72-0.97); however, at 1 year, there was no difference in the percentages of patients with a reduced eGFR. Therefore, recent RCTs have failed to sufficiently prove the efficacy of off-pump CABG for renoprotection.
## Other risk factors
In addition to the risk factors stated above, observational studies have also assessed obesity, diabetes, hypertension, and anemia as potential risk factors; however, due to contradictory results, no conclusions have been reached [bib_ref] Association of preoperative uric acid and acute kidney injury following cardiovascular surgery, Joung [/bib_ref] [bib_ref] Identification of modifiable risk factors for acute kidney injury after coronary artery..., Ng [/bib_ref] [bib_ref] Risk factors for perioperative acute kidney injury after adult cardiac surgery: role..., Parolari [/bib_ref] [bib_ref] Preoperative proteinuria predicts adverse renal outcomes after coronary artery bypass grafting, Huang [/bib_ref] [bib_ref] Pre-operative growth differentiation factor 15 as a novel biomarker of acute kidney..., Guenancia [/bib_ref]. Recently, transcatheter aortic valve implantation (TAVI) and transcatheter aortic valve replacement (TAVR) have become more common, since they can be performed with minimal invasiveness in the elderly and high-risk patients. In a meta-analysis of 13 studies, Elhmidi et al. reported that preoperative renal impairment was a significant risk factor for post-TAVI AKI development [bib_ref] Acute kidney injury after transcatheter aortic valve implantation: incidence, predictors and impact..., Elhmidi [/bib_ref].
## Literature review
PubMed was searched for relevant studies published between March 2011 and December 2015, and papers related to the present CQ were identified from the search results. The
[formula] 〇 〇 △ 〇 〇 〇 〇 Ozkaynak et al. [39] 〇 〇 × × 〇 - 〇 Kumar et al. [40] - - - - - - 〇 Parolari et al. [41] 〇 - - - - 〇 - Huang et al. [42] 〇 - 〇 - - 〇 - 1 3 [/formula]
## Summary of evidence
Among 10 observational studies on the development of AKI following liver transplantation, 5 studies demonstrated a significant association between the development of AKI and the intraoperative blood transfusion volume. Two studies excluded chronic kidney disease (CKD), while two others found CKD to be a significant risk factor for AKI development. Two studies demonstrated that the MELD score and intraoperative hypotension or the use of vasopressors were associated with the development of AKI. Only three studies about lung transplantation and AKI development were found, and these studies did not demonstrate a consistent trend.
## Commentary
# Background
The development of AKI is significantly associated with increased mortality. This lends great clinical significance to the development of AKI following non-cardiac surgery as well as cardiac surgery. Therefore, it is crucial to determine the incidence rate of AKI, the risk factors for its development, and its association with prognoses. Despite the existence of several studies about the development of AKI after liver transplantation, nearly all have been observational studies. Furthermore, there have been few studies on the development of AKI after non-cardiac surgeries other than liver transplantation.
## Liver transplantation
In liver disease, the development of AKI is generally a risk factor for the progression of hepatic dysfunction and increased mortality [bib_ref] Renal dysfunction in end-stage liver disease and post-liver transplant, Sampaio [/bib_ref]. In liver transplantation, one of the most invasive liver surgery procedures, postoperative AKI is associated with mortality; therefore, it is crucial to assess the risk factors that predict its development. Many studies have reported the incidence of AKI after liver transplantation; however, it has ranged greatly, between 17 and 95% [bib_ref] Renal replacement therapy before, during, and after orthotopic liver transplantation, Matuszkiewicz-Rowinska [/bib_ref]. Recent investigations have primarily used the AKIN classification system; in retrospective studies published between 2013 and 2015, the incidence of the postliver transplantation development of AKI ranged from 10 to 30% [bib_ref] Hepatic ischemia reperfusion injury is associated with acute kidney injury following donation..., Leithead [/bib_ref] [bib_ref] Serum neutrophil gelatinaseassociated lipocalin versus serum creatinine for the prediction of acute..., Khosravi [/bib_ref] [bib_ref] Causes and incidence of renal replacement therapy application in orthotopic liver transplantation..., Papadopoulos [/bib_ref] [bib_ref] The evolving use of higher risk grafts is associated with an increased..., Leithead [/bib_ref] [bib_ref] The predictors for continuous renal replacement therapy in liver transplant recipients, Kim [/bib_ref] [bib_ref] Incidence and outcomes of acute renal failure following liver transplantation: a population-based..., Chen [/bib_ref]. In 2014, Leithead et al. reported an investigation of the AKI onset among 1,152 patients who had undergone liver transplantation [bib_ref] Hepatic ischemia reperfusion injury is associated with acute kidney injury following donation..., Leithead [/bib_ref]. The study defined AKI as the progression to KDIGO stage 2 or higher within 1 week after transplantation. Based on this definition, the incidence of AKI was 33.8%; factors such as the preoperative MELD score, preoperative hyponatremia, a preoperative BMI ≥ 30 kg/m 2 , intraoperative red blood cell transfusion, and a long warm ischemic time were identified as risk factors for AKI development [bib_ref] A model to predict survival in patients with end-stage liver disease, Kamath [/bib_ref]. In transplantation, the length of time from the stopping of the organ blood flow to the resumption of the blood flow following transplantation is defined as the ischemic time; the exposition of the organ to an ischemic state, particularly at a normal temperature, increases the likelihood that cells will die. This time is called the warm ischemic time; the ideal time is 0 min for the heart and liver, and 30 min for the kidneys and lungs. In order to achieve these ideal times, the organs must be cooled at an early stage to reduce the cellular metabolism. The fact that these unique liver transplantation parameters are associated with AKI is fascinating in terms of organ crosstalks. There have been 10 observational studies on the development of AKI following liver transplantation [bib_ref] Hepatic ischemia reperfusion injury is associated with acute kidney injury following donation..., Leithead [/bib_ref] [bib_ref] Serum neutrophil gelatinaseassociated lipocalin versus serum creatinine for the prediction of acute..., Khosravi [/bib_ref] [bib_ref] Causes and incidence of renal replacement therapy application in orthotopic liver transplantation..., Papadopoulos [/bib_ref] [bib_ref] The evolving use of higher risk grafts is associated with an increased..., Leithead [/bib_ref] [bib_ref] The predictors for continuous renal replacement therapy in liver transplant recipients, Kim [/bib_ref] [bib_ref] Incidence and outcomes of acute renal failure following liver transplantation: a population-based..., Chen [/bib_ref] [bib_ref] Urinary neutrophil gelatinase-associated lipocalin as a marker of acute kidney injury after..., Wagener [/bib_ref] [bib_ref] Postliver transplant acute renal injury and failure by the RIFLE criteria in..., Chen [/bib_ref] [bib_ref] Risk factors for renal dysfunction in the postoperative course of liver transplant, Gallardo [/bib_ref] [bib_ref] Risk factors of acute renal failure after liver transplantation, Cabezuelo [/bib_ref]. Five of them have reported an intraoperative red blood cell transfusion as an independent risk factor for AKI development, while 2 studies have reported the preoperative MELD score, intraoperative hypertension, and the use of vasopressors as independent risk factors. A retrospective cohort study in 2015 reported the same results in relation to liver resection [bib_ref] Perioperative risk factors for acute kidney injury after liver resection surgery: an..., Tomozawa [/bib_ref]. In that study, [bib_ref] NT-pro-BNP predicts worsening renal function in patients with chronic systolic heart failure, Pfister [/bib_ref]
## Lung surgery
There have been 3 studies on AKI following lung surgery, and all of them have been retrospective cohort studies [bib_ref] Acute kidney injury influences mortality in lung transplantation, Xue [/bib_ref] [bib_ref] Acute kidney injury increases mortality after lung transplantation, George [/bib_ref] [bib_ref] Risk factors of acute kidney injury according to RIFLE criteria after lung..., Licker [/bib_ref]. In one of them, George et al. assessed the need for postoperative RRT in a multicenter study of 12,108 patients, and found an AKI incidence of 5.5%; increasing age, the male gender, a black ethnicity, a decreased preoperative renal function, a high preoperative bilirubin level, a preoperative comorbid lung disease, bilateral lung surgery, the use of intraoperative or postoperative extracorporeal membrane oxygenation (ECMO), and the ischemic time were identified as risk factors for AKI development [bib_ref] Acute kidney injury increases mortality after lung transplantation, George [/bib_ref]. Xue et al. examined the development of AKI of AKIN stage 1 or higher within 1 week after lung transplantation in 88 patients, and found an AKI incidence of 53.4%. The proposed risk factors included aging, preoperative hypertension, an intraoperative low mean blood pressure, the intraoperative use of vasopressors, the intraoperative use of aprotinin, the use of intraoperative or postoperative ECMO, and a comorbid postoperative infection [bib_ref] Acute kidney injury influences mortality in lung transplantation, Xue [/bib_ref]. In an investigation of the onset of AKI classified by the RIFLE criteria as "Risk" or more severe within 1 week after lung cancer surgery, Licker et al.
reported an AKI incidence of 6.8%. A low preoperative forced expiratory volume in 1 s (FEV1.0%), a high ASA score, and the duration of the anesthesia were identified as risk factors. The ASA score refers to the physical status assessment score advocated by the American Society of Anesthesiologists [bib_ref] Risk factors of acute kidney injury according to RIFLE criteria after lung..., Licker [/bib_ref].
## Bariatric surgery
Bariatric surgery has recently become a popular surgical intervention for severe obesity, mainly in the West. As obesity itself triggers renal impairment, multiple studies have examined the development of AKI following bariatric surgery [bib_ref] Acute kidney injury after gastric bypass surgery, Thakar [/bib_ref] [bib_ref] Acute kidney injury in bariatric surgery patients requiring intensive care admission: a..., Morgan [/bib_ref] [bib_ref] Acute kidney injury following bariatric surgery, Weingarten [/bib_ref]. In a cohort of 590 patients, reported that AKI of AKIN stage 1 or higher had developed in 103 patients, which represented an incidence of 17.5%; the male gender, preoperative hypertension, and a high preoperative APACHE II score were identified as risk factors [bib_ref] Acute kidney injury in bariatric surgery patients requiring intensive care admission: a..., Morgan [/bib_ref]. In a report of the outcomes in 1227 patients who underwent bariatric surgery at the Mayo Clinic between 2004 and 2011, the incidence of AKI [defined as a serum creatinine (sCr) increase of 0.3 mg/dl within 72 h] was 5.8%; the preoperative BMI and diabetes were identified as risk factors for AKI development [bib_ref] Acute kidney injury following bariatric surgery, Weingarten [/bib_ref].
## Colorectal surgery
Causey et al. examined the development of AKI following colorectal surgery in a cohort of 339 patients who underwent colorectal surgery between 2001 and 2009 [bib_ref] Identifying risk factors for renal failure and myocardial infarction following colorectal surgery, Causey [/bib_ref]. The incidence of AKI (defined as a postoperative increase in sCr of ≥ 50% from baseline) was 11.8%; intraoperative red blood cell transfusion was identified as a risk factor.
## Literature review
PubMed was searched for relevant studies published between March 2011 and December 2015, and papers related to the present CQ were identified from the search results. The literature published before March 2011 was referenced from the KDIGO clinical practice guideline for AKI.
## Cq3-3: what should be assessed as risk factors for aki development in heart failure?
Recommendation: Factors such as aging, renal impairment, and cardiac dysfunction should be assessed as risk factors.
## Strength of recommendation: 2
Quality of evidence: C
## Summary of evidence
Among the 11 identified observational studies that included the development of AKI as an outcome, 5 were multicenter studies involving more than 1000 subjects. In multivariate analyses, the following risk factors were found to be significantly associated with AKI: comorbid CKD (4 studies), aging (4 studies), diabetes (3 studies), and cardiac dysfunction (3 studies). Other factors found to be associated with AKI were the diuretic resistance, hypotension (defined as a systolic blood pressure < 90 mmHg), and elevated urinary neutrophil gelatinase-associated lipocalin (NGAL) (2 studies each).
## Commentary
# Background
In cardiovascular medicine, AKI has been recognized as worsening renal function (WRF) in heart failure patients. The interaction between heart failure and kidney failure has recently been defined as cardiorenal syndromes (CRS), which are classified into five types [bib_ref] Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference, Bagshaw [/bib_ref] [bib_ref] Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality..., Ronco [/bib_ref]. Among them, AKI associated with acute heart failure is classified as CRS type 1. Furthermore, AKI caused by acute heart failure is considered to exacerbate the heart failure, causing a vicious cycle and a poor survival prognosis for patients with CRS type 1 [bib_ref] Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong, Ronco [/bib_ref]. Therefore, it is clinically crucial to identify the incidence and risk factors of CRS type 1.
## Incidence of aki in acute heart failure
Studies have found an inconsistent incidence of AKI in acute heart failure due to differing definitions of AKI. A retrospective cohort study in 2010 by Amin et al. featured 2,098 enrolled patients (the largest cohort to date). In this study, the incidence of AKI-defined as an increase in sCr of ≥ 0.3 mg/dl during hospitalization-was 18.7% [bib_ref] The prognostic importance of worsening renal function during an acute myocardial infarction..., Amin [/bib_ref]. However, in a retrospective cohort study (n = 1010) in 2013 by [bib_ref] Identification and predicting short-term prognosis of early cardiorenal syndrome type 1: KDIGO..., Li [/bib_ref]. Based on the above studies, the incidence of AKI in heart failure is considered to range between 20% and 40%.
## Risk factors for aki development in acute heart failure
Observational studies have identified a number of risk factors for AKI following heart failure. A recent prospective observational study demonstrated a significant association between AKI and elevated levels (≥ 12 ng/ml) of the tubular dysfunction marker NGAL [bib_ref] Serum neutrophil gelatinase-associated lipocalin (NGAL) in predicting worsening renal function in acute..., Aghel [/bib_ref]. In 11 existing observational studies, comorbid CKD, aging, comorbid diabetes, and cardiac dysfunction were identified as independent risk factors for AKI. Diuretic resistance, hypotension (defined as a systolic blood pressure < 90 mmHg), and an elevated urinary NGAL were also shown to be associated with AKI in 2 studies each [fig_ref] Table 6: Risk factors for AKI development in heart failure [/fig_ref]. The degree of CKD considered to present a risk of AKI development is an eGFR < 60 ml/min/1.73 m 2 [bib_ref] The prognostic importance of worsening renal function during an acute myocardial infarction..., Amin [/bib_ref] [bib_ref] Acute and acute-on-chronic kidney injury of patients with decompensated heart failure: impact..., Zhou [/bib_ref] [bib_ref] Combined biomarker analysis for risk of acute kidney injury in patients with..., Tung [/bib_ref] [bib_ref] Worsening renal function in patients admitted with acute decompensated heart failure: incidence,..., Belziti [/bib_ref] or a sCr level ≥ 104 µmol/L (1.17 mg/dl) [bib_ref] Derivation and validation of a prediction score for acute kidney injury in..., Wang [/bib_ref]. In terms of age, one study stated that the odds ratio for the development of AKI increased by 1.17 (95% confidence interval: 1.08-1.28) with every 10 years' increase in age [bib_ref] The prognostic importance of worsening renal function during an acute myocardial infarction..., Amin [/bib_ref] , while other studies have reported ages of ≥ 70 years [bib_ref] Derivation and validation of a prediction score for acute kidney injury in..., Wang [/bib_ref] and ≥ 80 years [bib_ref] Worsening renal function in patients admitted with acute decompensated heart failure: incidence,..., Belziti [/bib_ref] as risk factors. One study defined the degree of cardiac dysfunction considered a risk factor for AKI development as a left ventricular ejection fraction (LVEF) < 40% [bib_ref] The prognostic importance of worsening renal function during an acute myocardial infarction..., Amin [/bib_ref] , while others set it at LVEF < 45% or a NYHA class IV [bib_ref] Derivation and validation of a prediction score for acute kidney injury in..., Wang [/bib_ref] [bib_ref] Acute and acute-on-chronic kidney injury of patients with decompensated heart failure: impact..., Zhou [/bib_ref]. The extent of diuretic resistance that is considered a risk factor for AKI development has been defined as persistent pulmonary congestion despite repeated doses of 80 mg furosemide, the continuous administration of 240 mg of furosemide per day, or the combination of furosemide with thiazide diuretics or an aldosterone antagonist [bib_ref] Derivation and validation of a prediction score for acute kidney injury in..., Wang [/bib_ref] [bib_ref] Acute and acute-on-chronic kidney injury of patients with decompensated heart failure: impact..., Zhou [/bib_ref].
## Literature review
PubMed was searched for relevant studies published between March 2011 and December 2015, and papers related to the present CQ were identified from the search results. The literature published before March 2011 was referenced from the KDIGO Clinical Practice Guideline for AKI.
## Cq3-4: what should be assessed as risk factors for aki development in sepsis?
Recommendation: Pre-existing renal dysfunction, aging, and the use of renin-angiotensin-aldosterone system inhibitors should be assessed as risk factors.
## Strength of recommendation: 2
Quality of evidence: C
## Summary of evidence
In 6 observational studies that examined the risk of AKI development in sepsis, pre-existing renal dysfunction, aging, and the use of renin-angiotensin-aldosterone system inhibitors were found to be associated with AKI development in sepsis.
## Commentary
# Background
Sepsis patients develop AKI frequently [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] [bib_ref] Acute kidney injury in patients with sepsis and septic shock: risk factors..., Suh [/bib_ref]. As AKI is associated with a significantly increased mortality [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] , it is crucial to assess the risk of its development in sepsis patients. In our search for observational studies aimed at identifying 1 3 the risk factors for AKI development in sepsis, the numbers of relevant studies and of patients did not make for sufficiently strong evidence; however, several clinical background factors were identified as risk factors for AKI development . [bib_ref] Acute kidney injury in septic patients admitted to emergency clinical room: risk..., Medeiros [/bib_ref]. Therefore, whenever possible, patients must be examined for preexisting renal dysfunction when sepsis develops. In addition, when treating septic patients with pre-existing renal dysfunction, it is necessary to monitor the renal function carefully.
## Pre-existing renal dysfunction
## Aging
Japanese society is aging rapidly. Aging is an underlying cause of age-related organ dysfunction, which creates various medical issues. Suh et al. reported that the risk of AKI development in sepsis increased with age (odds ratio 1.028, 95% CI 1.016-1.041) [bib_ref] Acute kidney injury in patients with sepsis and septic shock: risk factors..., Suh [/bib_ref]. Medeiros et al. reported a similar result in an observational study that found AKI to be significantly more frequent in septic patients aged over 65 (odds ratio 1.28, 95% CI 1.12-1.89) [bib_ref] Acute kidney injury in septic patients admitted to emergency clinical room: risk..., Medeiros [/bib_ref]. In addition, although the risk was not assessed in a logistic regression analysis, another observational study reported that AKI patients were of a significantly higher age [bib_ref] Association between systemic hemodynamics and septic acute kidney injury in critically ill..., Legrand [/bib_ref]. Therefore, the potential development of AKI must be considered while treating elderly patients with sepsis.
## Renin-angiotensin-aldosterone system inhibitors
An increase in patients with hypertension has led to a corresponding increase in the number of patients using renin-angiotensin-aldosterone system inhibitors. As these drugs reduce the systemic blood pressure and dilate the efferent arterioles, they may enhance the reduction of the GFR during shock. Therefore, there is a concern that renin-angiotensin-aldosterone system inhibitors may exacerbate the risk of AKI development. In two observational studies that examined whether the use of renin-angiotensin-aldosterone system inhibitors was a risk factor for AKI development in sepsis, the risk was found to be approximately twice as high when using these drugs than when not using them [bib_ref] Acute kidney injury in patients with sepsis and septic shock: risk factors..., Suh [/bib_ref] [bib_ref] Predictors of acute kidney injury in septic shock patients: an observational cohort..., Plataki [/bib_ref]. Therefore, when sepsis develops, the careful monitoring of potential AKI development is recommended in patients using renin-angiotensin-aldosterone system inhibitors. However, there have been no intervention trials to determine whether the withdrawal of these drugs during sepsis can prevent the development of AKI. This question needs to be examined in a RCT.
## Other risk factors
In addition to the above risk factors, observational studies have also assessed obesity, comorbid diabetes, intra-abdominal bacterial infection, the use of blood products, and hypotension as potential risk factors for AKI development [bib_ref] Acute kidney injury in patients with sepsis and septic shock: risk factors..., Suh [/bib_ref] [bib_ref] Predictors of acute kidney injury in septic shock patients: an observational cohort..., Plataki [/bib_ref] [bib_ref] Acute kidney injury in septic patients admitted to emergency clinical room: risk..., Medeiros [/bib_ref] [bib_ref] Diabetic patients with severe sepsis admitted to intensive care unit do not..., Chang [/bib_ref]. However, no definitive conclusions have been reached. For instance, one study found that diabetes is not associated with the development of AKI in sepsis [bib_ref] Acute Kidney Injury in Severe Sepsis and Septic Shock in Patients with..., Venot [/bib_ref]. Further evidence needs to be collected in order to determine whether these factors increase the risk of AKI development in sepsis.
## Summary of evidence
In a meta-analysis of eight observational studies, the mortality was significantly higher in hospital-acquired AKI than in community-acquired AKI (odds ratio 2.79, 95% CI 2. . In studies that used the RIFLE or KDIGO criteria, community-acquired AKI featured a high rate of stage 3 AKI, while hospital-acquired AKI featured a high rate of stage 1 AKI.
## Commentary
Acute kidney injury (AKI) is primarily treated with conservative therapies, such as the optimization of fluid volume or blood pressure and the avoidance of nephrotoxins; in addition, identification of the cause of the kidney injury is recommended. Therefore, it is crucial to recognize the risk factors for AKI and take steps to prevent it in order to improve its outcomes. Acute kidney injury encompasses a broad spectrum of diseases and can occur in the hospital or in the community. However, although community-acquired AKI occurs frequently in low-and median-income countries which account for roughly 85% of the world population, 80-90% of studies have examined hospital-acquired AKI in high-income countries [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] ; few studies have compared hospital-acquired and community-acquired AKI. Hospital-acquired AKI is frequently caused by ischemia, nephrotoxins, and sepsis [bib_ref] Hospital-acquired renal insufficiency, Nash [/bib_ref] , while community-acquired AKI has been found to frequently derived from preventable causes such as dehydration, infection, and childbirth [bib_ref] Community-acquired acute kidney injury: a challenge and opportunity for primary care in..., Mesropian [/bib_ref]. To determine the state of community-acquired AKI in low-and median-income countries, the multinational The 0 by 25 initiative conducted the global snapshot study in 2015 [bib_ref] International Society of Nephrology's 0by25 initiative for acute kidney injury (zero preventable..., Mehta [/bib_ref].
In order to develop the present guideline, PubMed was used to identify papers that compared hospital-acquired and community-acquired AKI. Eight observational studies were identified [bib_ref] Acute renal failure in a teaching hospital, Loo [/bib_ref] [bib_ref] Epidemiology of de novo acute renal failure in hospitalized African Americans: comparing..., Obialo [/bib_ref] [bib_ref] Prognosis of ARF in hospitalized elderly patients, Sesso [/bib_ref] [bib_ref] Hospital-acquired and communityacquired acute renal failure in hospitalized Chinese: a ten-year review, Wang [/bib_ref] [bib_ref] Characteristics and outcomes in community-acquired versus hospital-acquired acute kidney injury, Schissler [/bib_ref] [bib_ref] Long-term outcomes of community-acquired versus hospital-acquired acute kidney injury: a retrospective analysis, Der Mesropian [/bib_ref] [bib_ref] Epidemiology and outcomes in community-acquired versus hospitalacquired AKI, Wonnacott [/bib_ref] [bib_ref] Epidemiology and clinical correlates of AKI in Chinese hospitalized adults, Xu [/bib_ref] ; among them, two defined AKI based on the RIFLE criteria [bib_ref] Characteristics and outcomes in community-acquired versus hospital-acquired acute kidney injury, Schissler [/bib_ref] [bib_ref] Long-term outcomes of community-acquired versus hospital-acquired acute kidney injury: a retrospective analysis, Der Mesropian [/bib_ref] , two used the KDIGO criteria [bib_ref] Epidemiology and outcomes in community-acquired versus hospitalacquired AKI, Wonnacott [/bib_ref] [bib_ref] Epidemiology and clinical correlates of AKI in Chinese hospitalized adults, Xu [/bib_ref] , and the other four were published before the RIFLE and KDIGO criteria were proposed [bib_ref] Acute renal failure in a teaching hospital, Loo [/bib_ref] [bib_ref] Epidemiology of de novo acute renal failure in hospitalized African Americans: comparing..., Obialo [/bib_ref] [bib_ref] Prognosis of ARF in hospitalized elderly patients, Sesso [/bib_ref] [bib_ref] Hospital-acquired and communityacquired acute renal failure in hospitalized Chinese: a ten-year review, Wang [/bib_ref]. Four studies were conducted in high-income countries [bib_ref] Epidemiology of de novo acute renal failure in hospitalized African Americans: comparing..., Obialo [/bib_ref] [bib_ref] Characteristics and outcomes in community-acquired versus hospital-acquired acute kidney injury, Schissler [/bib_ref] [bib_ref] Long-term outcomes of community-acquired versus hospital-acquired acute kidney injury: a retrospective analysis, Der Mesropian [/bib_ref] [bib_ref] Epidemiology and outcomes in community-acquired versus hospitalacquired AKI, Wonnacott [/bib_ref] , while the other four were conducted in low-and median-income countries [bib_ref] Acute renal failure in a teaching hospital, Loo [/bib_ref] [bib_ref] Prognosis of ARF in hospitalized elderly patients, Sesso [/bib_ref] [bib_ref] Hospital-acquired and communityacquired acute renal failure in hospitalized Chinese: a ten-year review, Wang [/bib_ref] [bib_ref] Epidemiology and clinical correlates of AKI in Chinese hospitalized adults, Xu [/bib_ref]. In all of these studies, communityacquired AKI was associated with a lower mortality [fig_ref] Figure 1: In-hospital mortality in CA-AKI versus HA-AKI [/fig_ref] and shorter hospitalization duration. Moreover, the percentages of patients at each AKI stage (i.e. degree of severity) in the studies that used the AKIN criteria indicated that in all four studies, community-acquired AKI was more severe (i.e., with low percentages of stages 1 and 2 AKI and high Risk factors for AKI development in sepsis percentages of stage 3 AKI), while hospital-acquired AKI showed higher percentages of mild cases [fig_ref] CQ6- 2: Are loop diuretics recommended for the prevention and treatment of AKI?Recommendation [/fig_ref].
Thus, the above-cited studies demonstrate that hospitalacquired AKI and community-acquired AKI have different clinical pictures, as shown in the [fig_ref] Table 8: Differences between CA-AKI and HA-AKI [/fig_ref]. The relationship between the severity and mortality may differ between hospital-acquired AKI and community-acquired AKI; therefore, we suggest that they be discriminated from one another.
However, all the studies used were conducted outside Japan. Further investigation comparing hospital-acquired AKI and community-acquired AKI in Japan is necessary.
## Literature review
PubMed was searched for relevant studies published up to December 2015, and papers that compared hospitalacquired and community-acquired AKI were identified from the search results.
## Cq4-2: should septic aki and non-septic aki be discriminated from each other?
Recommendation: Septic AKI may lead to a higher mortality than non-septic AKI; therefore, we suggest that they should be discriminated from each other.
## Strength of recommendation: not graded
## Quality of evidence: d
## Summary of evidence
In a meta-analysis based on nine observational studies, compared to non-septic AKI, septic AKI resulted in a higher inhospital mortality (odds ratio 2.48, 95% CI 1.76-3.49) and a higher ICU mortality (odds ratio 1.60, 95% CI 1.52-1.69). Although studies that assessed the in-hospital mortality featured publication bias, no such bias was observed related to ICU mortality.
## Commentary
In a report of a large-scale prospective observational study conducted at 54 centers in 23 countries [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] , the cause of acute kidney injury (AKI) in the intensive care unit (ICU) was septic shock in 47.5% of cases and cardiogenic shock in 26.9% of cases. In a large-scale multinational multicenter prospective observational study published in 2015 [bib_ref] Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI..., Hoste [/bib_ref] , AKI occurred in 57.3% of ICU patients; the cause of AKI was sepsis in 40.7% of patients and cardiogenic shock in 13.2% of patients. In Japanese epidemiology, the Diagnosis Procedure Combination (DPC) database has been used to examine AKI patients who underwent continuous renal replacement therapy (CRRT) [bib_ref] Current state of continuous renal replacement therapy for acute kidney injury in..., Iwagami [/bib_ref]. Among these patients, the most common causes of AKI were cardiovascular disease and other medical diseases, which accounted for approximately half of patients, followed by sepsis and cardiovascular surgery; compared to all other causes, mortality was low only for cardiovascular surgery.
In developing the present guideline, PubMed was used to identify papers which compared septic and non-septic AKI. Nine observational studies were identified [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] [bib_ref] Prognostic factors in acute renal failure due to sepsis. Results of a..., Neveu [/bib_ref] [bib_ref] Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes, Bagshaw [/bib_ref] [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] [bib_ref] Sepsis may not be a risk factor for mortality in patients with..., Nagata [/bib_ref] [bib_ref] Renal function outcome prognosis in septic and non-septic acute kidney injury patients, Hamzic-Mehmedbasic [/bib_ref] [bib_ref] Septic versus non-septic acute kidney injury in critically ill patients: characteristics and..., Cruz [/bib_ref] [bib_ref] Sepsis and SOFA score: related outcome for critically ill renal patients, Carbonell [/bib_ref] [bib_ref] Impact of sepsis on levels of plasma cystatin C in AKI and..., Martensson [/bib_ref] ; seven of these studies were prospective, while two were retrospective. One of these studies was a retrospective study by Bagshaw et al., which utilized the Australian and New Zealand Intensive Care Society (ANZICS) database [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] ; the study featured 14,039 septic AKI patients and 29,356 nonseptic AKI patients, a prominently large number of patients compared to other studies. Seven studies compared in-hospital mortality [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] [bib_ref] Prognostic factors in acute renal failure due to sepsis. Results of a..., Neveu [/bib_ref] [bib_ref] Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes, Bagshaw [/bib_ref] [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] [bib_ref] Sepsis may not be a risk factor for mortality in patients with..., Nagata [/bib_ref] [bib_ref] Renal function outcome prognosis in septic and non-septic acute kidney injury patients, Hamzic-Mehmedbasic [/bib_ref] [bib_ref] Septic versus non-septic acute kidney injury in critically ill patients: characteristics and..., Cruz [/bib_ref] , while five studies compared ICU mortality [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] [bib_ref] Sepsis may not be a risk factor for mortality in patients with..., Nagata [/bib_ref] [bib_ref] Sepsis and SOFA score: related outcome for critically ill renal patients, Carbonell [/bib_ref] [bib_ref] Impact of sepsis on levels of plasma cystatin C in AKI and..., Martensson [/bib_ref].
As for AKI diagnostic criteria, six studies used the RIFLE criteria [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] [bib_ref] Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes, Bagshaw [/bib_ref] [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] [bib_ref] Sepsis may not be a risk factor for mortality in patients with..., Nagata [/bib_ref] [bib_ref] Renal function outcome prognosis in septic and non-septic acute kidney injury patients, Hamzic-Mehmedbasic [/bib_ref] [bib_ref] Septic versus non-septic acute kidney injury in critically ill patients: characteristics and..., Cruz [/bib_ref] ; the remaining three studies [bib_ref] Prognostic factors in acute renal failure due to sepsis. Results of a..., Neveu [/bib_ref] [bib_ref] Sepsis and SOFA score: related outcome for critically ill renal patients, Carbonell [/bib_ref] [bib_ref] Impact of sepsis on levels of plasma cystatin C in AKI and..., Martensson [/bib_ref] were published before the RIFLE criteria were proposed. Percentages of patients by RIFLE criteria severity were listed in four studies [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] [bib_ref] Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes, Bagshaw [/bib_ref] [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] [bib_ref] Renal function outcome prognosis in septic and non-septic acute kidney injury patients, Hamzic-Mehmedbasic [/bib_ref] ; Risk was the most common level of severity in one study [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] , while Injury was the most common in two studies [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] [bib_ref] Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes, Bagshaw [/bib_ref] , and Failure was the most common in one study [bib_ref] Renal function outcome prognosis in septic and non-septic acute kidney injury patients, Hamzic-Mehmedbasic [/bib_ref]. Causes of sepsis were demonstrated in two studies [bib_ref] Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes, Bagshaw [/bib_ref] [bib_ref] Sepsis may not be a risk factor for mortality in patients with..., Nagata [/bib_ref] ; in these studies, sepsis was caused by intrathoracic infections (such as pneumonia) and intra-abdominal infections in approximately 30 and 25% of cases, respectively, thus accounting for more than half of all cases. The severities of patients' illnesses were assessed with the APACHE II, SAPS, and SAPS II severity scores in eight studies [bib_ref] Early acute kidney injury and sepsis: a multicentre evaluation, Bagshaw [/bib_ref] [bib_ref] Prognostic factors in acute renal failure due to sepsis. Results of a..., Neveu [/bib_ref] [bib_ref] Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes, Bagshaw [/bib_ref] [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] [bib_ref] Sepsis may not be a risk factor for mortality in patients with..., Nagata [/bib_ref] [bib_ref] Septic versus non-septic acute kidney injury in critically ill patients: characteristics and..., Cruz [/bib_ref] [bib_ref] Sepsis and SOFA score: related outcome for critically ill renal patients, Carbonell [/bib_ref] [bib_ref] Impact of sepsis on levels of plasma cystatin C in AKI and..., Martensson [/bib_ref] ; in all of these studies, septic AKI was more severe than nonseptic AKI. [fig_ref] Figure 3: In-hospital mortality in septic AKI versus non-septic AKI 1 3 [/fig_ref] shows the results of meta-analysis of seven studies which compared in-hospital mortality. In-hospital mortality and ICU mortality may both be higher for septic AKI than for non-septic AKI; therefore, we suggest that the two forms of AKI be discriminated from each other. Septic AKI should be handled in specific ways, such as admission of patients to the ICU depending on severity, consideration of hemodynamic monitoring, and maintaining fluid volume and renal perfusion pressure.
## 3
## Literature searches
Searches were conducted on PubMed for literature published up to November 2015. Papers which compared septic and non-septic AKI were identified from the search results.
## Cq4-3: should renal aki and pre-renal aki be differentiated?
Recommendation: The in-hospital mortality may be higher in renal AKI than in pre-renal AKI; therefore, we suggest that they should be differentiated from one another.
## Strength of recommendation: not graded
Quality of evidence: D
## 3
## Summary of evidence
In a meta-analysis of 10 observational studies, the in-hospital mortality from renal AKI was higher than that from prerenal AKI (odds ratio 3.63, 95% CI 1.68-7.83). A significant publication bias was present.
## Commentary
Acute kidney injury (AKI) is classified as either pre-renal, renal (intrinsic), or post-renal. Pre-renal AKI is considered as azotemia resulting from a decreased renal perfusion pressure; conceptually, it is a form of renal impairment with no renal tissue damage, in which the renal function can recover rapidly with early treatment. There are two conceivable approaches to the differentiation of pre-renal AKI from renal AKI. The first approach is to comprehensively assess whether the AKI is pre-renal or renal based on an assessment of the cause of the AKI, hemodynamics, and urinalyses with measuring factors such as the body weight change, vital signs, urine osmality, fractional excretion of sodium (FENa), fractional excretion of urea nitrogen (FEUN), and urinary sediment. The second approach is to determine whether the renal function recovers immediately after fluid resuscitation. If the renal function recovers within 2-3 days after appropriate fluid resuscitation, the AKI is considered to be volume-responsive, which allows for clinical classification as pre-renal AKI. If the renal function does not recover despite fluid resuscitation, the AKI is considered to be volume-unresponsive, which corresponds to renal AKI. However, when a continued or prolonged reduced renal perfusion pressure results in renal parenchymal injury, or when the reduced renal perfusion pressure is accompanied by a low cardiac output, sepsis, or liver failure, the renal function does not necessarily recover with fluid resuscitation alone [bib_ref] Evaluation and initial management of acute kidney injury, Himmelfarb [/bib_ref]. Therefore, even if the AKI is initially assessed as pre-renal, a second test should be performed within 3 days. However, even if the AKI is assessed as pre-renal, a mild elevation in the urinary biomarkers can sometimes be suggestive of a renal tissue injury [bib_ref] Mild elevation of urinary biomarkers in prerenal acute kidney injury, Doi [/bib_ref]. As AKI is known to be involved in injuries to multiple organs, including the heart and lungs, even pre-renal AKI may affect the survival prognosis.
Many studies have reported that the in-hospital mortality is lower in volume-responsive AKI-in which the renal function recovers within 3 days of intervention-than in volume-unresponsive AKI. In a recent AKI cohort study of 283 patients in intensive care units (ICUs) at multiple hospitals, the in-hospital mortality rates for non-AKI, volume-responsive AKI, and renal AKI were 23.8, 29.6, and 38.9%, respectively; thus, renal AKI showed the worst outcomes [bib_ref] Transient and persistent acute kidney injury and the risk of hospital mortality..., Perinel [/bib_ref]. However, in a study that evaluated AKI based on its underlying causes at diagnosis, the in-hospital mortality was 27.3% in pre-renal AKI versus 19.3% in intrinsic AKI; although the difference was not significant, pre-renal AKI tended to have worse outcomes [bib_ref] Clinical analysis of cause, treatment and prognosis in acute kidney injury patients, Yang [/bib_ref].
To develop the present guideline, PubMed was used to identify papers that compared renal and pre-renal AKI in order to assess the difference in the survival outcomes. Ten cohort studies were identified; among them, three differentiated between pre-renal and renal AKI based on the underlying causes of AKI and the urine findings at diagnosis [bib_ref] Clinical analysis of cause, treatment and prognosis in acute kidney injury patients, Yang [/bib_ref] [bib_ref] Communityacquired acute renal failure, Kaufman [/bib_ref] [bib_ref] Adjudication of etiology of acute kidney injury: experience from the TRIBE-AKI multi-center..., Koyner [/bib_ref] , while seven differentiated between pre-renal and renal AKI based on the volume responsiveness [bib_ref] Mild elevation of urinary biomarkers in prerenal acute kidney injury, Doi [/bib_ref] [bib_ref] Transient and persistent acute kidney injury and the risk of hospital mortality..., Perinel [/bib_ref] [bib_ref] Sensitivity and specificity of a single emergency department measurement of urinary neutrophil..., Nickolas [/bib_ref] [bib_ref] Mortality in elderly patients with acute renal failure, Santacruz [/bib_ref] [bib_ref] Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts..., Singer [/bib_ref] [bib_ref] Cystatin C as a marker of acute kidney injury in the emergency..., Soto [/bib_ref]. In our meta-analysis, the in-hospital mortality was significantly higher in renal AKI than in pre-renal AKI .
Based on the above, pre-renal AKI and renal (intrinsic) AKI have different survival outcomes; therefore, we suggest that they should be distinguished from one another.
## Literature review
PubMed was searched for relevant studies published up to August 2015, and papers related to the present CQ were identified from the search results.
## Cq5-1: should urinary biomarkers be used for the early diagnosis of aki?
Recommendation: Due to their potential utility in the early diagnosis of AKI, we suggest measuring the urinary NGAL and L-FABP. However, the utility of the urinary cystatin C is limited; therefore, we cannot make a recommendation about its use.
## Summary of evidence
Multiple systematic reviews/meta-analyses have found the urinary NGAL and L-FABP to serve as useful markers for the early diagnosis of AKI. However, future clinical trials that compare AKI interventions based on the conventional diagnostic method using the serum creatinine levels with those based on diagnoses made with urinary biomarkers are necessary to examine whether novel urinary biomarkers are truly useful for the diagnosis of AKI.
Only one systematic review/meta-analysis has assessed the utility of the urinary cystatin C; therefore, firm conclusions as to its utility for the early diagnosis of AKI cannot be made.
## Commentary
The pathological condition previously recognized as acute renal failure (ARF) is now broadly understood to pose a risk of death at an earlier or milder stage than failure. This has prompted a paradigm shift from ARF to acute kidney injury (AKI). However, with the present method of diagnosis, which is based on the identification of an increased level of serum creatinine (sCr) and a reduced urine output, interventions are often mistimed; therefore, there is an urgent need for the clinical application of more sensitive biomarkers. The early diagnosis of AKI enables earlier consultation with a nephrologist, appropriate management of the renal hemodynamics, and the avoidance of exposure to nephrotoxins. Therefore, we examined whether urinary biomarkers should be used for the early diagnosis of AKI based on a relatively large number of studies on AKI in adult patients having received cardiovascular surgery and those in intensive care units (ICUs).
Neutrophil gelatinase-associated lipocalin (NGAL) is a low molecular weight protein (molecular weight: approximately 25,000) that belongs to the lipocalin protein family and is secreted by activated neutrophils. In addition to inducing kidney development and possessing renoprotective and antibacterial effects, NGAL is also expressed in the distal nephron in kidney injury. Multiple systematic reviews/meta-analyses have found the urinary NGAL to be useful for the early diagnosis of AKI In-hospital mortality in renal AKI versus pre-renal AKI [bib_ref] Urinary, plasma, and serum biomarkers' utility for predicting acute kidney injury associated..., Ho [/bib_ref] [bib_ref] Tubular proteinuria in acute kidney injury: a critical evaluation of current status..., Parikh [/bib_ref] [bib_ref] Biomarkers for the diagnosis and risk stratification of acute kidney injury: a..., Coca [/bib_ref] [bib_ref] Neutrophil gelatinaseassociated lipocalin as a biomarker of acute kidney injury: a critical..., Haase-Fielitz [/bib_ref] [bib_ref] Clinical review: Predictive value of neutrophil gelatinase-associated lipocalin for acute kidney injury..., Hjortrup [/bib_ref] [bib_ref] Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute..., Haase [/bib_ref]. Among the studies cited in these systematic reviews/meta-analyses, 16 (for a total of 2194 patients) were related to the present CQ [fig_ref] Table 9: Urinary NGAL for early AKI diagnosis sCr serum creatinine, UO urine output,... [/fig_ref] [bib_ref] Rapid detection of acute kidney injury by plasma and urinary neutrophil gelatinase-associated..., Tuladhar [/bib_ref] [bib_ref] Neutrophil gelatinase-associated lipocalin at ICU admission predicts for acute kidney injury in..., De Geus [/bib_ref] [bib_ref] Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction..., Wagener [/bib_ref] [bib_ref] Urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery, Wagener [/bib_ref] [bib_ref] Urine neutrophil gelatinase-associated lipocalin and interleukin-18 predict acute kidney injury after cardiac..., Xin [/bib_ref] [bib_ref] Urinary biomarkers in the early detection of acute kidney injury after cardiac..., Han [/bib_ref] [bib_ref] Comparative analysis of urinary biomarkers for early detection of acute kidney injury..., Liangos [/bib_ref] [bib_ref] Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of acute kidney..., Makris [/bib_ref] [bib_ref] Comparison of urinary neutrophil glucosaminidase-associated lipocalin, cystatin C, and alpha1-microglobulin for early..., Heise [/bib_ref] [bib_ref] Post-operative serum uric acid and acute kidney injury, Ejaz [/bib_ref] [bib_ref] Assessment of NGAL as an early biomarker of acute kidney injury in..., Sargentini [/bib_ref] [bib_ref] Neutrophil gelatinase-associated lipocalin (NGAL) for the early detection of cardiac surgery associated..., Liebetrau [/bib_ref] [bib_ref] Urinary L-FABP and its combination with urinary NGAL in early diagnosis of..., Liu [/bib_ref] [bib_ref] Rapid detection of acute kidney injury by urinary neutrophil gelatinaseassociated lipocalin after..., Munir [/bib_ref] [bib_ref] Duration of cardiopulmonary bypass is an important confounder when using biomarkers for..., Paarmann [/bib_ref]. The subjects consisted of patients who had undergone cardiovascular surgery (14 studies, 1531 patients in all) [bib_ref] Rapid detection of acute kidney injury by plasma and urinary neutrophil gelatinase-associated..., Tuladhar [/bib_ref] [bib_ref] Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction..., Wagener [/bib_ref] [bib_ref] Urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery, Wagener [/bib_ref] [bib_ref] Urine neutrophil gelatinase-associated lipocalin and interleukin-18 predict acute kidney injury after cardiac..., Xin [/bib_ref] [bib_ref] Urinary biomarkers in the early detection of acute kidney injury after cardiac..., Han [/bib_ref] [bib_ref] Comparative analysis of urinary biomarkers for early detection of acute kidney injury..., Liangos [/bib_ref] [bib_ref] Comparison of urinary neutrophil glucosaminidase-associated lipocalin, cystatin C, and alpha1-microglobulin for early..., Heise [/bib_ref] [bib_ref] Post-operative serum uric acid and acute kidney injury, Ejaz [/bib_ref] [bib_ref] Assessment of NGAL as an early biomarker of acute kidney injury in..., Sargentini [/bib_ref] [bib_ref] Neutrophil gelatinase-associated lipocalin (NGAL) for the early detection of cardiac surgery associated..., Liebetrau [/bib_ref] [bib_ref] Urinary L-FABP and its combination with urinary NGAL in early diagnosis of..., Liu [/bib_ref] [bib_ref] Rapid detection of acute kidney injury by urinary neutrophil gelatinaseassociated lipocalin after..., Munir [/bib_ref] [bib_ref] Duration of cardiopulmonary bypass is an important confounder when using biomarkers for..., Paarmann [/bib_ref] and ICU patients (two studies, 663 patients in all) [bib_ref] Neutrophil gelatinase-associated lipocalin at ICU admission predicts for acute kidney injury in..., De Geus [/bib_ref] [bib_ref] Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of acute kidney..., Makris [/bib_ref]. The majority of these studies defined AKI according to the RIFLE or AKIN criteria (i.e. an increase in sCr) or to criteria conforming to the RIFLE or AKIN ones. A total of 549 patients (25%) were diagnosed with AKI. In an assessment of the early diagnostic capacity of the urinary NGAL over the 6-h period immediately after surgery or ICU admission, the area under the receiver operating characteristic curve (AUC) was 0.50-0.98 (0.77 with an unweighted mean). In 75% (12/16) of the studies, the AUC was ≥ 0.70, thus showing moderate-or-better diagnostic accuracy; therefore, the urinary NGAL was found to be useful for the early diagnosis of AKI. However, the clinical studies related to the present CQ raised several issues about the clinical application of the urinary NGAL, including the following: some studies did not use officially approved measurement methods; multiple measurement methods were used, and they were not standardized; there was no set cutoff value; urinary tract infections and urologic diseases increase the urinary NGAL levels [bib_ref] Urinalysis is more specific and urinary neutrophil gelatinase-associated lipocalin is more sensitive..., Schinstock [/bib_ref] ; and there are very few relevant clinical studies of Japanese subjects.
The L-type fatty acid-binding protein (L-FABP) is a low molecular weight protein (molecular weight: approximately 14,000) localized in the cytoplasm of human renal proximal tubular cells. By binding to free fatty acids and transporting them to mitochondria and peroxisomes, the L-FABP promotes beta-oxidation, contributes to energy production, and helps to maintain homeostasis. When the proximal tubule is subjected to ischemia or oxidative stress, the expression of the L-FABP is enhanced and its urinary excretion increases. The urinary L-FABP has been demonstrated to be useful for the early diagnosis of AKI [bib_ref] Urinary, plasma, and serum biomarkers' utility for predicting acute kidney injury associated..., Ho [/bib_ref] [bib_ref] Tubular proteinuria in acute kidney injury: a critical evaluation of current status..., Parikh [/bib_ref] [bib_ref] Performance of urinary liver-type fatty acid-binding protein in acute kidney injury: a..., Susantitaphong [/bib_ref] by multiple systematic reviews/meta-analyses. Among the studies cited in these systematic reviews/ meta-analyses, seven (for a total of 2416 patients) were related to the present CQ [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref] [bib_ref] Urinary L-FABP and its combination with urinary NGAL in early diagnosis of..., Liu [/bib_ref] [bib_ref] Usefulness of urinary biomarkers in early detection of acute kidney injury after..., Matsui [/bib_ref] [bib_ref] Evaluation of new acute kidney injury biomarkers in a mixed intensive care..., Doi [/bib_ref] [bib_ref] Clinical significance of tubular and podocyte biomarkers in acute kidney injury, Matsui [/bib_ref] [bib_ref] The role of urinary liver-type fatty acid-binding protein in critically ill patients, Cho [/bib_ref] [bib_ref] Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of..., Nickolas [/bib_ref] [bib_ref] Combination of two urinary biomarkers predicts acute kidney injury after adult cardiac..., Katagiri [/bib_ref]. The subjects consisted of patients who had undergone cardiovascular surgery (three studies, 271 patients in all) [bib_ref] Urinary L-FABP and its combination with urinary NGAL in early diagnosis of..., Liu [/bib_ref] [bib_ref] Usefulness of urinary biomarkers in early detection of acute kidney injury after..., Matsui [/bib_ref] [bib_ref] Combination of two urinary biomarkers predicts acute kidney injury after adult cardiac..., Katagiri [/bib_ref] and ICU patients (four studies, 2,145 patients in all) [bib_ref] Evaluation of new acute kidney injury biomarkers in a mixed intensive care..., Doi [/bib_ref] [bib_ref] Clinical significance of tubular and podocyte biomarkers in acute kidney injury, Matsui [/bib_ref] [bib_ref] The role of urinary liver-type fatty acid-binding protein in critically ill patients, Cho [/bib_ref] [bib_ref] Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of..., Nickolas [/bib_ref]. These studies generally defined AKI according to the RIFLE or AKIN criteria (i.e. an increase in sCr). A total of 298 patients (12%) were diagnosed with AKI. In an assessment of the early diagnostic capacity of the urinary L-FABP over the 12-h period immediately after surgery or ICU admission, the AUC was 0.70-0.95 (0.81 with an unweighted mean). In all seven studies, the AUC was ≥ 0.70, thus showing moderate-or-better diagnostic accuracy; therefore, the urinary L-FABP was found to be useful for the early diagnosis of AKI. However, the timing of the urinary L-FABP measurement must be chosen carefully according to the different AKI etiologies. Measuring reagents for the L-FABP are available in Japan; these are standardized and covered by public health insurance.
Cystatin C is a low molecular weight protein (molecular weight: approximately 13,000) produced by nucleated cells all over the body that inhibits the cell injury caused by cysteine proteases. After being secreted outside cells, cystatin C is filtered by the glomerulus; 99% of it is then absorbed by the proximal tubule and catabolized. Therefore, tubular injuries are affected by the reabsorption of cystatin C; consequently, the cystatin C concentration in urine has been examined as a biomarker of AKI. There has been one systematic review/meta-analysis of the early diagnostic capacity of the urinary cystatin C [bib_ref] Cystatin C in prediction of acute kidney injury: a systemic review and..., Zhang [/bib_ref] ; the latter cited six studies [bib_ref] Cystatin C as a marker of acute kidney injury in the emergency..., Soto [/bib_ref] [bib_ref] Comparative analysis of urinary biomarkers for early detection of acute kidney injury..., Liangos [/bib_ref] [bib_ref] Comparison of urinary neutrophil glucosaminidase-associated lipocalin, cystatin C, and alpha1-microglobulin for early..., Heise [/bib_ref] [bib_ref] Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and..., Nejat [/bib_ref] [bib_ref] Urinary biomarkers in the clinical prognosis and early detection of acute kidney..., Koyner [/bib_ref]. In a pool analysis of four studies that used urinary creatinine-adjusted data [bib_ref] Cystatin C as a marker of acute kidney injury in the emergency..., Soto [/bib_ref] [bib_ref] Comparative analysis of urinary biomarkers for early detection of acute kidney injury..., Liangos [/bib_ref] [bib_ref] Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and..., Nejat [/bib_ref] [bib_ref] Urinary biomarkers in the clinical prognosis and early detection of acute kidney..., Koyner [/bib_ref] , the sensitivity for the early diagnostic capacity of urinary cystatin C was 0.52, the specificity was 0.70, and the AUC was 0.64 (95% CI 0.62-0.66); therefore, the diagnostic accuracy was low, indicating that the urinary cystatin C is of limited utility for the early diagnosis of AKI. The measurement of cystatin C in urine samples is not covered by public health insurance in Japan. Although the urinary albumin has been reported to be a potential biomarker of early AKI [bib_ref] Renal cortical albumin gene induction and urinary albumin excretion in response to..., Ware [/bib_ref] , the number of relevant studies is limited; thus, the utility of the urinary albumin as a biomarker remains unknown.
As described above, the urinary NGAL and L-FABP have been identified as useful biomarkers for the early diagnosis of AKI. However, future clinical trials that compare AKI interventions based on the conventional diagnostic method using the serum creatinine levels with those based on diagnoses made with urinary biomarkers are necessary to examine whether novel urinary biomarkers are truly useful for the diagnosis of AKI.
## Literature review
## Cq5-2: should urinary biomarkers be used to predict the aki severity and mortality?
Recommendation: Although the urinary NGAL is of limited utility in predicting the AKI severity and s mortality, we suggest measuring urinary NGAL. The utilities of the urinary L-FABP, and cystatin C in this regard are unclear.
## Summary of evidence
Multiple systematic reviews/meta-analyses about the use of the urinary NGAL to predict the AKI severity and survival outcomes have suggested that the urinary NGAL is potentially useful, albeit limitedly, in predicting the severity in relation to death and renal replacement therapy initiation. The number of studies on the urinary L-FABP and cystatin C is limited; therefore, their utilities in predicting the AKI severity in relation to death and renal replacement therapy initiation are unclear.
## Commentary
Acute kidney injury (AKI) has been shown to be involved not only in short-term kidney injury, but also in the subsequent renal outcomes and mortality. Therefore, the prediction of these outcomes is of clinical importance. In addition to the serum creatinine (sCr), the cystatin C, and the estimated glomerular filtration rate (eGFR), all of which reflect the renal function, studies have examined the urinary NGAL, NAG, L-FABP, and cystatin C as biomarkers of kidney injury . The results of several systematic reviews and meta-analyses of these studies have been reported in recent years.
Regarding the utility of the urinary NGAL for the prediction of the renal outcomes and mortality, multiple systematic reviews/meta-analyses have indicated that the urinary NGAL could help to predict the AKI severity in relation to death and the initiation of renal replacement therapy (RRT). In a meta-analysis of nine studies (a total of 1948 patients), the odds ratios for RRT requirement and in-hospital mortality based on increased urinary and serum NGAL levels were 12.9 and 8.8, respectively [bib_ref] Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute..., Haase [/bib_ref]. Meanwhile, in an analysis of 13 studies (a total of 1079 patients) on the recovery of the renal function after kidney transplantation, the NGAL was shown to be a useful predictor of AKI, with an area under the curve (AUC) of receiver operating characteristic (ROC) is 0.87 [bib_ref] Neutrophil gelatinaseassociated lipocalin as a biomarker of acute kidney injury: a critical..., Haase-Fielitz [/bib_ref]. However, these meta-analyses examined both urine and blood specimens; therefore, the results should be interpreted cautiously. Another cautionary point is that reports of NGAL measurements have used multiple measurement kits with different upper and lower limits.
In a meta-analysis of studies that used the urinary L-FABP to predict the need for RRT (three studies, 436 patients in all) and the in-hospital mortality (three studies, 561 patients in all), while no significant difference was observed in the need for RRT, the in-hospital mortality odds ratio was 13.7 (p = 0.008) [bib_ref] Performance of urinary liver-type fatty acid-binding protein in acute kidney injury: a..., Susantitaphong [/bib_ref]. Although measurement of the urinary L-FABP is covered by public health insurance in Japan, in principle, it can only be calculated once every 3 months. In addition, the urinary L-FABP has been reported to be elevated in patients with diabetes and chronic kidney diseases.
Regarding examinations of the cystatin C, a meta-analysis of seven studies (a total of 2941 patients) showed that high levels of cystatin C are a risk factor for death (odds ratio 2.3) [bib_ref] Relationship of cystatin-C change and the prevalence of death or dialysis need..., Feng [/bib_ref]. However, both blood and urine samples were examined in this analysis. Although measurement of the serum cystatin C is covered by public health insurance in Japan, that of the urinary cystatin C is not.
Other AKI markers that have been used in the past include the NAG, which increases by release from the tubular epithelium brush border into urine, and the β2microglobulin (β2MG) and α1microglobulin (α1MG), which will be increased by impaired tubular epithelial cell reabsorption. However, these markers are fraught with problems, as the samples are unstable (e.g. they are subject to changes in the urinary pH) and they are easily affected by the serum concentration of β2MG and α1MG. In addition, the levels of these markers can be increased by tubular disorders caused by proteinuria associated with glomerular injuries.
In measuring and assessing these urinary biomarkers, one should be cautious about the timing of the sample collection. In surgeries that use cardiopulmonary bypasses, the levels of the urinary NGAL and L-FABP increase 2-6 h after the surgery before declining gradually. Other biomarkers' levels
## Cq5-3: should urinary biomarkers be used to differentiate pre-renal aki from renal aki?
Recommendation: Although the urinary NGAL is of limited utility for the differentiation of pre-renal AKI from renal AKI, we suggest measuring urinary NGAL. The utilities of the urinary NAG, L-FABP, and cystatin C in this regard are unknown.
## Summary of evidence
Observational studies have reported that the urinary NGAL is mildly elevated in pre-renal AKI and highly elevated in renal AKI; therefore, the urinary NGAL can be useful in the differentiation of pre-renal from renal AKI. However, the measurement points and cutoff values have not yet been determined. Therefore, we recommend incorporating other laboratory findings and physical findings to differentiate prerenal from renal AKI. The utility of other urinary biomarkers in this regard is unknown.
## 3
## Commentary
The conventional indicators for the differentiation of prerenal acute kidney injury (AKI) and renal AKI include the urine osmolality, the fractional excretion of sodium (FENa), the fractional excretion of urea nitrogen (FEUN), and urine sediment findings; however, none of these tests can be considered sufficiently sensitive or specific. There have been no systematic reviews or meta-analyses of studies on the use of urinary biomarkers for the differentiation of pre-renal from renal AKI; only a small number of observational studies are available. In multiple studies in which patients diagnosed with AKI were divided into patients with pre-renal or renal AKI, the degree of elevation of the urinary NGAL was found to be potentially useful for the differentiation of these two types of AKI.
In Nickolas et al.'s examination of the urinary NGAL in 635 patients hospitalized after emergency room visits, the mean urinary NGAL level was significantly higher in renal AKI patients (n = 30; 416 ± 387 µg/gCr) than in pre-renal AKI patients (n = 88; 30.1 ± 92.0 µg/gCr) [bib_ref] Sensitivity and specificity of a single emergency department measurement of urinary neutrophil..., Nickolas [/bib_ref]. In a report of 145 hospitalized patients by Singer et al., the median urinary NGAL level was significantly higher in renal AKI patients [n = 75; 255.6 µg/L (98.5-872.9 µg/L)] than in prerenal AKI patients [n = 32; 31.3 µg/L (15.9-75.5 µg/L)] [bib_ref] Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts..., Singer [/bib_ref]. Moreover, a urinary NGAL cutoff level of 104 µg/L yielded a high sensitivity (0.75), high specificity (0.88), and high positive likelihood ratio (5.97) for the diagnosis of renal AKI. In a report by Seibert et al., the urinary NGAL levels within 3 days of hospital admission were significantly higher in renal AKI patients (458.1 ± 695.3 ng/ ml) than in pre-renal AKI patients (64.8 ± 62.1 ng/ml). In addition, a urinary NGAL cutoff level of 52 ng/ml yielded high sensitivity (0.75), high specificity (0.72), and a high area under the receiver operating characteristic curve (AUC 0.89) for the diagnosis of renal AKI [bib_ref] Calprotectin and neutrophil gelatinase-associated lipocalin in the differentiation of pre-renal and intrinsic..., Seibert [/bib_ref].
Although one study found that the urinary NGAL levels of pre-renal AKI patients were not elevated [bib_ref] Post cardiac surgery acute kidney injury: a woebegone status rejuvenated by the..., Jayaraman [/bib_ref] , other studies have reported that the urinary biomarker levels were mildly but significantly higher in pre-renal AKI patients than in patients without AKI. In a study by Doi et al. in which 129 out of 337 patients who were admitted to the intensive care unit (ICU) were diagnosed with AKI and in which transient AKI (pre-renal AKI) was defined as the recovery of the serum creatinine (sCr) to within 0.3 mg/ dl above baseline within 48 h, 51 patients were diagnosed with transient AKI [bib_ref] Mild elevation of urinary biomarkers in prerenal acute kidney injury, Doi [/bib_ref]. Upon ICU admission, transient AKI patients' levels of urinary NGAL, urinary L-FABP, NAG, and urinary albumin were mildly but significantly higher than those of non-AKI patients. Nejat et al. compared the urinary biomarkers upon ICU admission of 285 non-AKI patients, 61 pre-renal AKI patients (with prerenal AKI defined as a FENa < 1.0% and recovery of the sCr levels within 48 h), and 114 renal AKI patients [bib_ref] Some biomarkers of acute kidney injury are increased in pre-renal acute injury, Nejat [/bib_ref]. The median urinary NGAL levels of non-AKI patients and of pre-renal AKI patients were 7.7 µg/mmolCr (3.3-35 µg/ mmolCr) and 14 µg/mmolCr (6.5-56 µg/mmolCr), respectively; thus, pre-renal AKI patients showed a tendency to have a mildly higher urinary NGAL level (p = 0.052). In addition, the median urinary NGAL level of renal AKI patients was 44 µg/mmolCr (16-345 µg/mmolCr), which was significantly higher than that of pre-renal AKI patients. The median urinary cystatin C levels of non-AKI patients and pre-renal AKI patients were 0.026 mg/ mmolCr (0.010-0.12 mg/mmolCr) and 0.054 mg/mmolCr (0.017-0.53 mg/mmolCr), respectively; thus, the urinary cystatin C was significantly higher in pre-renal AKI patients than in non-AKI patients. The median urinary cystatin C level of renal AKI patients was 0.21 mg/mmolCr (0.05-1.9 mg/mmolCr), which was significantly higher than that of pre-renal AKI patients.
As described above, the urinary NGAL is mildly elevated in pre-renal AKI patients and highly elevated in renal AKI patients, which suggests that the urinary NGAL is potentially useful for the differentiation of pre-renal from renal AKI. However, the measurement points, cutoff values, and the need for urine creatinine correction have not yet been determined; these issues must be considered in the future. Therefore, pre-renal and renal AKI cannot be differentiated based on the urinary NGAL alone; hence, we recommend a comprehensive assessment that also incorporates other laboratory and physical findings.
## Literature review
## Cq6-1: is low-dose atrial natriuretic peptide recommended for prevention or treatment of aki?
Recommendation: Although low-dose atrial natriuretic peptide has been suggested to be useful for prevention of AKI, relevant reports remain insufficient. Evidence of low-dose atrial natriuretic peptide for treatment of AKI is limited.
## Strength of recommendation: not graded
## Quality of evidence: d
## Summary of evidence
Since atrial natriuretic peptide (ANP) preparation "carperitide" is covered by health insurance for treatment of congestive heart failure in Japan, we only investigated randomized controlled trials (RCTs) of ANP in which carperitide was used. A 2009 Cochrane review [bib_ref] Atrial natriuretic peptide for preventing and treating acute kidney injury, Nigwekar [/bib_ref] suggested that lowdose ANP may reduce the frequency of renal replacement therapy (RRT) in the setting of AKI prevention. However, the 2012 KDIGO Clinical Practice Guideline for AKIand a 2013 Cochrane review [bib_ref] Interventions for protecting renal function in the perioperative period, Zacharias [/bib_ref] carefully assessed individual pieces of evidence, and lead to a revised conclusion that there is insufficient evidence to declare that low-dose ANP is effective for treatment or prevention of AKI. Regarding 2009 and 2011 reports on cardiovascular surgery which focused on AKI prevention [bib_ref] Influence of continuous infusion of low-dose human atrial natriuretic peptide on renal..., Sezai [/bib_ref] [bib_ref] Results of low-dose human atrial natriuretic peptide infusion in nondialysis patients with..., Sezai [/bib_ref] , doubts were raised concerning issues such as randomization and blinding methods. In a 2011 paper, administration of low-dose ANP resulted in a significantly reduced rate of RRT after 1 year [bib_ref] Results of low-dose human atrial natriuretic peptide infusion in nondialysis patients with..., Sezai [/bib_ref]. Since 2011, there have been two new RCTs related to AKI prevention; however, due to few numbers of patients, we judged these RCTs lack sufficient statistical power. Currently, there is no strong evidence indicating that low-dose ANP is ineffective for prevention or treatment of AKI, but rather the evidence that does indicate its effectiveness is of insufficient quality.
## Commentary
Atriuretic peptide (ANP) is a circulating hormone that was discovered in Japan. Along with brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), they make up the natriuretic peptide family [bib_ref] Purification and complete amino acid sequence of alpha-human atrial natriuretic polypeptide (alpha-hANP), Kangawa [/bib_ref] [bib_ref] Molecular biology and biochemistry of the natriuretic peptide system. I: natriuretic peptides, Nakao [/bib_ref] [bib_ref] Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for..., Mukoyama [/bib_ref]. In healthy conditions, ANP is produced from the atria; however, in heart failure, the production and secretion of ANP from both the atria and ventricles are enhanced [bib_ref] Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for..., Mukoyama [/bib_ref] [bib_ref] Localization and mechanism of secretion of B-type natriuretic peptide in comparison with..., Yasue [/bib_ref]. ANP possesses multiple independent modes of actions, including vasodilation, inhibition of sodium reabsorption, inhibition of water reabsorption, elevation of glomerular filtration rate via afferent arteriole dilation and efferent arteriole constriction, reduction of renin activity, angiotensin II concentration, aldosterone concentration in the blood, and sympathetic nerve inhibition [bib_ref] Pathophysiological significance and clinical application of ANP and BNP in patients with..., Yoshimura [/bib_ref]. Combined together, continuous infusion of ANP or BNP on laboratory animals and humans exerts a powerful natriuretic effect [bib_ref] Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients..., Yoshimura [/bib_ref]. Therefore, in the prevention or treatment of AKI, ANP is expected to elicit renoprotective effect through diuresis and increase of glomerular filtration rate. Many clinical studies have been carried out in this context. However, administration of high-dose ANP reduces systemic blood pressure, thereby potentially cancelling out the above-mentioned renoprotective effect. Therefore, it is crucial to identify the optimal dose of ANP for the achievement of renoprotective effect. Based on the 2012 KDIGO Clinical Practice Guideline for AKI, the present guideline defined low-dose ANP as ≤ 50 ng/kg/min and high-dose ANP as ≥ 100 ng/kg/min.
As to assessment of therapeutic effect of ANP after development of AKI, there are two large-scale randomized controlled trials (RCTs) in which more than 200 participants were assigned into two arms. In both RCTs, high-dose ANP (200 ng/kg/min, 24 h) failed to reduce the incidence of RRT [bib_ref] Anaritide in acute tubular necrosis. Auriculin anaritide acute renal failure study group, Allgren [/bib_ref] [bib_ref] Atrial natriuretic factor in oliguric acute renal failure. Anaritide acute renal failure..., Lewis [/bib_ref]. In a later small-scale RCT using low-dose ANP (50 ng/kg/min, mean 127 h), the ANP group exhibited a significant reduction in the frequency of RRT as compared with the placebo group [bib_ref] Recombinant human atrial natriuretic peptide in ischemic acute renal failure: a randomized..., Sward [/bib_ref]. There have been no subsequent RCTs investigating the therapeutic effects of low-dose ANP for AKI. Therefore, the present guideline could not offer a definitive recommendation.
On the hand, concerning prevention of AKI by ANP, 13 RCTs were found (excluding AKI from contrast-induced nephropathy); all of these were Japanese clinical trials which used low-dose ANP. In most of them, the serum creatinine (sCr) values became significantly lower in the ANP group than in the control group. However, based on a strict application of the AKI diagnostic criteria from the 2012 KDIGO Clinical Practice Guideline for AKI, we found no studies in which the ANP group demonstrated a significant reduction in the incidence of AKI.
In a 2009 Cochrane review by Nigwekar et al. [bib_ref] Atrial natriuretic peptide for preventing and treating acute kidney injury, Nigwekar [/bib_ref] , lowdose ANP was reported to potentially reduce the need for RRT during prevention of AKI in major surgery, particularly cardiovascular surgery. However, the administration of highdose ANP for AKI treatment was shown to increase the frequency of adverse events such as hypotension and arrhythmia. The 2012 KDIGO Clinical Practice Guideline for AKI and a 2013 Cochrane review by Zacharias et al. [bib_ref] Interventions for protecting renal function in the perioperative period, Zacharias [/bib_ref] judged that the numbers of patients, the details of the randomization and blinding, and the rigor of the endpoint definitions were 1 3 insufficient in previous studies. Consequently, the effectiveness of low-dose ANP for the prevention of AKI was deemed inconclusive.
Although RCTs conducted in Japan have suggested that ANP is useful for the prevention of AKI, the quality of the research methods used was debatable. Therefore, we conclude that evidence for the effectiveness of low-dose ANP both for the prevention and treatment of AKI is insufficient, making a definitive recommendation impossible. The ANP preparations used in RCTs in Japan and in the West are carperitide (product name: Hamp ® ) and anaritide, respectively. Although carperitide has been available in Japan for the treatment of congestive heart failure since 1995, its use for the prevention or treatment of AKI is not covered by health insurance. Urodilatin (product name: Ularitide ® ) is ANPrelated hormone with four-amino-acid residues added to the N-terminus of ANP; it is produced in the distal nephron [bib_ref] Evidence that urodilatin, rather than ANP, regulates renal sodium excretion, Goetz [/bib_ref]. Clinical trials for ularitide have been conducted outside Japan [bib_ref] Significance of prophylactic urodilatin (INN: ularitide) infusion for the prevention of acute..., Brenner [/bib_ref] , and we did not mention it in the present guideline.
## Literature review
Searches were conducted for relevant studies published between January 2008 and August 2015. The literature published prior to 2008 was referenced from a 2009 Cochrane review by Nigwekar et al. [bib_ref] Atrial natriuretic peptide for preventing and treating acute kidney injury, Nigwekar [/bib_ref]. All RCTs related to contrast-induced nephropathy were excluded.
## Summary of evidence
Previous guidelines and systematic reviews do not recommend the use of loop diuretics for the prevention or treatment of AKI. There have been no new RCTs to contradict the results of previous clinical trials on loop diuretics for AKI.
## Commentary
Loop diuretics inhibit the sodium reabsorption and exert a diuretic effect by inhibiting the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle. Due to their theoretical effectiveness against acute kidney injury (AKI), clinical trials involving loop diuretics have long been performed. For example, by ensuring a diuretic effect, loop diuretics can prevent the tubular obstruction induced by cell shedding; in addition, they increase the medullary oxygenation and the renal medullary blood flow.
Three randomized controlled trials (RCTs) have compared the use of loop diuretics to that of a placebo or to standard therapy for the prevention of AKI [bib_ref] Effect of postoperative intravenous loop diuretic on renal function after major surgery, Hager [/bib_ref] [bib_ref] Lack of renoprotective effects of dopamine and furosemide during cardiac surgery, Lassnigg [/bib_ref] [bib_ref] Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of..., Mahesh [/bib_ref]. In a meta-analysis by Ho et al., loop diuretics failed to yield a significant improvement in the in-hospital mortality or in the percentage of patients who required renal replacement therapy (RRT) [bib_ref] Benefits and risks of furosemide in acute kidney injury, Ho [/bib_ref]. Moreover, although different RCTs have defined AKI differently, none has yet demonstrated a statistically significant reduction in the incidence of AKI in a loop diuretics group. In fact, in an RCT by Lassnigg et al., the loop diuretics group showed an increased incidence of renal dysfunction (14.6 vs 0%, p < 0.01) [bib_ref] Lack of renoprotective effects of dopamine and furosemide during cardiac surgery, Lassnigg [/bib_ref]. Based on the above, the present guideline does not recommend the use of loop diuretics for AKI prevention.
Seven RCTs have also compared the use of loop diuretics to that of a placebo or to standard therapy for the treatment of existing AKI [bib_ref] Frusemide in high doses in the treatment of acute renal failure, Cantarovich [/bib_ref] [bib_ref] High-dose frusemide in renal failure, Karayannopoulos [/bib_ref] [bib_ref] Furosemide in acute oliguric renal failure. A controlled trial, Kleinknecht [/bib_ref] [bib_ref] High dose frusemide in acute renal failure: a controlled trial, Brown [/bib_ref] [bib_ref] Loop diuretics in the management of acute renal failure: a prospective, double-blind,..., Shilliday [/bib_ref] [bib_ref] High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial, Cantarovich [/bib_ref] [bib_ref] Furosemide does not improve renal recovery after hemofiltration for acute renal failure..., Van Der Voort [/bib_ref]. In the above-mentioned meta-analysis, the loop diuretics group did not demonstrate a significant improvement in the in-hospital mortality or the percentage of patients who required RRT [bib_ref] Benefits and risks of furosemide in acute kidney injury, Ho [/bib_ref]. Although different RCTs have used different definitions of recovery from renal dysfunction, no RCT to date has demonstrated a significant increase in the percentage of patients who recovered from renal dysfunction in the loop diuretics group. Among the above-mentioned seven RCTs, two limited their subjects to AKI patients who underwent RRT; in both of these, the loop diuretics group did not demonstrate a significant reduction in the duration of the RRT or in the early recovery from renal dysfunction [bib_ref] High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial, Cantarovich [/bib_ref] [bib_ref] Furosemide does not improve renal recovery after hemofiltration for acute renal failure..., Van Der Voort [/bib_ref]. In addition, one meta-analysis showed that high-dose furosemide, which is often used to treat AKI, significantly increased symptoms such as tinnitus and temporary deafness (as compared with their incidence in control groups) [bib_ref] Meta-analysis of frusemide to prevent or treat acute renal failure, Ho [/bib_ref]. Based on the above, the present guideline does not recommend the use of loop diuretics for AKI treatment.
On the other hand, in AKI with a reduced urine output, loop diuretics may help to correct the fluid overload and to improve any electrolyte imbalance (such as hyperkalemia). However, there are currently no RCTs in which loop diuretics were administered specifically to treat AKI with these sorts of clinical manifestations-hence the above suggestion. The guidelines published by the KDIGO and NICE (National Institute for Health and Clinical Excellence) do not exclude the use of loop diuretics for the correction of fluid overload.
As for diuretics other than loop diuretics, RCTs have also examined mannitol for the prevention of AKI. In a metaanalysis by Yang et al., mannitol did not demonstrate evident effectiveness for the prevention of AKI [bib_ref] Intravascular administration of mannitol for acute kidney injury prevention: a systematic review..., Yang [/bib_ref]. In subsequent RCTs, the mannitol groups also failed to demonstrate significant improvement in their RRT initiation rates or in-hospital mortality [bib_ref] The effect of mannitol administration to kidney donor on short-term outcomes of..., Esfahani [/bib_ref] [bib_ref] Mannitol and renal dysfunction after endovascular aortic aneurysm repair procedures: a randomized..., Kalimeris [/bib_ref].
## Literature review
PubMed was searched for relevant studies published between January 2012 and April 2015, and papers related to the present CQ were identified from the search results. The literature published before January 2012 was referenced from the KDIGO Clinical Practice Guideline for AKI.
## Cq6-3: is low-dose dopamine recommended to prevent and treat aki?
Recommendation: We recommend not using lowdose dopamine to prevent or treat AKI.
## Strength of recommendation: 1
## Quality of evidence: a
## Summary of evidence
The KDIGO Clinical Practice Guideline for AKI suggests not to use low-dose dopamine to prevent or treat AKI. Since the publication of the KDIGO guideline, the efficacy of lowdose dopamine for the prevention of AKI has been examined in five RCTs. None of them have found low-dose dopamine to be effective.
## Commentary
Dopamine has been widely used to treat severely ill patients especially before 2000. The administration of dopamine, particularly low-dose (1-3 µg/kg/min), to healthy individuals, is considered to bring increases in renal vasodilation, in natriuresis, and in the glomerular filtration rate (GFR); therefore, low-dose dopamine had been anticipated to have a renoprotective effect. However, many of the clinical studies on dopamine have been found to be of poor quality due to a variety of issues, including small numbers of patients, unsuitable randomization, insufficient statistical powers, and unsuitable outcomes related to the clinical utility. Furthermore, due to the negative results in several randomized controlled trials (RCTs) that applied appropriate statistical powers and sample sizes, the use of dopamine is less commonly recommended today [bib_ref] Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial...., Bellomo [/bib_ref]. In addition, the renal vasodilation effect observed in healthy individuals has been found not to occur in acute kidney injury (AKI) patients [bib_ref] Low-dose' dopamine worsens renal perfusion in patients with acute renal failure, Lauschke [/bib_ref].
However, there is only limited evidence of harm caused by the use of low-dose dopamine to prevent or treat AKI. Although a 2005 meta-analysis by Friedrich et al. [bib_ref] Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction..., Friedrich [/bib_ref] did not find low-dose dopamine to significantly increase the incidence of adverse effects, there is many literature related to the adverse effects of dopamine. The potential adverse effects of dopamine include tachycardia, myocardial ischemia, a reduced intestinal blood flow, hypopituitarism, and the inhibition of the T-cell function.
Friedrich et al. conducted a meta-analysis of studies in which low-dose dopamine was used to treat or prevent AKI [bib_ref] Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction..., Friedrich [/bib_ref]. Their analysis of 61 randomized and semi-randomized trials determined that low-dose dopamine did not prolong survival, reduce the rate of dialysis initiation, or improve the renal function; in addition, the urine output was found to be only improved on the day the dopamine treatment was initiated. Based on the absence of positive studies about the use of dopamine to prevent and treat AKI, and in consideration of the information about the previously-described adverse effects of dopamine, the 2012 KDIGO Clinical Practice Guideline for AKI recommends that low-dose dopamine should not be used to prevent or treat AKI (1A).
For the present CQ, we searched the literature to retrieve new evidence that has emerged since the publication of the KDIGO guideline. The literature review and assessment of the abstracts revealed five trials that potentially contained new evidence not included in the existing meta-analyses [bib_ref] A prospective, randomized study to evaluate the efficacy of various diuretic strategies..., Shah [/bib_ref] [bib_ref] Efficacy and safety of high dose versus low dose furosemide with or..., Triposkiadis [/bib_ref] [bib_ref] Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction:..., Chen [/bib_ref] [bib_ref] Dopamine infusion and fluid administration improve renal function during laparoscopic surgery, Russo [/bib_ref] [bib_ref] Renal function after dopamine and fluid administration in patients with malignant obstructive..., Naranjo [/bib_ref]. The subjects were heart failure patients in three trials, laparoscopic surgery patients in one trial, and severe obstructive jaundice patients in one trial. In the three trials involving heart failure patients, dopamine failed to improve the outcomes. The trials involving laparoscopic surgery patients and severe obstructive jaundice patients did not examine any clinically useful outcomes.
Based on the above-described KDIGO Guideline recommendation and on the fact that no subsequent trials have demonstrated low-dose dopamine to be effective in the prevention or treatment of AKI, we offer the same quality of evidence and strength of recommendation as the KDIGO guideline.
## 3
## Literature review
## Cq6-4: what nutritional support is recommended for aki treatment?
## Recommendation:
We suggest that the administration of calorie and protein as nutritional support for AKI treatment be tailored to the severity and the underlying disease. For severe AKI, we recommend enteral nutrition whenever possible. Unless there is an advanced electrolyte imbalance, strict protein restriction is not necessary.
## Strength of recommendation: 2
## Quality of evidence: d
## Summary of evidence
Since the publication of the KDIGO Guideline, there have been no RCTs regarding nutritional support with subjects limited to AKI patients. The KDIGO Guideline recommends a calorie intake of 20-30 kcal/kg/day for AKI patients of any stage. The desired amounts of protein administration are 0.8-1.0 g/kg/day in hypermetabolic AKI patients who do not require dialysis, and 1.7 g/kg/day in hypermetabolic patients undergoing CRRT; when possible, nutrition through the enteral route is preferred.
## Commentary
Acute kidney injury (AKI) is the form of organ failure to which severely ill patients are most susceptible. Thus, the metabolism is greatly affected by the primary disease, the malnutrition severity, the presence of comorbid organ failure, and the performance of renal replacement therapy (RRT). Therefore, the target levels of the calorie intake and the necessary protein should ideally be tailored to the individual pathology; however, the specific efficacy of nutritional support for AKI has not been demonstrated [bib_ref] ESPEN guidelines on enteral nutrition: adult renal failure, Cano [/bib_ref] [bib_ref] Nutritional support for acute kidney injury, Li [/bib_ref].
Enteral nutrition is considered to be more effective than intravenous nutrition for intestinal mucosa maintenance, bacterial translocation, and the prevention of organ dysfunction. In meta-analyses of studies involving critically ill patients (including AKI patients), the initiation of enteral nutrition within 24 h after intensive care unit (ICU) admission was shown to significantly reduce the mortality and the incidence of infectious complications, and to shorten the hospital stay lengths; however, negative results have also been reported [bib_ref] Early enteral nutrition in acutely ill patients: a systematic review, Marik [/bib_ref] [bib_ref] Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill..., Heyland [/bib_ref] [bib_ref] Early enteral nutrition reduces mortality in trauma patients requiring intensive care: a..., Doig [/bib_ref] [bib_ref] Timing of (supplemental) parenteral nutrition in critically ill patients: a systematic review, Bost [/bib_ref]. In order to provide sufficient calorie, amino acids, and protein, a combination of intravenous and enteral nutrition is sometimes considered. A group of patients who only received vitamins and trace elements through enteral nutrition for the first 7 days following ICU admission and started intravenous nutrition on day 8 (late-initiation group) demonstrated a significant increase in early discharge (alive) from the ICU/ hospital, as well as reductions in the incidence of infections, the number of patients on mechanical ventilation for > 2 days, the duration of RRT, and the health care costs [bib_ref] Early versus late parenteral nutrition in critically ill adults, Casaer [/bib_ref].
The target calorie provision levels can be determined with a simple body mass conversion equation (25 kcal/kg/day), a calorie consumption prediction equation (Harris-Benedict equation), or the measurement of the energy consumption with an indirect calorimeter. In the first 7 days of sepsis treatment of patients who are not yet critically ill and are not malnourished, energy replenishment by enteral nutrition is recommended; however, supplemental intravenous nutrition to reach the target energy level is not recommended, as it can affect the prognosis adversely [bib_ref] Combination enteral and parenteral nutrition in critically ill patients: harmful or beneficial?..., Dhaliwal [/bib_ref]. The preferable method to reach the target energy level is to start with a small amount of energy and to increase it gradually based on factors such as the presence of aspiration and/or regurgitation of gastric contents and diarrhea. In obese patients, it must be noted that the use of the actual body weight in the prediction formula will cause an overestimation of the target energy provision level. Based on reports that intensive insulin therapy is not useful for mortality reduction, the initiation of insulin control at a blood glucose level ≥ 180 mg/dl and the setting of a target blood glucose level of 144-180 mg/dl can be considered valid in severe AKI [bib_ref] Hypoglycemia and risk of death in critically ill patients, Finfer [/bib_ref] [bib_ref] Hyper/hypoglycemia and acute kidney injury in critically ill patients, Fiaccadori [/bib_ref]. At the same time, AKI is reported to occur frequently in acute myocardial infarction patients with a blood glucose level ≥ 200 mg/dl at hospital admission [bib_ref] Admission hyperglycemia is an independent predictor of acute kidney injury in patients..., Moriyama [/bib_ref] [bib_ref] Admission glucose levels and the risk of acute kidney injury in nondiabetic..., Shacham [/bib_ref].
Protein restriction for the prevention or delay of RRT initiation is not recommended; however, it can be considered when an advanced electrolyte imbalance is present. In non-hypermetabolic AKI patients who do not require RRT, a protein provision of 0.8-1.0 g/kg/day is recommended. A protein provision of < 1 g/kg/day can induce negative nitrogen balance in patients undergoing RRT, due to factors such as the loss of approximately 10-15 g/day of amino acids, especially in continuous renal replacement therapy (CRRT). Therefore, in hypermetabolic patients undergoing CRRT, the KDIGO guideline recommends the administration of 1.7 g/ kg/day of protein to account for the amount of protein loss, while a protein intake of 2.5 g/kg/day is reportedly needed to achieve a positive nitrogen balance [bib_ref] Prospective randomized trial to assess caloric and protein needs of critically Ill,..., Scheinkestel [/bib_ref] [bib_ref] Metabolic and nutritional aspects of acute renal failure in critically ill patients..., Wooley [/bib_ref]. However, the excess provision of amino acids is indicated to potentially cause azotemia and prolonged RRT [bib_ref] Impact of early parenteral nutrition on metabolism and kidney injury, Gunst [/bib_ref]. During CRRT, commercially available dialysates and replacement fluids in Japan can cause hypokalemia and hypophosphatemia, and the latter is reported to delay weaning from mechanical ventilation; therefore, appropriate supplementation of potassium and/or phosphate through intravenous or enteral nutrition can be beneficial [bib_ref] ESPEN guidelines on enteral nutrition: adult renal failure, Cano [/bib_ref] [bib_ref] Practical implications of nutritional support during continuous renal replacement therapy, Marin [/bib_ref] [bib_ref] Nutrition in patients with acute renal failure, Bozfakioglu [/bib_ref] [bib_ref] Effect of hypophosphatemia on the withdrawal of mechanical ventilation in patients with..., Zhao [/bib_ref]. Outside of Japan, a CRRT dialysate containing 4.0 mEq/L potassium and 3.7 mg/ dl phosphorus has been developed [bib_ref] Electrolytes-enriched hemodiafiltration solutions for continuous renal replacement therapy in acute kidney injury:..., Besnard [/bib_ref]. However, a switch from CRRT to intermittent renal replacement therapy (IRRT) can easily cause an electrolyte imbalance, thereby calling for a reexamination of the content of the intravenous nutrition or enteral nutrition, including the total fluid volume; in particular, the risk of hyperkalemia must be kept in mind.
There is no clear evidence to recommend nutritional support for mild AKI without fluid overload, dehydration, or an electrolyte imbalance. The International Nutrition Survey conducted a recent international cross-sectional study on nutritional intervention, in which nine Japanese facilities participated. In this study, the calorie sufficiency rate, protein sufficiency rate, nutrition provision rate, and in nearly all other parameters in Japanese ICU patients were found to be below the global mean; in addition, the initiation of enteral nutrition was demonstrated to be late. Further research is needed.
## Literature review
PubMed was searched for relevant studies published between January 2012 and April 2016, and papers related to the present CQ were abstracted from the search results. The literature published before January 2012 was referenced from the KDIGO Clinical Practice Guideline for Acute Kidney Injury.
## Cq7-1: should blood purification for aki be initiated early?
Recommendation: There is little evidence to support the idea that the early initiation of blood purification for AKI improves the outcomes. The timing of the initiation should be decided in broad consideration of the clinical symptoms and disease conditions.
## Strength of recommendation: not graded
## Quality of evidence: c
## Summary of evidence
Out of nine relevant RCTs, three were performed at a single center (two involving patients having undergone cardiac surgery, one involving ICU patients); in all three RCTs, the early initiation of blood purification was associated with a reduced mortality. However, in a meta-analysis that included multicenter RCTs, the efficacy of the early initiation of blood purification was not supported.
## Commentary
There has been a consensus that emergent blood purification should be initiated for serious, life-threatening disease states. The KDIGO Clinical Practice Guideline for Acute Kidney Injury (AKI) also states that renal replacement therapy (RRT) should be initiated immediately in the event of potentially fatal changes in the body fluid, electrolyte, and acid-base balance (Not Graded). The indications for emergent RRT in clinical settings are listed in the [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref].
In observational studies from the 1960s that examined the timing of blood purification initiation, hemodialysis was demonstrated to improve the survival rates not when initiated after AKI had progressed to the point at which symptoms of uremia were present, but when initiated before that point. Since 2000, multiple observational studies have examined the initiation of blood purification when the blood urea nitrogen (BUN) is at a level even lower than that set in the aforementioned observational study. Bagshaw et al. conducted a meta-analysis of 15 clinical studies [including two randomized controlled trials (RCTs), four prospective observational studies, and nine retrospective observational studies] [bib_ref] A comparison of early versus late initiation of renal replacement therapy in..., Karvellas [/bib_ref]. Although the early initiation of blood purification was found to be associated with favorable outcomes, the timing of the initiation across the different studies examined was significantly heterogeneous; therefore, the early initiation of blood purification could not be definitively recommended.
The effect of the early initiation of blood purification on death has been examined in nine RCTs to date-including some that were not covered in Bagshaw et al.'s meta-analysis. Bouman et al. randomly assigned intensive care unit (ICU) patients presenting with oliguria to early high-volume, [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref] Indications for emergent renal replacement therapy Fluid overload resistant to diuretics Hyperkalemia or rapid elevation of serum potassium Uremic symptoms (pericarditis, consciousness disturbance with unknown etiology) Severe metabolic acidosis early low-volume, and late low-volume hemofiltration, with the survival at day 28 and the recovery of the renal function as primary endpoints; however, the three groups did not demonstrate any differences in their survival at day 28 or their recovery of the renal function [bib_ref] Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of..., Bouman [/bib_ref]. An Indian RCT involving patients who developed AKI in the hospital divided the subjects into two groups: a group in which dialysis was initiated early, when the BUN was ≥ 70 mg/dl or the serum creatinine (sCr) was ≥ 7 mg/dl (n = 102), and a control group in which dialysis was initiated upon fluid overload, hyperkalemia, or any other indication for emergent dialysis (ultimately, BUN: 100.9 ± 32.6 mg/dl, sCr: 10.41 ± 3.3 mg/ dl; n = 106). The comparisons of these two groups revealed no significant differences in the mortality or the recovery of the renal function [bib_ref] Earlier-start versus usual-start dialysis in patients with community-acquired acute kidney injury: a..., Jamale [/bib_ref]. In a Canadian open-label pilot trial [bib_ref] Comparison of standard and accelerated initiation of renal replacement therapy in acute..., Wald [/bib_ref] reported in 2015, patients with volume-replete AKI were randomly assigned to an early treatment group (n = 48) or a standard treatment group (n = 52); the mortality and the recovery of the renal function did not show any significant differences between the two groups. In two singlecenter RCTs involving post-cardiac surgery patients [bib_ref] Prophylactic dialysis in patients with renal dysfunction undergoing on-pump coronary artery bypass..., Durmaz [/bib_ref] [bib_ref] Early start on continuous hemodialysis therapy improves survival rate in patients with..., Sugahara [/bib_ref] , the early initiation of blood purification was associated with a reduced mortality. In a multicenter RCT (the HEROICS study) [bib_ref] Early high-volume hemofiltration versus standard care for post-cardiac surgery shock. The HEROICS..., Combes [/bib_ref] , patients experiencing shock requiring catecholamine support following cardiac surgery were randomly assigned to one of two groups: an early hemofiltration group (80 ml/kg/hr for 48 h) or a standard therapy group that included continuous hemodiafiltration (CHDF) if necessary (n = 112 for both groups). The two groups did not demonstrate a significant difference in their mortality or recovery of the renal function.
Two additional RCTs involving AKI patients in the ICU were reported in May 2016. In a French multicenter RCT (the AKIKI trial) [bib_ref] Initiation strategies for renal-replacement therapy in the intensive care unit, Gaudry [/bib_ref] , critically ill patients with severe AKI (stage 3) who required mechanical ventilation or catecholamine infusion were randomly assigned to one of two groups: an early initiation group (n = 311), in which RRT was initiated immediately after randomization, or a delayed initiation group (n = 308), in which RRT was not initiated until a criterion such as hyperkalemia, metabolic acidosis, pulmonary edema, a high BUN level (> 112 mg/dl), or oliguria (> 72 h) was met. The investigation of the utility of early RRT did not reveal a significant difference in the 60-day mortality of the two groups. In a German single-center RCT (the ELAIN trial) [bib_ref] Effect of early vs delayed initiation of renal replacement therapy on mortality..., Zarbock [/bib_ref] , 231 critically ill patients with stage 2 AKI and a plasma NGAL > 150 ng/ml were randomly assigned to an early group (initiation of RRT immediately after randomization) or a delayed group (initiation of RRT upon progression of AKI to stage 3 or the presence of any absolute indications); the assessment of the 90-day mortality found the latter to be significantly reduced in the early group. However, in the AKIKI trial, the RRT initiation in the early group was late, upon validation of stage 3 AKI; this timing corresponded to the delayed group in the ELAIN trial. Moreover, in the ELAIN trial, RRT was initiated as continuous renal replacement therapy (CRRT) and was performed for at least one week in all patients; however, in the AKIKI trial, CRRT was performed as the sole method of RRT in only 30% of patients. Although both of these RCTs examined the early initiation of RRT, it must be noted that they differed in their timing of initiation and their treatment modalities.
Among the nine RCTs reported to date, those that recorded the 28-or 30-day mortality were subjected to a meta-analysis; this meta-analysis did not support the efficacy of early initiation . Moreover, a meta-analysis that included the AKIKI [bib_ref] Initiation strategies for renal-replacement therapy in the intensive care unit, Gaudry [/bib_ref] and ELAIN [bib_ref] Effect of early vs delayed initiation of renal replacement therapy on mortality..., Zarbock [/bib_ref] trials was published [bib_ref] Timing of initiation of renal replacement therapy for acute kidney injury: a..., Xu [/bib_ref]. In this analysis of six RCTs, including the AKIKI and ELAIN trials as well as the three previously-mentioned RCTs involving non-post-cardiac surgery patients [bib_ref] Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of..., Bouman [/bib_ref] [bib_ref] Earlier-start versus usual-start dialysis in patients with community-acquired acute kidney injury: a..., Jamale [/bib_ref] [bib_ref] Comparison of standard and accelerated initiation of renal replacement therapy in acute..., Wald [/bib_ref] , the early initiation of blood purification did not show evident efficacy in terms of either mortality (relative risk 0.93, 95% CI 0.68-1.26) or recovery of the renal function (relative risk 0.88, 95% CI 0.48-1.62).
As of August 2016, the multicenter STARRT RCT [bib_ref] Standard versus accelerated initiation of renal replacement therapy in acute kidney injury..., Smith [/bib_ref] is ongoing. In France, a multicenter RCT assessing the utility of early initiation of RRT for septic AKI (corresponding to KDIGO stage 3) is ongoing (the IDEAL-ICU study [bib_ref] Impact on mortality of the timing of renal replacement therapy in patients..., Barbar [/bib_ref]. Both of these RCTs are larger in scale than previous investigations; therefore, the results obtained may lead to new directions about early initiation.
## Literature review
PubMed was searched for relevant studies published up to August 2015, and papers related to the present CQ were identified from the search results. Important manuscripts published after the search period [bib_ref] Initiation strategies for renal-replacement therapy in the intensive care unit, Gaudry [/bib_ref] [bib_ref] Effect of early vs delayed initiation of renal replacement therapy on mortality..., Zarbock [/bib_ref] [bib_ref] Timing of initiation of renal replacement therapy for acute kidney injury: a..., Xu [/bib_ref] were also incorporated into our recommendation.
## Cq7-2: what indicators should be used for discontinuation of the blood purification for aki?
Recommendation: Improvements in the clinical data and the urine output can be used to determine the timing of the blood purification discontinuation.
## Strength of recommendation: not graded
## Quality of evidence: c
## Summary of evidence
There have been no RCTs relevant to the discontinuation of blood purification. In three observational studies, the urine output and SOFA score were reported to be predictors of the possibility to wean patients from blood purification.
## Commentary
The blood purification for acute kidney injury (AKI) is stopped when the renal function sufficiently recovers. However, very few studies have examined the criteria for discontinuation of the blood purification for AKI. Our literature search found three observational studies that identified predictors of the possibility to wean patients from blood purification to date. Wu et al. retrospectively examined AKI patients (n = 304) who required renal replacement therapy (RRT) in the intensive care unit (ICU) after surgery [bib_ref] Risk factors of early redialysis after weaning from postoperative acute renal replacement..., Wu [/bib_ref]. Of the 94 patients in whom RRT was discontinued, 30 patients needed to resume it within 30 days; the duration of the RRT [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.02-1.10], the SOFA score at cessation (OR 1.44, 95% CI 1.13-1.83), oliguria (< 100 ml over 8 h) (OR 4.17, 95% CI 1.07-16.13), and an age over 65 years (OR 6.35, 95% CI 1.61-24.99) were identified as predictors of discontinuation failure. Kawarazaki et al. retrospectively examined AKI patients (n = 343) in Japanese ICUs who required continuous renal replacement therapy (CRRT) [bib_ref] Who may not benefit from continuous renal replacement therapy in acute kidney..., Kawarazaki [/bib_ref]. The comparison of an early recovery group (those who could discontinue CRRT within 48 h of initiation; n = 52) and a control group that excepted patients who died early (n = 239) revealed that the urine output upon CRRT initiation (ml/h) (OR 1.02, 95% CI 1.01-1.03), the SOFA score upon CRRT initiation (OR 0.87, 95% CI 0.78-0.96), and the time from ICU admission to CRRT initiation (in days) (OR 0.65, 95% CI 0.43-0.87) were significantly associated with early weaning from CRRT. It is of note that the urine output and SOFA score data were collected upon CRRT initiation and some patients who ceased the CRRT within 48 h may not have required blood purification; therefore, these results should be interpreted with caution.
The urine output is perhaps the most clinically emphasized predictor; one useful reference is a sub-analysis of the BEST study (n = 1,006), in which Uchino et al. examined AKI patients in ICUs in 23 countries [bib_ref] Discontinuation of continuous renal replacement therapy: a post hoc analysis of a..., Uchino [/bib_ref]. Those who did not require RRT for at least 7 days after the initial discontinuation were defined as the success group (n = 313), while those who had to resume RRT within 7 days after the initial discontinuation were defined as the repeat-RRT group (n = 216). Comparisons of the two groups revealed that the urine output was the most useful predictor of RRT weaning; the cutoff values for the use and the non-use of diuretics were 2330 ml/day (approximately 100 ml/h) and 436 ml/day (approximately 20 ml/h), respectively.
In the previously-cited sub-analysis of the BEST study, the serum creatinine (sCr) was also reported to be a significant predictor of weaning (OR 0.996, 95% CI 0.994-0.998). Creatinine is produced from creatine in the muscle tissue and is released into the blood. Both blood purification and the kidneys of the patients remove creatinine. The balance of creatinine between muscle production and elimination by blood purification and kidneys defines the sCr. Therefore, if the sCr level remains constant for at least 2-3 days, the production and elimination can be considered equal. The phenomenon by which the amount of sCr remains constant for several days before suddenly decreasing sharply without changing blood purification doses-called "spontaneous fall"-indicates that the renal function has recovered. In the VA/NIH ATN study [bib_ref] Intensity of renal support in critically ill patients with acute kidney injury, Palevsky [/bib_ref] that examined the association between the dialysis doses and the AKI outcomes, the recovery of the renal function was defined as a urine output > 30 ml/h in 6 h of collection or a spontaneous fall in the sCr. The following protocol was adopted: if the creatinine clearance in the 6-h urine collection was > 20 ml/ min, the CRRT was discontinued; if the creatinine clearance was < 12 ml/min, the CRRT was continued; if the creatinine clearance was between 12 and 20 ml/min, the decision to continue or discontinue the CRRT was left to the clinician.
However, in AKI and advanced chronic kidney disease (CKD), creatinine not only undergoes glomerular filtration, but is also excreted into urine due to re-secretion from the renal tubule; consequently, the creatinine clearance is greater than the actual glomerular filtration rate (GFR). In addition, if the sCr continues to decrease in 6-h urine collection, the sCr value selected for use in the GFR calculation may result in an overestimation or underestimation of the GFR. At the AKI recovery stage, in which the renal function fluctuates dynamically, the sCr and creatinine clearance are markedly unreliable; however, due to the absence of other appropriate endpoints, the sCr may be an acceptable basis upon which to determine whether to discontinue the blood purification, with the above-described background considered.
## Literature review
PubMed was searched for relevant studies published up to August 2015, and papers related to the present CQ were identified from the search results.
## Cq7-3: how should the blood purification dose be determined for aki?
Recommendation: There is no evidence allowing for the recommendation of an optimal blood purification dose. The does must be determined individually by considering disease conditions.
## Strength of recommendation: 2
## Quality of evidence: b
## Summary of evidence
Increasing the dose of blood purification for AKI to higher than the level recommended as the international standard (20-25 ml/kg/h) has not been reported to improve the AKI outcomes. No RCTs have compared the blood purification dose covered by health insurance in Japan (10-15 ml/kg/h) to that recommended internationally; only two observational studies have evaluated this issue, and neither observed a significant difference in mortality. Thus, there is no definitive evidence to support the need to change the dose used in Japan to that recommended as the international standard.
## Commentary
The appropriate dose of renal replacement therapy (RRT) for acute kidney injury (AKI) has been investigated so far. Several studies have reported that increased doses do not lead to improved outcomes [bib_ref] Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of..., Bouman [/bib_ref] [bib_ref] Intensity of renal support in critically ill patients with acute kidney injury, Palevsky [/bib_ref] [bib_ref] Standard versus high-dose CVVHDF for ICU-related acute renal failure, Tolwani [/bib_ref] [bib_ref] Intensity of continuous renal-replacement therapy in critically ill patients, Bellomo [/bib_ref] ; in addition, there is insufficient evidence to determine an optimal dose.
The dose of continuous renal replacement therapy (CRRT) for AKI was firstly examined by a 2000 study by Ronco et al. [bib_ref] Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute..., Ronco [/bib_ref]. A total of 425 AKI patients who required continuous hemofiltration (CHF) were randomly assigned a filtration flow rate (QF) of 20, 35, or 45 ml/kg/h. The comparisons of the three groups revealed respective survival rates of 41, 57, and 58%; the 20 ml/kg/h group demonstrated a significantly lower survival rate than the other two groups, while there was no significant difference between the 35 ml/ kg/h group and the 45 ml/kg/h group. Since then, two multicenter, large-scale randomized controlled trials (RCTs) have been reported [fig_ref] CQ6- 2: Are loop diuretics recommended for the prevention and treatment of AKI?Recommendation [/fig_ref] [bib_ref] Intensity of renal support in critically ill patients with acute kidney injury, Palevsky [/bib_ref] [bib_ref] Intensity of continuous renal-replacement therapy in critically ill patients, Bellomo [/bib_ref] ; unlike in the trial reported by Ronco et al., these two RCTs found that increased doses of RRT for AKI did not improve the outcomes. In the ATN study [bib_ref] Intensity of renal support in critically ill patients with acute kidney injury, Palevsky [/bib_ref] , 1124 AKI patients who required RRT were randomly assigned to a standard therapy group or an intensive therapy group, and the two groups' mortality and recovery of the renal function were compared. In the standard therapy group, hemodynamically stable patients underwent hemodialysis (HD) three times a week, while hemodynamically unstable patients either underwent continuous hemodiafiltration (CHDF) at a rate of 25 ml/kg/h or received sustained low-efficiency dialysis (SLED) three times a week. In the intensive therapy group, hemodynamically stable patients underwent HD six times a week, while hemodynamically unstable patients either underwent CHDF at a rate of 35 ml/kg/h or received SLED six times a week. The comparisons revealed no significant differences in the mortality or recovery of the renal function of the two groups. In the RENAL study [bib_ref] Intensity of continuous renal-replacement therapy in critically ill patients, Bellomo [/bib_ref] , 1508 AKI patients were randomly assigned to an intensive therapy group (35 ml/kg/h CHDF) or a standard therapy group (25 ml/kg/h CHDF), and the two groups' mortality and recovery of the renal function were compared. Likewise, the two groups in this study did not demonstrate any significant differences in their mortality or recovery of the renal function. Based on the results of two multicenter, large scale RCTs, the recent KDIGO Clinical Practice Guideline for AKIrecommends a CRRT dose of 20-25 ml/kg/h. However, both the ATN and RENAL studies examined AKI collectively with a wide variety of causes, including ischemia, nephrotoxic substances, and sepsis; to date, there have been very few studies of the optimal doses in function of the underlying disease. Regarding septic AKI, four RCTs [bib_ref] Serum IL-6 and IL-1-ra with sequential organ failure assessment scores in septic..., Ghani [/bib_ref] [bib_ref] A pilot randomized study comparing high and low volume hemofiltration on vasopressor..., Boussekey [/bib_ref] [bib_ref] Effect of the intensity of continuous renal replacement therapy in patients with..., Zhang [/bib_ref] have compared the CRRT outcomes from doses of 35-45 ml/kg/h and larger doses (65-100 ml/kg/h); in these RCTs, increased doses were not found to improve the outcomes. Based on the above, there is currently no definitive evidence allowing for the recommendation of optimal doses according to the underlying disease. However, in the event of acute hyperkalemia-such as in tumor lysis syndrome-the blood purification doses must be temporarily increased or otherwise tailored to the individual pathologies.
The common dose of CRRT for AKI in Japan (10-15 ml/ kg/h) is generally smaller than the recommended dose outside of Japan (20-25 ml/kg/h). This seems to be because Japanese health insurance only covers a dialysis dose of approximately 15 L/day. No RCTs have compared the standard Japanese dialysis dose of 10-15 ml/kg/h with the recommended international dose of 20-25 ml/kg/h; however, two retrospective observational studies [bib_ref] Low-dose continuous renal replacement therapy for acute kidney injury, Fujii [/bib_ref] [bib_ref] Validity of low-intensity continuous renal replacement therapy*, Uchino [/bib_ref] have concluded that the standard Japanese dose did not lead to worse outcomes. As mentioned above, although reported an optimal blood purification dose of 35 ml/kg/h, this was controverted by two subsequent large-scale RCTs. However, there is currently insufficient evidence to determine that 20-25 ml/kg/h is an optimal dose, and the standard Japanese dose must be examined as well. Moreover, while it is unknown whether the reduction of doses to below the standard Japanese dose of 10-15 ml/kg/h would worsen the outcomes, we would like to address that there is no evidence to recommend the reduction of dialysis doses.
The appropriate doses of HD for AKI have been examined in three RCTs [bib_ref] Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of..., Bouman [/bib_ref] [bib_ref] Intensity of renal support in critically ill patients with acute kidney injury, Palevsky [/bib_ref] [bib_ref] Daily hemodialysis and the outcome of acute renal failure, Schiffl [/bib_ref]. In those, the different groups demonstrated no significant differences in their mortality or recovery of the renal function. For intermittent renal replacement therapy (IRRT) or extended RRT, the KDIGO Clinical Practice Guideline for AKI recommends a weekly standardized dialysis dose (Kt/V) of 3.9. However, there is insufficient evidence to establish this as the optimal hemofiltration dose for AKI. An RCT that compared HD and predilution on-line HF rather than HD doses was reported in 2012 [bib_ref] Intermittent high-volume predilution on-line haemofiltration versus standard intermittent haemodialysis in critically ill..., Skofic [/bib_ref]. The mean volume of infusate in predilution on-line HF was 81 L; the HF and HD groups did not demonstrate significant differences in their mortality or recovery of the renal function. In a prospective study by Schiffl et al. that compared a daily HD group with an alternate-day HD group [bib_ref] Daily hemodialysis and the outcome of acute renal failure, Schiffl [/bib_ref] , the daily HD group demonstrated a significantly lower mortality and a significantly earlier recovery of the renal function. However, several issues have been raised with this study: the HD doses were extremely low, and the randomization was inadequate. The Hannover Dialysis Outcomes Study randomly assigned 156 AKI patients to a standard dialysis group and an intensified dialysis group, and compared the mortality and the recovery of the renal function in the two groups [bib_ref] The Hannover dialysis outcome study: comparison of standard versus intensified extended dialysis..., Faulhaber-Walter [/bib_ref]. The standard dialysis was dosed to maintain a blood urea nitrogen (BUN) level of 120-150 mg/ dl, while the intensified dialysis was dosed to achieve a target BUN level of < 90 mg/dl. However, the two groups did not demonstrate significant differences in their mortality or recovery of the renal function.
## Literature review
PubMed was searched for relevant studies published up to July 2015, and papers related to the present CQ were identified from the search results.
## Cq7-4: should blood purification for aki be performed continuously or intermittently?
Recommendation: In hemodynamically stable patients, blood purification may be performed either continuously or intermittently. In hemodynamically unstable patients, continuous blood purification is preferable.
## Hemodynamically stable patients:
Strength of recommendation: 2
## Quality of evidence: b
Hemodynamically unstable patients:
## Strength of recommendation: not graded
## Quality of evidence: c
## Summary of evidence
Several RCTs and meta-analyses have compared CRRT with IRRT, but none have demonstrated differences in mortality. It must be noted that some of these RCTs excluded hemodynamically unstable patients, and that none limited their subjects to hemodynamically unstable patients. In meta-analyses of sustained low-efficiency dialysis (SLED), which combines the advantages of both CRRT and IRRT, comparisons with CRRT revealed no significant difference in the mortality.
## Commentary
The optimal modality of blood purification for acute kidney injury (AKI) has been investigated. The primary continuous and intermittent modalities used in Japan are continuous hemodiafiltration (CHDF) and hemodialysis (HD), respectively [bib_ref] Current status of blood purification in critical care in Japan, Kaizu [/bib_ref]. The choice of therapy is generally based on a consideration of various factors, including the patient's hemodynamics and anticoagulation, the facility's equipment, and the staff's experience and manpower. The advantages and disadvantages of these modalities are summarized in the Table 12. The greatest advantage of continuous renal replacement therapy (CRRT), which is mostly conducted with CHDF in Japan, is that its effects on the hemodynamics are minimized as it removes the body fluids and solutes gradually. CRRT is also associated with a reduced risk of cerebral edema [bib_ref] Continuous renal replacement therapies in patients with acute neurological injury, Davenport [/bib_ref]. However, continuous blood purification not only restrains the patient over a long period of time, but also places a great burden on the medical care staff. In addition, the continuous administration of anticoagulants increases the risk of hemorrhage. Intermittent renal replacement therapy (IRRT), which is mostly conducted with HD in Japan, removes the body fluids and solutes quickly, thereby easily affecting the hemodynamics and increasing the risk of cerebral edema. However, in addition to being completed faster, IRRT places a lesser burden on the staff and poses a lower risk of hemorrhage than CRRT. As CRRT and IRRT possess evidently different characteristics, direct comparisons of their utility have been found to be worthless [bib_ref] Pro/con debate: continuous versus intermittent dialysis for acute kidney injury: a never-ending..., Vanholder [/bib_ref].
For the present CQ, we abstracted a total of 15 randomized controlled trials (RCTs) [bib_ref] A randomized cross-over comparison of the hemodynamic response to intermittent hemodialysis and..., Misset [/bib_ref] [bib_ref] A randomized clinical trial of continuous versus intermittent dialysis for acute renal..., Mehta [/bib_ref] [bib_ref] Effects of continuous haemofiltration vs intermittent haemodialysis on systemic haemodynamics and splanchnic..., John [/bib_ref] [bib_ref] Continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD)-what is the procedure..., Gasparovic [/bib_ref] [bib_ref] A randomized controlled trial comparing intermittent with continuous dialysis in patients with..., Augustine [/bib_ref] [bib_ref] Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: a..., Kielstein [/bib_ref] [bib_ref] Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute renal..., Kumar [/bib_ref] [bib_ref] Comparison of continuous and intermittent renal replacement therapy for acute renal failure, Uehlinger [/bib_ref] [bib_ref] Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients..., Vinsonneau [/bib_ref] [bib_ref] Comparison of sustained hemodiafiltration with continuous venovenous hemodiafiltration for the treatment of..., Abe [/bib_ref] [bib_ref] Intermittent versus continuous renal replacement therapy for acute kidney injury patients admitted..., Lins [/bib_ref] [bib_ref] A pilot randomized controlled comparison of extended daily dialysis with filtration and..., Baldwin [/bib_ref] [bib_ref] Comparison of sustained hemodiafiltration with acetate-free dialysate and continuous venovenous hemodiafiltration for..., Abe [/bib_ref] [bib_ref] Sustained low efficiency dialysis using a single-pass batch system in acute kidney..., Schwenger [/bib_ref] [bib_ref] The effect of continuous versus intermittent renal replacement therapy on the outcome..., Schefold [/bib_ref] and eight metaanalyses [bib_ref] Continuous versus intermittent renal replacement therapy: a meta-analysis, Kellum [/bib_ref] [bib_ref] Acute renal failure in the intensive care unit: a systematic review of..., Tonelli [/bib_ref] [bib_ref] Renal replacement therapy in patients with acute renal failure: a systematic review, Pannu [/bib_ref] [bib_ref] Continuous versus intermittent renal replacement therapy for critically ill patients with acute..., Bagshaw [/bib_ref] [bib_ref] A systematic review of continuous renal replacement therapy and intermittent haemodialysis in..., Ghahramani [/bib_ref] [bib_ref] Choice of renal replacement therapy modality and dialysis dependence after acute kidney..., Schneider [/bib_ref] [bib_ref] Intermittent versus continuous renal replacement therapy for acute renal failure in adults, Rabindranath [/bib_ref] [bib_ref] Extended daily dialysis versus continuous renal replacement therapy for acute kidney injury:..., Zhang [/bib_ref] that compared the utility of the two modalities of renal replacement therapy (RRT) for AKI. A primary meta-analysis was reported as part of a Cochrane joint project in 2008 [bib_ref] Intermittent versus continuous renal replacement therapy for acute renal failure in adults, Rabindranath [/bib_ref]. An analysis of 15 RCTs involving a total of 1550 AKI patients who required RRT revealed no significant differences between CRRT and IRRT in the in-hospital mortality, the ICU mortality, or the discontinuation of RRT in surviving patients. Several other meta-analyses have demonstrated similar results [bib_ref] Acute renal failure in the intensive care unit: a systematic review of..., Tonelli [/bib_ref] [bib_ref] Renal replacement therapy in patients with acute renal failure: a systematic review, Pannu [/bib_ref] [bib_ref] Continuous versus intermittent renal replacement therapy for critically ill patients with acute..., Bagshaw [/bib_ref] [bib_ref] A systematic review of continuous renal replacement therapy and intermittent haemodialysis in..., Ghahramani [/bib_ref]. However, in a meta-analysis of 13 studies (including three RCTs) by Kellum et al., while CRRT and IRRT yielded no significant difference in mortality, adjustments for the severity of the illness and the study quality revealed that the risk of death was significantly reduced in CRRT [relative risk (RR) 0.72, 95% confidence interval (CI) 0.60-0.87] [bib_ref] Continuous versus intermittent renal replacement therapy: a meta-analysis, Kellum [/bib_ref]. In Schneider et al.'s meta-analysis of 23 studies (including 7 RCTs) related to the rates of dialysis dependence, although the risk of dialysis dependence was significantly higher in patients undergoing IRRT (RR 1.73, 95% CI 1. , there was no significant difference when the analysis was limited to RCTs [bib_ref] Choice of renal replacement therapy modality and dialysis dependence after acute kidney..., Schneider [/bib_ref]. The KDIGO Guideline and the Surviving Sepsis Campaign Guideline (SSCG) 2012 [bib_ref] Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic..., Dellinger [/bib_ref] considered the same matter as the present CQ and gave similar recommendations based on the results described above.
It must be noted that two RCTs [bib_ref] A randomized clinical trial of continuous versus intermittent dialysis for acute renal..., Mehta [/bib_ref] [bib_ref] Intermittent versus continuous renal replacement therapy for acute kidney injury patients admitted..., Lins [/bib_ref] excluded hemodynamically unstable patients. Theoretically and empirically, CRRT has been considered useful, and has therefore been used, for the treatment of hemodynamically unstable patients. No RCT has ever compared CRRT and IRRT in hemodynamically unstable patients. Based on the above, our expert opinion is that CRRT is preferable for hemodynamically unstable patients. However, there is no standard opinion on the degree of instability at which CRRT should be chosen. In addition, many hemodynamically unstable patients are of course critically ill and may have comorbid coagulation disorders, such as disseminated intravascular coagulation (DIC). HD may be more useful in patients with an advanced bleeding tendency, as it can be performed with only a short course of anticoagulant administration. In addition, the selection of a modality must take into account the equipment at the facility, the staff's experience and resources, and a variety of other factors unrelated to the patient. The modality should be decided by a physician with sufficient knowledge and experience of blood purification (i.e. an intensive care specialist, nephrologist, or dialysis physician) according to the patient's disease condition.
Sustained low-efficiency dialysis (SLED), or extended daily dialysis (EDD), uses the lower blood flow and the lower dialysate flow, and is performed more frequently than standard HD; it incorporates the advantages of both CRRT and IRRT, and is now performed widely. Although no RCTs have compared SLED and intermittent hemodialysis (IHD), the effects of SLED on the hemodynamics are reported to be the same as those of CRRT [bib_ref] The hemodynamic tolerability and feasibility of sustained low efficiency dialysis in the..., Fieghen [/bib_ref]. Recently, Zhang et al. conducted a meta-analysis of 17 studies (including 7 RCTs) that compared EDD and CRRT for AKI [bib_ref] Extended daily dialysis versus continuous renal replacement therapy for acute kidney injury:..., Zhang [/bib_ref]. In the RCTs, no significant difference was observed in the mortality of the different groups; however, in the 10 observational studies, the risk of death was lower with EDD (RR 0.86, 95% CI 0.74-1.00). No significant difference in the recovery of the renal function was evidenced by the RCTs or the observational studies. By establishing appropriate implementation conditions, not only CRRT but also EDD may be performed in hemodynamically unstable patients.
## Literature review
PubMed was searched for relevant studies published up to July 2015, and papers related to the present CQ were identified from the search results.
## Cq7-5: should nafamostat mesilate be used as an anticoagulant in blood purification for aki?
Recommendation: Nafamostat mesilate may be considered for patients with a high risk of bleeding. For patients with active bleeding, blood purification without the use of anticoagulants may also be considered.
## Strength of recommendation: not graded
## Quality of evidence: c
## Summary of evidence
There have only been two RCTs involving the use of nafamostat mesilate as an anticoagulant during blood purification for AKI (nafamostat mesilate versus no anticoagulant). No significant difference was observed in the survival outcomes. Two observational studies that compared the use of nafamostat mesilate and heparin also found no significant difference in the survival outcomes.
## Commentary
Blood coagulates when it comes into contact with anything including artificial materials other than vascular endothelial cells. Therefore, renal replacement therapy (RRT)-which involves extracorporeal circulation-usually requires the use of anticoagulants. Patients with severe acute kidney injury (AKI) requiring RRT frequently present with a hemorrhagic complication. Thus, the use of anticoagulants that pose the lowest possible risk of bleeding is required. Japanese health insurance currently covers four types of anticoagulants for RRT: unfractionated heparin, low molecular weight heparin (LMWH), nafamostat mesilate (NM), and argatroban. Citrate is widely used as an anticoagulant outside of Japan. Although it can be used in Japan as well, this is not frequent, since its use as an anticoagulant for RRT is considered offlabel. In the BEST kidney study [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] , which included an examination of the anticoagulants used in continuous renal replacement therapy (CRRT) for AKI, the most commonly used anticoagulant was unfractionated heparin (42.9% of patients), followed by no anticoagulant (33.1%), citrate (9.9%), NM (6.1%), and LWMH (4.4%).
When possible, CRRT without anticoagulation is the safest option for AKI patients, as it does not increase the risk of bleeding; however, the lifespans of the filter and circuit may be shortened, and CRRT cannot be performed without anticoagulation in all patients. In Japan, NM is widely used as an anticoagulant in CRRT for AKI since it has a short half-life and is associated with a relatively lower risk of bleeding than other anticoagulants. However, it has not been approved only in the limited countries. In addition, NM causes adverse effects, including agranulocytosis, hyperkalemia, and anaphylactoid reactions [bib_ref] Agranulocytosis in a haemodialysed patient induced by a proteinase inhibitor, nafamostate mesilate, Okada [/bib_ref] [bib_ref] Mechanisms of hyperkalemia caused by nafamostat mesilate, Muto [/bib_ref] [bib_ref] Anaphylactoid reaction induced by nafamostat mesilate in a hemodialysis patient, Maruyama [/bib_ref] [bib_ref] Anaphylactoid reaction induced by a protease inhibitor, nafamostat mesilate, following nine administrations..., Higuchi [/bib_ref]. In Japan, unfractionated heparin is the most commonly used anticoagulant for hemodialysis (HD) in chronic dialysis patients. However, due to concerns over the risk of bleeding, it is seldom used as an anticoagulant in CRRT for AKI in Japan. Similarly, although LMWH is also associated with a lower risk of bleeding than unfractionated heparin, the test that indicates anticoagulant action (the anti-Xa assay) is not common. Therefore, LMWH is infrequently used as an anticoagulant in CRRT for AKI [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref].
Five studies have examined the use of NM as an anticoagulant in CRRT for AKI [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] [bib_ref] Ability of nafamostat mesilate to prolong filter patency during continuous renal replacement..., Lee [/bib_ref] [bib_ref] Nafamostat mesilate as an anticoagulant during continuous renal replacement therapy in patients..., Choi [/bib_ref] [bib_ref] The role of nafamostat mesylate in continuous renal replacement therapy among patients..., Baek [/bib_ref] [bib_ref] Nafamostat mesilate for anticoagulation in continuous renal replacement therapy, Hwang [/bib_ref]. Only two of these studies were randomized controlled trials (RCTs) [bib_ref] Ability of nafamostat mesilate to prolong filter patency during continuous renal replacement..., Lee [/bib_ref] [bib_ref] Nafamostat mesilate as an anticoagulant during continuous renal replacement therapy in patients..., Choi [/bib_ref] , while one was a prospective observational study [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] and two were retrospective studies [bib_ref] The role of nafamostat mesylate in continuous renal replacement therapy among patients..., Baek [/bib_ref] [bib_ref] Nafamostat mesilate for anticoagulation in continuous renal replacement therapy, Hwang [/bib_ref]. Both of the RCTs compared NM with no coagulation, and neither observed a significant difference in the survival outcomes of the groups.
In one RCT, the lifetime of the hemofilter was found to be significantly longer with NM than without coagulation. The two groups demonstrated no significant difference in their hemorrhagic complications. A prospective observational study the BEST kidney study and a retrospective study by Hwang et al. [bib_ref] Nafamostat mesilate for anticoagulation in continuous renal replacement therapy, Hwang [/bib_ref] also observed no significant differences in the survival outcomes. In a retrospective observational study in which continuous hemodiafiltration (CHDF) was performed without anticoagulation in patients at a high risk of bleeding, Baek et al. reported that only NM was used when the hemofilter lifespan was less than 12 h [bib_ref] The role of nafamostat mesylate in continuous renal replacement therapy among patients..., Baek [/bib_ref]. The in-hospital mortality was significantly lower in the NM group (anticoagulation-free group versus NM group: 64.6 vs 41.9%, p = 0.003), while there was no significant difference between the groups in the transfusion volume (anticoagulation-free group versus NM group: 0.7 units/day versus 0.7 units/day). In addition to the five studies cited above, another study in which NM was compared with heparin was recently published in Japan [bib_ref] Comparison of nafamostat mesilate and unfractionated heparin as anticoagulants during continuous renal..., Makino [/bib_ref]. Despite being a retrospective observational study, its analysis featured propensity scorematched cohorts. Although the mortality was not examined, hemorrhagic complications were significantly less frequent in the NM group, while there was no significant difference in the filter lifespan.
Citrate is commonly used as an anticoagulant in CRRT for AKI outside of Japan. Although the safety and efficacy of citrate have been assessed, its use as an anticoagulant in CRRT for AKI is considered off-label in Japan. Although no RCTs have compared citrate with NM, 10 RCTs have compared citrate and unfractionated heparin [bib_ref] Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized..., Monchi [/bib_ref] [bib_ref] Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically..., Kutsogiannis [/bib_ref] [bib_ref] Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low..., Betjes [/bib_ref] [bib_ref] A pilot randomized controlled crossover study comparing regional heparinization to regional citrate..., Fealy [/bib_ref] [bib_ref] Regional citrate anticoagulation reduces polymorphonuclear cell degranulation in critically ill patients treated..., Tiranathanagul [/bib_ref] [bib_ref] Regional citrate versus systemic heparin for anticoagulation in critically ill patients on..., Hetzel [/bib_ref] [bib_ref] Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill..., Schilder [/bib_ref] [bib_ref] Randomised trial of software algorithm driven regional citrate anticoagulation versus heparin in..., Brain [/bib_ref] [bib_ref] A randomized controlled trial of regional citrate versus regional heparin anticoagulation for..., Gattas [/bib_ref] [bib_ref] Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with..., Stucker [/bib_ref] ; in the six RCTs that examined the survival outcomes , no significant difference was observed. Eight studies found the filter lifespan to be significantly longer with citrate [bib_ref] Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized..., Monchi [/bib_ref] [bib_ref] Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically..., Kutsogiannis [/bib_ref] [bib_ref] Regional citrate anticoagulation reduces polymorphonuclear cell degranulation in critically ill patients treated..., Tiranathanagul [/bib_ref] [bib_ref] Regional citrate versus systemic heparin for anticoagulation in critically ill patients on..., Hetzel [/bib_ref] [bib_ref] Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill..., Schilder [/bib_ref] [bib_ref] Randomised trial of software algorithm driven regional citrate anticoagulation versus heparin in..., Brain [/bib_ref] [bib_ref] A randomized controlled trial of regional citrate versus regional heparin anticoagulation for..., Gattas [/bib_ref] [bib_ref] Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with..., Stucker [/bib_ref] , while two observed no significant difference [bib_ref] Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low..., Betjes [/bib_ref] [bib_ref] A pilot randomized controlled crossover study comparing regional heparinization to regional citrate..., Fealy [/bib_ref]. The frequency of hemorrhagic complications with citrate and unfractionated heparin was found to be either equal, or significantly lower with citrate. Five more RCTs examined the use of LMWH as an anticoagulant in CRRT [bib_ref] A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant..., Reeves [/bib_ref] [bib_ref] Enoxaparin vs. unfractionated heparin for anticoagulation during continuous veno-venous hemofiltration: a randomized..., Joannidis [/bib_ref] [bib_ref] Citrate anticoagulation for continuous venovenous hemofiltration, Oudemans-Van Straaten [/bib_ref] [bib_ref] Enoxaparin versus unfractioned heparin as anticoagulant for continuous venovenous hemodialysis: a randomized..., Garces [/bib_ref] [bib_ref] Randomized controlled trial to evaluate regional citrate anticoagulation plus lowdose of dalteparin..., Wu [/bib_ref] ; three of them [bib_ref] A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant..., Reeves [/bib_ref] [bib_ref] Enoxaparin vs. unfractionated heparin for anticoagulation during continuous veno-venous hemofiltration: a randomized..., Joannidis [/bib_ref] [bib_ref] Enoxaparin versus unfractioned heparin as anticoagulant for continuous venovenous hemodialysis: a randomized..., Garces [/bib_ref] compared LMWH with unfractionated heparin, while two [bib_ref] Citrate anticoagulation for continuous venovenous hemofiltration, Oudemans-Van Straaten [/bib_ref] [bib_ref] Randomized controlled trial to evaluate regional citrate anticoagulation plus lowdose of dalteparin..., Wu [/bib_ref] compared LMWH with citrate. Only one of the five RCTs [bib_ref] Citrate anticoagulation for continuous venovenous hemofiltration, Oudemans-Van Straaten [/bib_ref] examined the clinical outcomes; in this RCT, the mortality was significantly lower in the citrate group. With regard to bleeding, only one RCT found a significant difference [bib_ref] Enoxaparin versus unfractioned heparin as anticoagulant for continuous venovenous hemodialysis: a randomized..., Garces [/bib_ref] ; however, the results related to the filter lifespan varied across studies.
## Literature review
PubMed was searched for relevant studies published up to December 2015, and papers related to the present CQ were identified from the search results. The study by Makino et al. [bib_ref] Comparison of nafamostat mesilate and unfractionated heparin as anticoagulants during continuous renal..., Makino [/bib_ref] , which was published after the search period, was found through a hand search.
## Cq7-6: what membrane material should be chosen for blood purification in aki?
Recommendation: There is no evidence for the recommendation of a specific membrane material to improve the outcomes.
## Strength of recommendation: 2
Quality of evidence: C
## Summary of evidence
The majority of blood purification filters currently used in Japan are biocompatible high-flux membranes. However, no studies have found the differences in these membranes to affect the AKI outcomes or the recovery of the renal function. For AKI-and particularly septic AKI-blood purification is performed in Japan to improve hypercytokinemia by using the principle of adsorption; however, there is no high-level evidence for the effect of this blood purification method on the outcomes.
## Commentary
The blood purification membrane materials currently used in Japan include cellulose triacetate (CTA), polymethyl methacrylate (PMMA), ethylene vinyl alcohol (EVAL), polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), and polyester polymer alloy (PEPA). These materials will activate complement system less than cuprophan and other regenerated celluloses that have been used since the 1960s, and are considered to be highly biocompatible membranes. Many of these membranes currently in use have been developed as high-flux (HF) membranes, with the goal to remove the β2 microglobulin (β2MG) and other smallmolecule proteins.
The therapeutic effects of each membrane material have been compared in a few small-scale randomized clinical trials (RCTs) that primarily featured comparisons of regenerated cellulose with synthetic polymeric membranes. These RCTs have also featured comparisons of HF membranes with the low-flux (LF) membranes that were developed prior to the existence of HF membranes. With regard to the present CQ, we found seven relevant RCTs that compared different types of membranes [bib_ref] Biocompatible membranes in acute renal failure: prospective case-controlled study, Schiffl [/bib_ref] [bib_ref] Haemodialysis-membrane biocompatibility and mortality of patients with dialysis-dependent acute renal failure: a..., Jorres [/bib_ref] [bib_ref] Comparison of cellulose diacetate and polysulfone membranes in the outcome of acute..., Gastaldello [/bib_ref] [bib_ref] Patient survival and renal recovery in acute renal failure: randomized comparison of..., Albright [/bib_ref] [bib_ref] Hemodynamics and survival of patients with acute renal failure treated by continuous..., Jones [/bib_ref] [bib_ref] Lowflux versus high-flux synthetic dialysis membrane in acute renal failure: prospective randomized..., Ponikvar [/bib_ref] [bib_ref] Hemodialysis membrane with a high-molecularweight cutoff and cytokine levels in sepsis complicated..., Haase [/bib_ref].
Five of these RCTs primarily compared the effects of the differences in the membranes' biocompatibility, along with the effects of the differences between LF and HF membranes. Schiff et al. [bib_ref] Biocompatible membranes in acute renal failure: prospective case-controlled study, Schiffl [/bib_ref] examined the recycled cellulose Cuprophan ® (LF membrane) and the synthetic polymer polyacrylonitrile (PAN; HF membrane) in 2 groups of 26 postoperative acute kidney injury (AKI) patients each, and compared the results of the two groups. In later trials, Jörres et al. [bib_ref] Haemodialysis-membrane biocompatibility and mortality of patients with dialysis-dependent acute renal failure: a..., Jorres [/bib_ref] compared 76 AKI patients in whom Cuprophan ® (LF membrane) was used with 84 patients in whom PMMA (LF membrane) was used. Meanwhile, Gastaldello et al. [bib_ref] Comparison of cellulose diacetate and polysulfone membranes in the outcome of acute..., Gastaldello [/bib_ref] and Albright et al. [bib_ref] Patient survival and renal recovery in acute renal failure: randomized comparison of..., Albright [/bib_ref] compared cellulose acetate (LF membrane) with PS (HF membrane)-both of which are improved versions of Cuprophan ® -in AKI patients. However, none of the above three trials observed differences in the outcomes or in the recovery of the renal function. In 2008, Cochrane reported a meta-analysis of 1100 patients from the five RCTs cited above and from five others (10 RCTs in all); the comparisons of the biocompatible membranes (synthetic polymeric membranes, n = 575) with the bioincompatible membranes (regenerated cellulose membranes, n = 525) revealed no significant differences in the mortality (relative risk 0.93, 95% confidence interval 0.81-1.07) or in the recovery of the renal function (n = 1,038, relative risk 1.09, 95% confidence interval 0.90-1.31) [bib_ref] Biocompatible hemodialysis membranes for acute renal failure, Alonso [/bib_ref]. Although these results are not directly relevant to comparisons of the synthetic polymeric membranes mainly used today, it should be acknowledged that no significant differences have been found between synthetic polymeric membranes and so-called bioincompatible regenerated cellulose membranes.
Jones et al. [bib_ref] Hemodynamics and survival of patients with acute renal failure treated by continuous..., Jones [/bib_ref] compared the survival rates for the use of the two synthetic polymeric membranes PAN (n = 97) and PS (n = 100) (both HF membranes) in the continuous hemodialysis (CHD) of ventilated patients with AKI. No significant difference was observed (PAN: 29%, PS: 27%). In the 2000s, another trial compared HF and LF membranes made of the same material. Ponkivar et al. [bib_ref] Lowflux versus high-flux synthetic dialysis membrane in acute renal failure: prospective randomized..., Ponikvar [/bib_ref] compared HF membranes (n = 34) and LF membranes (n = 38) both made of PS in AKI patients; the two groups' results were similar. Based on the above, none of the blood purification membranes currently used in Japan can produce better AKI treatment outcomes.
The core of the pathophysiology of septic AKI is assumed hypercytokinemia. The improvement of hypercytokinemia may be useful for improvement of the performance status and of AKI. This has led to attempts at blood purification designed to remove all types of cytokines. Haase et al. [bib_ref] Hemodialysis membrane with a high-molecularweight cutoff and cytokine levels in sepsis complicated..., Haase [/bib_ref] conducted a crossover RCT in which 10 sepsis patients with AKI classified by the RIFLE criteria as Failure underwent hemodialysis (HF) using a standard HF membrane (with in vivo molecular wright cutoff values of 15-20 kD) and a membrane with a larger pore size (50-60 kD). Comparisons of the cytokine removal efficiency revealed that the use of a membrane with a larger pore size significantly reduced the blood concentrations of the cytokines IL-6, -8, and -10 at 4 h of HD. In Japan, PMMA membranes [bib_ref] Comparison of interleukin-6 removal properties among hemofilters consisting of varying membrane materials..., Hirayama [/bib_ref] and AN69ST membranes [bib_ref] Continuous hemodiafiltration with a cytokine-adsorbing hemofilter in patients with septic shock: a..., Shiga [/bib_ref] , which are based on the principle of adsorption and are considered to highly efficient at removing cytokines, have been used in attempts at blood purification. Since 2014, AN69ST membranes have been covered by health insurance in Japan for patients with severe sepsis and septic shock. However, there is no high-level evidence of the clinical efficacy of membranes with large pore sizes or of adsorption membranes. Therefore, in regard to blood purification for the treatment of sepsis, the KDIGO Guideline states, "Until further evidence becomes available, the use of RRT to treat sepsis should be considered experimental". The collection of further evidence is anticipated.
## Literature review
PubMed was searched for relevant studies published up to July 2015, and papers related to the present CQ were identified from the search results.
## Cq8: do aki patients require long-term followup?
Recommendation: The long-term outcomes of AKI are poor. Therefore, we suggest confirming patients' condition at approximately 3 months later, and conducting long-term follow-up in accordance with their condition.
## Strength of recommendation: 2
## Quality of evidence: c
## Summary of evidence
At present, there have been no RCTs to examine the longterm outcomes of AKI (≥ 12 months following onset). However, there have been systematic reviews and meta-analyses of observational studies related to the survival outcomes, cerebrovascular and cardiovascular, and renal outcomes; the most reliable and most recent one is a study by Sawhney et al. Based on the search query used in that systematic review, we further searched the literature for studies related to the survival outcomes, the cardiovascular and cerebral disease outcomes, and the renal outcomes with an extended search period. We then conducted a meta-analysis of the search results, along with a consideration of any new studies related to the survival outcomes and renal outcomes, and of observational studies related to the cerebral and cardiovascular disease outcomes. In the results of our meta-analysis, the long-term outcomes of AKI patients were consistently poor. Moreover, although there have been no meta-analyses of the long-term QOL, some observational studies report that the onset of AKI is associated with a reduced long-term QOL.
## Commentary
The term "acute renal failure" (ARF) was used for the first time in writing by Heberden et al. in 1802 [bib_ref] Emergence of the concept of acute renal failure, Eknoyan [/bib_ref]. Although ARF was once considered to be reversible and therefore to have a favorable outcome, Hishida et al. reported that ARF patients have extremely poor survival outcomes, and cited multiple organ failure as a crucial underlying factor [bib_ref] Acute renal failure, Hishida [/bib_ref]. There were already multiple definitions of ARF [bib_ref] Developing a consensus classification system for acute renal failure, Kellum [/bib_ref]. In order to avoid confusion over the definition of ARF and to define acute syndromes related to the renal function more broadly, the term "acute kidney injury" (AKI) was suggested globally.
As the concept of AKI spread worldwide, many clinical studies on AKI have been performed. These studies have shown that the survival outcomes of AKI is poor [bib_ref] RIFLE criteria for acute kidney injury are associated with hospital mortality in..., Hoste [/bib_ref] [bib_ref] An assessment of the RIFLE criteria for acute renal failure in hospitalized..., Uchino [/bib_ref] [bib_ref] The RIFLE criteria and mortality in acute kidney injury: a systematic review, Ricci [/bib_ref] [bib_ref] Acute kidney injury in critically ill patients classified by AKIN versus RIFLE..., Joannidis [/bib_ref] , that its long-term outcomes is also poor [bib_ref] Incidence and outcomes in acute kidney injury: a comprehensive population-based study, Ali [/bib_ref] , and that the stage of AKI in the intensive care unit (ICU) is correlated with the mortality [bib_ref] North East Italian prospective hospital renal outcome survey on acute kidney injury..., Cruz [/bib_ref] ; as a result, perspectives on the outcomes of AKI have been changing. In 2015, Sawhney et al. reported the results of a systematic review that assembled the results of individual studies [bib_ref] Long-term prognosis after acute kidney injury (AKI): what is the role of..., Sawhney [/bib_ref] ; the survival outcomes and renal outcomes 1 year after the AKI onset were both shown to be poor. However, other clinically important outcomes such as the cerebral outcomes, the cardiovascular outcomes, and the quality of life (QOL) have not been examined.
## Survival outcomes
Sawhney et al.'s systematic review reported poor long-term post-AKI survival outcomes [bib_ref] Long-term prognosis after acute kidney injury (AKI): what is the role of..., Sawhney [/bib_ref]. We could not find any subsequent clinical study that yielded different conclusions about the long-term post-AKI survival outcomes.
## Cerebral and cardiovascular disease outcomes
Several meta-analyses of existing observational studies were reported in 2015 [bib_ref] Intervention associated acute kidney injury and long-term cardiovascular outcomes, Saratzis [/bib_ref] [bib_ref] Impact of postoperative acute kidney injury on clinical outcomes after transcatheter aortic..., Gargiulo [/bib_ref] [bib_ref] Acute kidney injury and prognosis after cardiopulmonary bypass: a meta-analysis of cohort..., Pickering [/bib_ref]. Although each of these reports used different subjects and endpoints, they consistently showed that the long-term outcomes of cerebral and cardiovascular diseases in AKI patients are poor. Of note, the subjects in these meta-analyses were limited to all postcardiovascular surgery patients (post-aortic aneurysm repair [bib_ref] Intervention associated acute kidney injury and long-term cardiovascular outcomes, Saratzis [/bib_ref] , post-aortic valve implantation [bib_ref] Impact of postoperative acute kidney injury on clinical outcomes after transcatheter aortic..., Gargiulo [/bib_ref] , and post-cardiopulmonary bypass [bib_ref] Acute kidney injury and prognosis after cardiopulmonary bypass: a meta-analysis of cohort..., Pickering [/bib_ref].
## Renal outcomes
Sawhney et al.'s systematic review revealed that the longterm post-AKI renal outcomes are poor [bib_ref] Long-term prognosis after acute kidney injury (AKI): what is the role of..., Sawhney [/bib_ref]. We could not find any subsequent manuscript that yielded different conclusions about the long-term post-AKI renal outcomes.
## Qol
As of the end of 2015, there had been few reports and no meta-analysis results relevant to the long-term post-AKI QOL; however, an observational study by Nisula et al. used the EQ5D score [bib_ref] Six-month survival and quality of life of intensive care patients with acute..., Nisula [/bib_ref] , and another by Hofhuis et al. used the SF36 [bib_ref] The effect of acute kidney injury on long-term healthrelated quality of life:..., Hofhuis [/bib_ref]. In both studies, the QOL was worse in the AKI group than in the non-AKI group. We did not find any studies on the long-term prognoses of AKI that adopted the ADL or fractures as outcomes.
Based on the above, the long-term post-AKI survival outcomes, cerebral and cardiovascular outcomes, and renal outcomes can all be considered poor. Therefore, patients who develop AKI are thought to require long-term followup. Moreover, we recommend conducting an initial followup-in which it is recommended to assess the performance status and possible complications-at 3 months in order to evaluate the possible development of chronic kidney disease (CKD). We chose this timing for two reasons: (1) according to the current diagnostic criteria, CKD is defined as a kidney injury that continues for 3 months, meaning that the renal assessment at 3 months post-AKI can be considered valid; (2) we considered consistency with the KDIGO Clinical Practice Guideline for AKI.
## Literature review
Based on the search query used by Sawhney et al. in their systematic review [bib_ref] Long-term prognosis after acute kidney injury (AKI): what is the role of..., Sawhney [/bib_ref] , we developed a search query to encompass four types of outcomes: survival outcomes, cerebral and cardiovascular outcomes, renal outcomes, and the QOL. PubMed was searched for relevant studies published between January 1, 2005 and April 30, 2015. In regard to the long-term survival outcomes and the long-term renal outcomes, we abstracted results from beyond the subject period used in existing systematic reviews. With regard to the titles and abstracts, we conducted a preliminary review and selected potentially relevant manuscripts; we then conducted a secondary review of these manuscripts (full-text assessments) to identify our final target manuscripts.
## Cq9-1: should the kdigo diagnostic criteria for aki be used for children?
## Recommendation:
Age ≥3 months: We suggest using the KDIGO AKI diagnostic criteria to predict the survival outcomes.
Age <3 months: We suggest using the modified KDIGO diagnostic criteria for neonates.
## Summary of evidence
Age ≥ 3 months: Two single-center retrospective observational studies have assessed the KDIGO diagnostic criteria in sufficiently large cohorts; these studies consistently demonstrated that the KDIGO diagnostic criteria were useful for the prediction of the mortality and of other outcomes.
Age < 3 months: Two review papers have examined the diagnosis of AKI in neonates and have commented on the results obtained in a total of 11 observational studies. The modified neonatal KDIGO criteria was suggested with the data of associations with the AKI onset, mortality, and neurological outcomes.
## 3
## Commentary
The early diagnosis and treatment of acute kidney injury (AKI) is crucial to the improvement of the outcomes not only in adults, but also in children. Several diagnostic criteria have been suggested for children. These have included the Pediatric RIFLE (pRIFLE) [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref] , AKIN, and KDIGO [fig_ref] Table 3: KDIGO criteria sCr serum creatinine, UO urine output, RRT renal replacement therapy [/fig_ref] criteria. It is known that the normal serum creatinine (sCr) values change with the age [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref] [bib_ref] Age, gender, and body length effects on reference serum creatinine levels determined..., Uemura [/bib_ref]. As urine collection is difficult in children, the pRI-FLE classification uses a Schwartz formula-based [bib_ref] The use of plasma creatinine concentration for estimating glomerular filtration rate in..., Schwartz [/bib_ref] calculation of the estimated glomerular filtration rate (eGFR) [bib_ref] Modified RIFLE criteria in critically ill children with acute kidney injury, Akcan-Arikan [/bib_ref]. Due to differences between the Japanese and Western body constitutions and renal functions, the assessment of the GFR based on the Schwartz formula is considered unsuitable for Japanese children [bib_ref] Is the new Schwartz equation derived from serum creatinine and body length..., Uemura [/bib_ref] ; therefore, another equation has been proposed to estimate the GFR in Japanese children [bib_ref] Creatinine-based equation to estimate the glomerular filtration rate in Japanese children and..., Uemura [/bib_ref]. The AKIN and KDIGO classifications of AKI are based on the sCr and on the duration of oliguria/anuria (i.e. a urine output < 0.5 mLlkg/h). Hereafter, we will describe studies that have compared these multiple diagnostic criteria for pediatric AKI.
Sutherland et al. compared the pRIFLE, AKIN, and KDIGO diagnostic criteria in 14,795 children aged under 18 who were hospitalized for AKI [bib_ref] AKI in hospitalized children: comparing the pRI-FLE, AKIN, and KDIGO definitions, Sutherland [/bib_ref]. The AKIN and KDIGO classifications, which both use the sCr criteria, were almost completely in agreement; however, as the eGFRbased pRIFLE classification has a higher incidence for stage 1 than the AKIN or KDIGO classifications; a larger number of patients were diagnosed with mild AKI. In all three classifications, the mortality was higher in patients with AKI than in those without AKI; particularly in the intensive care unit (ICU), the increasing severity of AKI (according to all three classifications) was associated with increased mortality. Selewski et al. used the KDIGO classification to examine the AKI outcomes in a cohort of 2415 patients in pediatric ICUs [bib_ref] Validation of the KDIGO acute kidney injury criteria in a pediatric critical..., Selewski [/bib_ref]. In comparison with patients who did not develop AKI, pediatric AKI patients demonstrated a significantly increased length of mechanical ventilation, a longer ICU stay, a longer duration of hospitalization, and a higher mortality rate. In addition, the length of the ICU stay was proportional to the worsening of the KDIGO AKI stages. These two single-center retrospective observational studies involved sufficient numbers of patients to demonstrate that the KDIGO classification is useful for the diagnosis of pediatric AKI. Moreover, as the KDIGO classification does not involve an estimation of the GFR but instead allows to stage AKI based on the sCr, it can be considered superior to the pRIFLE classification. Therefore, we suggest the use of the KDIGO diagnostic criteria for pediatric AKI patients aged ≥ 3 months. However, it must be noted that the use of the AKI diagnostic criteria has not yet been specifically evaluated in Japanese children [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref].
Neonates and children aged < 3 months possess a unique background that includes immaturity and perinatal factors; therefore, children under 3 months must be considered separately from those aged ≥ 3 months. Although there have been investigations of the AKI diagnosis, treatment, and outcomes in neonates, there used to be no definitive diagnostic criteria for neonatal AKI [bib_ref] Acute kidney injury in the neonate, Jetton [/bib_ref]. As the use of adult diagnostic tools such as the RIFLE, AKIN, and KDIGO criteria spread, their use for the diagnosis of AKI in neonates came to be researched too. Although the pRIFLE classification [bib_ref] The use of plasma creatinine concentration for estimating glomerular filtration rate in..., Schwartz [/bib_ref] [bib_ref] Modified RIFLE criteria in critically ill children with acute kidney injury, Akcan-Arikan [/bib_ref] was proposed for pediatric use, it requires calculation of the eGFR and is therefore unsuitable for neonates, in whom the eGFR cannot be calculated. In 2014, Jetton et al. and Askenazi et al. introduced the neonatal modified KDIGO criteria [fig_ref] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease,... [/fig_ref] , which are based on the KDIGO diagnostic criteria [bib_ref] Acute kidney injury in the neonate, Jetton [/bib_ref]. Similarly to the adult and pediatric KDIGO criteria, the neonatal modified KDIGO criteria define stages 1, 2, and 3 AKI primarily according to sCr values 1.5-1.9, 2.0-2.9, and ≥ 3 times higher than baseline, respectively. Although the baseline sCr is the minimum value prior to AKI diagnosis, it is only established at age ≥ 3 months in Japan [bib_ref] Age, gender, and body length effects on reference serum creatinine levels determined..., Uemura [/bib_ref] , and not in children under 3 months. The level of sCr in neonates immediately after birth is extremely close to the level of maternal sCr (generally ≤ 1 mg/dl) [bib_ref] Why do newborn infants have a high plasma creatinine?, Guignard [/bib_ref]. It peaks at day 0-3, and declines to a minimum value (0.2-0.5 mg/dl) over the following 1 week to 20 months [bib_ref] Why do newborn infants have a high plasma creatinine?, Guignard [/bib_ref] [bib_ref] Reference values for serum creatinine in children younger than 1 year of..., Boer [/bib_ref] [bib_ref] Serum creatinine concentration in very-low-birthweight infants from birth to 34-36 wk postmenstrual..., Bateman [/bib_ref]. (Note that prematurity (in terms of gestational age and birth weight) is reported to affect the postnatal sCr levels and the speed at which they decline 330]). Going forward, it is necessary to collect data on Japanese neonates to establish their baseline sCr levels. It should be taken into consideration that the current absence of established baseline levels requires multiple measurements. Koralkar et al. used the neonatal modified KDIGO criteria to examine AKI and mortality in 229 very low-birth-weight infants both at 36 weeks of gestational age and with a birth weight of 500-1500 kg [bib_ref] Acute kidney injury reduces survival in very low birth weight infants, Koralkar [/bib_ref] ; the very low-birth-weight infants diagnosed with AKI had a significantly higher mortality than those not diagnosed with AKI. In an examination of 455 very low-birth-weight infants using the neonatal modified KDIGO criteria, Carmody et al. found AKI to be associated with mortality and prolonged hospitalization [bib_ref] Recognition and reporting of AKI in very low birth weight infants, Carmody [/bib_ref]. In addition, a gestational age < 28 weeks was strongly associated with the onset of AKI; furthermore, all infants with a gestational age < 24 weeks were diagnosed with AKI, which indicates an association between prematurity and AKI. Rhone et al. used the neonatal modified KDIGO criteria to examine the association between the AKI onset and nephrotoxic medications (acyclovir, amphotericin B, gentamicin, ibuprofen, indomethacin, iohexol, tobramycin, and vancomycin) in 107 very lowbirth-weight infants; consequently, these drugs were shown to be associated with the onset of AKI [bib_ref] Nephrotoxic medication exposure in very low birth weight infants, Rhone [/bib_ref]. In an examination of 96 neonates with moderate to severe asphyxia who underwent therapeutic hypothermia, Sarkar et al. demonstrated that abnormal brain MRIs at 7-10 days of age were significantly more frequent in infants diagnosed with AKI according to the neonatal modified KDIGO criteria [bib_ref] Relationship between acute kidney injury and brain MRI findings in asphyxiated newborns..., Sarkar [/bib_ref]. As detailed above, many recent studies have employed the neonatal modified KDIGO criteria for the diagnosis of neonatal AKI.
## Literature review
PubMed was searched for relevant studies published between January 1, 1980 and August 1, 2015, and papers related to the present CQ were identified from the search results.
## Cq9-2: should biomarkers be used for the early diagnosis of aki and for prediction of the survival outcomes in children?
Recommendation: The use of biomarkers for the early diagnosis of AKI or to predict the survival outcomes cannot be recommended in children.
## Strength of recommendation: not graded
Quality of evidence: C
## Summary of evidence
Many studies have indicated that biomarkers such as NGAL, cystatin C, L-FABP, IL-18, and KIM-1 may be useful for the early diagnosis of AKI and to predict the survival outcomes in children. However, interventions based on these indicators have not been reported to improve the renal or survival outcomes of AKI; therefore, their utility is limited.
## Commentary
Neutrophil gelatinase-associated lipocalin (NGAL) is a secretory protein that has a molecular weight of 25,000 Da and is secreted from activated neutrophils and tubular epithelial cells; the levels of NGAL in the blood and urine are known to be elevated in the hyperacute phase (i.e. the initial 2-4 h) of kidney injury. In an examination of 71 children undergoing a cardiopulmonary bypass (CPB) [bib_ref] Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after..., Mishra [/bib_ref] , the children who developed acute kidney injury (AKI) showed significantly elevated levels of serum and urinary NGAL 2 h after the CPB, with areas under the receiver operating characteristic curve (AUC) of 0.998 and 0.906, respectively; this study was the first to indicate the utility of biomarkers for the early diagnosis of AKI. An examination of 311 children undergoing cardiac surgery for congenital heart disease registered at three institutions [bib_ref] Postoperative biomarkers predict acute kidney injury and poor outcomes after pediatric cardiac..., Parikh [/bib_ref] also indicated that the urinary NGAL is useful for the early diagnosis of AKI, despite a relatively low AUC of 0.71. The urinary NGAL was also reported to be useful for the early diagnosis of AKI in a heterogeneous pediatric intensive care unit (PICU) patient cohort which had undergone mechanical ventilation and bladder catheterization [bib_ref] Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury..., Zappitelli [/bib_ref]. Likewise, in a systematic review/meta-analysis of 19 studies [bib_ref] Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute..., Haase [/bib_ref] , a subgroup analysis of six studies featuring populations of pediatric patients only demonstrated the utility of NGAL for the early diagnosis of AKI. With regard to the survival outcomes, two studies have reported that NGAL is significantly associated with mortality [bib_ref] Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a..., Bennett [/bib_ref] [bib_ref] Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after..., Dent [/bib_ref]. Cystatin C is a low-weight molecular protein (molecular weight: approximately 13,000 Da) produced by nucleated cells all over the body. It is unaffected by environmental changes inside or outside the cells, and is produced and secreted constantly; therefore, its concentration in the serum is constant. In addition, cystatin C is unaffected by factors such as inflammation, aging, the gender, the muscle mass, or exercise. The serum cystatin C passes freely through the glomerular basement membrane and is filtered by the glomerulus. As more than 99% of the serum cystatin C is reabsorbed by the proximal tubule and catabolized, healthy individuals excrete only a minimal amount of it in their urine. The serum cystatin C has been indicated to be useful for early, accurate diagnoses of AKI. The cystatin C concentrations in the serum and urine are known to increase 12-24 h after the onset of kidney injury. In an examination of 374 children undergoing CPB [bib_ref] Serum cystatin C is an early predictive biomarker of acute kidney injury..., Krawczeski [/bib_ref] , AKI patients demonstrated significantly elevated serum cystatin C levels 12 and 24 h after the onset of AKI, with AUCs of 0.81 and 0.84, respectively; thus, the serum cystatin C was shown to be a useful biomarker for the early diagnosis of AKI. It was also reported to be useful for the early diagnosis of AKI in a study of 288 children undergoing cardiac surgery [bib_ref] Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric..., Zappitelli [/bib_ref]. While measurement of the serum cystatin C is covered by insurance in Japan, that of the urinary cystatin C is not.
Interleukin-18 (IL-18) is an inflammatory cytokine induced in the proximal tubule. In a study of 55 children undergoing CPB [bib_ref] Urinary IL-18 is an early predictive biomarker of acute kidney injury after..., Parikh [/bib_ref] , children with AKI demonstrated a significant acute phase (4-6 h after CPB) increase in their urinary IL-18 levels. The latter peaked at 12 h and remained high at 48 h. The AUC at 12 h (i.e. at the urinary IL-18 levels' peak) was 0.75, demonstrating the utility of the urinary IL-18 as a biomarker for the early diagnosis of AKI. In a systematic review/meta-analysis of 18 studies [bib_ref] Urinary interleukin 18 for detection of acute kidney injury: a meta-analysis, Liu [/bib_ref] , the urinary IL-18 was also shown to be useful for the early diagnosis of AKI in a subgroup analysis of five studies featuring populations of pediatric patients only. Measurement of the urinary IL-18 is not covered by insurance in Japan.
The L-type fatty acid-binding protein (L-FABP), kidney injury molecule-1 (KIM-1), and albumin are also known to show a marked increase in urine as a result of kidney injury; these biomarkers have been studied for their potential utility in the early diagnosis of AKI. The L-FABP is a protein with a molecular weight of 14,000 Da that is expressed in the liver, the small intestine, and the proximal tubular epithelial cells; since 2011, measurement of the L-FABP as a biomarker has been covered by insurance in Japan. In a study of 40 pediatric patients having undergone CPB [bib_ref] Liver fatty acid-binding protein as a biomarker of acute kidney injury after..., Portilla [/bib_ref] , children who developed AKI demonstrated a significant acute phase (4 h after AKI onset) increase in the urinary L-FABP. KIM-1 is a membrane-spanning glycoprotein expressed in the proximal tubular epithelial cells. In a study of 40 children undergoing CPB [bib_ref] Urinary biomarkers in the early diagnosis of acute kidney injury, Han [/bib_ref] , children with AKI demonstrated a significant acute phase (12 h after CPB) increase in KIM-1. Moreover, in a prospective study of 294 children undergoing cardiac surgery, the urinary albumin/creatinine ratios 0-6 h after surgery were useful for the prediction of AKI [bib_ref] The association of albumin/creatinine ratio with postoperative AKI in children undergoing cardiac..., Zappitelli [/bib_ref].
Due to the diversity of the pathologies involved in AKI and the decline in the glomerular filtration rate (GFR), the use of a single biomarker to increase the accuracy of early diagnosis is of limited efficacy. One attempt to increase the accuracy of biomarkers for the diagnosis of AKI is to assemble a "panel" that combines multiple biomarkers and the renal angina index (RAI), an indicator of the risk of AKI onset [bib_ref] Temporal relationship and predictive value of urinary acute kidney injury biomarkers after..., Krawczeski [/bib_ref] [bib_ref] Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney..., Basu [/bib_ref]. Another advantage of panels is that, as each of the biomarkers that comprise them demonstrate favorable sensitivity and specificity at different periods, these different time phases may complement one another.
The uses of biomarkers have been studied in children, though not as often as in adults. Relevant studies indicate that these biomarkers may be useful for the early diagnosis of AKI and for the prediction of the survival outcomes. However, many of these studies involved relatively homogeneous populations, e.g. children undergoing CPB; the utility of these biomarkers has not been sufficiently assessed in populations of patients with diverse pathologies. Furthermore, the interventions based on these indicators have not yet been reported to improve the renal outcomes or survival outcomes of AKI; therefore, their utility is limited.
## Literature review
PubMed was searched for relevant studies published between January 1980 and July 2015, and papers related to the present CQ were identified from the search results.
## Cq9-3: should fluid overload be considered as a blood purification indication for pediatric aki?
Recommendation: When determining whether blood purification is indicated in pediatric AKI, we suggest considering the fluid overload assessment in addition to absolute indications.
## Strength of recommendation: 2
## Quality of evidence: c
## Summary of evidence
Many observational studies have reported that pediatric AKI non-survivors exhibit fluid overload compared to survivors. Few manuscripts have discussed fluid overload in neonatal AKI; there is little evidence to support prioritization of the fluid overload assessment for determination of the indication of blood purification in neonates.
## Commentary
In pediatric acute kidney injury (AKI), life-threatening conditions resistant to conservative therapy, such as electrolyte disorders (hyperkalemia, etc.), fluid overload (pulmonary edema, heart failure, etc.) metabolic acidosis, and uremia symptoms (pericarditis, impaired consciousness, convulsions, etc.) are absolute indications for blood purification just like in adult AKI; in these cases, blood purification must be initiated immediately. However, for relative indications that are not considered to be immediately life-threatening, the criteria for the initiation of blood purification have not yet been defined. No randomized controlled trials have assessed the indications for blood purification and the timing of its initiation in pediatric AKI.
Although they were only observational studies, many recent papers have reported that fluid overload at the initiation of blood purification affects the survival outcomes. Body water is known to account for a larger percentage of the body weight in children than in adults. The percent fluid overload (%FO) is considered to be useful for the assessment of fluid overload.
In 2001, Goldstein et al. conducted a single-center study [bib_ref] Sachdeva R. Outcome in children receiving continuous venovenous hemofiltration, Goldstein [/bib_ref] , followed by a large-scale multi-center study of continuous renal replacement therapy (CRRT) for pediatric AKI whose results were reported in 2005. This study examined the predictors of survival and death in 116 children registered in the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry who underwent CRRT for multiple organ failure. Even when controlling for the severity of the illness (as measured by pediatric risk of mortality [PRISM] score), the %FO at CRRT initiation was an independent predictor of survival; the %FO was significantly lower in survivors than in non-survivors (survivors: 14.2 ± 15.9 versus non-survivors: 25.4 ± 32.9, p < 0.05), while the mortality was significantly higher when the %FO was > 20% (< 20:40 vs. > 20:58%) at CRRT initiation. The same group later demonstrated that the %FO at the initiation of blood purification was correlated with mortality (< 10:29.4%, 10-20:43.1%, > 20:65.6%) [bib_ref] Fluid overload and mortality in children receiving continuous renal replacement therapy: the..., Sutherland [/bib_ref]. reported that FO is a factor of poor survival outcomes [bib_ref] Timing of continuous renal replacement therapy and mortality in critically ill children*, Modem [/bib_ref]. Many studies of AKI in multiple organ failure [bib_ref] Fluid overload before continuous hemofiltration and survival in critically ill children: a..., Foland [/bib_ref] [bib_ref] Effect of fluid overload and dose of replacement fluid on survival in..., Gillespie [/bib_ref] [bib_ref] Outcomes of critically ill children requiring continuous renal replacement therapy, Hayes [/bib_ref] , stem cell transplantation [bib_ref] Fluid overload and acute renal failure in pediatric stem cell transplant patients, Michael [/bib_ref] , and Fluid in − fluid out ∶ in − out balance before and after PIC U admission extracorporeal membrane oxygenation (ECMO) following cardiac surgery [bib_ref] Fluid overload and fluid removal in pediatric patients on extracorporeal membrane oxygenation..., Selewski [/bib_ref] [bib_ref] Early initiation of renal replacement therapy in pediatric heart surgery is associated..., Sanchez-De-Toledo [/bib_ref] have also reported that a lower %FO at CRRT initiation is associated with more favorable survival outcomes. Similar results have also been reported in assessments of FO based on the body weight at hospital admission, at intensive care unit (ICU) admission, and at the initiation of blood purification [bib_ref] Weight-based determination of fluid overload status and mortality in pediatric intensive care..., Selewski [/bib_ref]. Therefore, the early initiation of blood purification to prevent fluid overload may improve the survival outcomes; when determining whether blood purification is indicated in pediatric AKI, we suggest that the fluid overload assessment be taken into consideration in addition to absolute indications.
However, these results all were obtained from observational studies; there is no high-quality evidence from interventional studies. In addition, a study of blood purification in children undergoing cardiac surgery failed to find an effective timing for initiation [bib_ref] Success of continuous veno-venous hemodiafiltration treatment in children monitored in the intensive..., Kara [/bib_ref] , while fluid overload was reported not to be an absolute predictor of the survival outcomes [bib_ref] Continuous renal replacement therapy in children: fluid overload does not always predict..., De Galasso [/bib_ref]. Unnecessary blood purification should be avoided in cases of mild AKI, in which the renal function recovers quickly. Blood purification carries serious complications, including catheter-related infection, an increased risk of bleeding from anticoagulation, and hemodynamic fluctuations unique to children of small constitution; therefore, the indication for blood purification and the timing of initiation must be considered comprehensively.
In neonatal AKI just like in pediatric AKI, renal replacement therapy (RRT) is considered when prolonged oliguria/ anuria prevents the appropriate adjustment of the body fluid, electrolytes, and blood nitrogen level. The overall mortality in neonatal AKI is reported to range between 11.3 and 48.3% [bib_ref] Etiology and outcome of acute kidney injury in children, Duzova [/bib_ref] [bib_ref] Acute renal failure in the neonatal period, Agras [/bib_ref] [bib_ref] Acute kidney injury in a single neonatal intensive care unit in Turkey, Bolat [/bib_ref] [bib_ref] Defining reduced urine output in neonatal ICU: importance for mortality and acute..., Bezerra [/bib_ref] [bib_ref] Pediatric ARF epidemiology at a tertiary care center from 1999 to, Hui-Stickle [/bib_ref] [bib_ref] Acute kidney injury and renal replacement therapy independently predict mortality in neonatal..., Askenazi [/bib_ref] [bib_ref] Epidemiology of cardiac surgery-associated acute kidney injury in neonates: a retrospective study, Alabbas [/bib_ref] [bib_ref] Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia, Selewski [/bib_ref] [bib_ref] AKI in hospitalized children: epidemiology and clinical associations in a national cohort, Sutherland [/bib_ref] [bib_ref] Potential risk factors for the development of acute renal failure in preterm..., Cataldi [/bib_ref] [bib_ref] Acute kidney failure in neonatal period, Mortazavi [/bib_ref] ; while the mortality is reported to be 4.1-71.7% in premature neonates [bib_ref] Acute kidney injury reduces survival in very low birth weight infants, Koralkar [/bib_ref] [bib_ref] Risk factors associated with acute kidney injury in extremely low birth weight..., Viswanathan [/bib_ref] [bib_ref] Acute kidney injury is independently associated with mortality in very low birthweight..., Askenazi [/bib_ref] [bib_ref] Elevation in plasma creatinine and renal failure in premature neonates without major..., Walker [/bib_ref] [bib_ref] Risk factors for and outcomes of acute kidney injury in neonates undergoing..., Morgan [/bib_ref] , 13.9-70.0% in asphyxiated neonates [bib_ref] Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia, Selewski [/bib_ref] [bib_ref] Renal failure in asphyxiated neonates, Gupta [/bib_ref] [bib_ref] Renal injury in the asphyxiated newborn infant: relationship to neurologic outcome, Perlman [/bib_ref] , 2.9-11.6% in neonates undergoing a cardiopulmonary bypass/cardiac surgery [bib_ref] Renal replacement therapy in neonates with congenital heart disease, Morelli [/bib_ref] [bib_ref] Congenital heart surgery in infants: effects of acute kidney injury on outcomes, Blinder [/bib_ref] [bib_ref] A small post-operative rise in serum creatinine predicts acute kidney injury in..., Zappitelli [/bib_ref] , 71.2% in sepsis [bib_ref] Acute renal failure in neonatal sepsis, Mathur [/bib_ref] , and 50-100% in neonates with AKI who undergo blood purification [bib_ref] Acute renal failure in the neonatal period, Agras [/bib_ref] [bib_ref] Acute kidney injury and renal replacement therapy independently predict mortality in neonatal..., Askenazi [/bib_ref] [bib_ref] Epidemiology of cardiac surgery-associated acute kidney injury in neonates: a retrospective study, Alabbas [/bib_ref] [bib_ref] Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia, Selewski [/bib_ref]. Due to the different definitions of AKI in these studies and to the major differences in the standards of neonatal intensive care medicine between countries and institutions, uniform comparisons of past studies are difficult. The risk factors for death in neonatal AKI include mechanical ventilation, hypervolemia (%FO ≥ 7%), chronic heart failure, a low birth weight, hypoxia, oliguria/anuria, dialysis, and metabolic acidosis [bib_ref] Etiology and outcome of acute kidney injury in children, Duzova [/bib_ref]. The risk of death is particularly high in neonates with oliguria . However, no studies have discussed FO in neonatal AKI; there is little evidence to support prioritization of the fluid overload assessment when determining the indication of blood purification in neonates. Low-birth-weight infants present technical problems such as vascular access; however, the indication for acute blood purification in neonates must be determined comprehensively on a case-by-case basis.
## Literature review
PubMed was searched for relevant studies published between January 1980 and July 2015, and papers related to the present CQ were identified from the search results. Manuscripts that supplemented the commentary were hand searched as appropriate.
CQ9-4: What modalities of blood purification therapy should be selected for pediatric AKI patients?
Recommendation: For pediatric AKI patients requiring blood purification, an appropriate modality tailored to the patient's constitution and disease condition should be considered.
## Strength of recommendation: not graded
## Quality of evidence: d
## Summary of evidence
Observational studies of children and neonates who underwent CRRT or other modalities of blood purification have been performed. However, there has been no evidence to demonstrate the effects of different blood purification modalities on the outcomes, nor of their superiority to peritoneal dialysis.
## Commentary
The modalities of blood purification for acute kidney injury (AKI) include peritoneal dialysis (PD), extracorporeal intermittent renal replacement therapy (IRRT), and continuous renal replacement therapy (CRRT). In the past, PD was often the first choice; however, due to progress in the techniques of vascular access, in the types of catheters, the hemodialysis (HD) devices, and the pediatric intensive care management, extracorporeal CRRT has become more common. At present, the only studies that have compared PD and extracorporeal CRRT are observational studies [bib_ref] Pediatric acute renal failure: outcome by modality and disease, Bunchman [/bib_ref] [bib_ref] Management of acute renal failure in the pediatric patient: hemofiltration versus hemodialysis, Maxvold [/bib_ref] , and there is no evidence that one modality is superior to the other. However, as in adults, CRRT is considered preferable to IRRT for hemodynamically unstable patients. Many evidences that inform the blood purification modality selection for adults can be applied pediatric AKI; however, the incidence of pediatric AKI is < 1% in all hospitalized children [bib_ref] Childhood acute renal failure: 22-year experience in a university hospital in southern..., Vachvanichsanong [/bib_ref] , and 4.5% in children admitted to the ICU 1 3 [bib_ref] Risk factors of acute renal failure in critically ill children: A prospective..., Bailey [/bib_ref]. Differences in knowledge and health care resources between regions and institutions may greatly affect the selection of blood purification modalities. Further investigations are necessary to better inform the selection of suitable blood purification modalities.
In children (aside from neonates), blood purification can be performed safely with a combination of low priming volume and multipurpose blood purification devices. For vascular access, the size of the catheter is chosen to suit the patient's constitution [fig_ref] Figure 6: Blood purification for pediatric patients [/fig_ref]. The standard values for the quantity of blood flow (QB), the dialysate flow rate (QD), and the filtration rate (QF) are 1-5 ml/kg/min, QB × 0.2-2.0, and 0-20% of the QB, respectively. With regard to circuit priming before the initiation of HD, a priming volume of ≥ 10% of the circulating blood volume causes hypotension at the initiation of dialysis; therefore, priming with blood products is preferred [bib_ref] Zero balance ultrafiltration (Z-BUF) in blood-primed CRRT circuits achieves electrolyte and acidbase..., Hackbarth [/bib_ref]. After priming with blood products, it is recommended dialyzing the priming blood in the circuit to adjust the electrolyte and acid-base balance, and by removing the potassium and citric acid in the blood products.
In the past, PD used to be the method of choice for lowbirth-weight infants (including neonates) due to the technical problems. However, extracorporeal blood purification can recently be performed safely. Extracorporeal blood purification has been technically possible in Japan since 2001, when blood purification devices (QB can be adjusted from 1 ml/ min), filters, and other related devices became commercially available. In 2013, the Pediatric Acute Blood Purification Handbook described blood purification in neonates and the Guideline for Neonatal Extracorporeal Blood Purification was published in Japan. In addition, the Neonatal Extracorporeal Blood Purification Manual was published in 2014. Meanwhile, there have been many reports on blood purification primarily in pediatric patients (including some neonates) both in Japan and outside of Japan [bib_ref] Demographic characteristics of pediatric continuous renal replacement therapy: a report of the..., Symons [/bib_ref] [bib_ref] Continuous renal replacement therapy for children </=10 kg: a report from the..., Askenazi [/bib_ref].
In blood purification for low birth-weight-infants (including neonates), vascular access is a specific and important issue; in addition to the standard central venous route, the umbilical arteries/veins and peripheral arteries can also be used (when the flow rate is low, the peripheral veins can sometimes also be used). There has been a Japanese case report of blood purification in an infant weighing < 500 g; however, blood purification in infants weighing < 2 kg is considered to require experienced skill. Central venous catheter size should be large. Although variations between institutions exist, the catheter sizes used for infants weighing 1, 2, and 3 kg are generally 17 G, 15 G, and 6 Fr, respectively. As in pediatric patients, the circuit is basically primed with mixed blood in order to prevent hypotension. The blood preparation is recycled and dialyzed to remove potassium and citric acid before initiating the blood purification. Prevention for hypothermia is necessary. Details are described in the above-cited guidelines and handbooks [fig_ref] Figure 6: Blood purification for pediatric patients [/fig_ref].
Outside Japan, the blood purification of low-birth-weight infants (including neonates) was primarily consisted of peritoneal dialysis [bib_ref] Acute peritoneal dialysis in very low birth weight neonates using a vascular..., Yu [/bib_ref] [bib_ref] Use of the multipurpose drainage catheter for the provision of acute peritoneal..., Auron [/bib_ref] [bib_ref] Dialysis therapy for children with acute renal failure: survey results, Warady [/bib_ref]. The improvements in blood purification devices have recently led to an increase in extracorporeal acute blood purification [bib_ref] Continuous renal replacement therapy in children up to 10 kg, Symons [/bib_ref] [bib_ref] Continuous renal replacement therapy in neonates and small infants: development and first-in-human..., Ronco [/bib_ref] [bib_ref] Haemodialysing babies weighing < 8 kg with the Newcastle infant dialysis and..., Coulthard [/bib_ref]. However, there have been no randomized controlled trials (RCTs) to examine the performance of extracorporeal blood purification in Japan or elsewhere.
The optimal blood purification modality also depends on the disease conditions. For AKI with acute brain injury, intracranial hypertension, or cerebral edema, CRRT [continuous hemodiafiltration (CHDF) or 24 h of PD] is recommended, as IRRT may cause intracranial hypertension, dialysis disequilibrium syndrome, and reduced blood pressure [bib_ref] Brain density changes during renal replacement in critically ill patients with acute..., Ronco [/bib_ref].
## Literature review
PubMed was searched for relevant studies published between January 1980 and July 2015, and papers related to the present CQ were identified from the search results. The literature needed for the commentary was manually extracted from PubMed as appropriate.
## Cq9-5: how should therapeutic strategies be discussed and determined in cases of neonates and children with aki who have serious impairments and poor survival prognoses?
Recommendation: Medical care staff should first consider the patient's present status and survival prognosis, and discuss the indication for renal replacement therapy amongst themselves. Afterwards, they should explain the advantages and disadvantages of the different treatments to the patient's family, and consult with them about suitable therapeutic strategies. Each patient should be dealt with as appropriate on a case-by-case basis, and with reference to the "Guideline on Determining Medical Care of Children with Serious Diseases." of the Japan Pediatric Society.
## Strength of recommendation: not graded
## Quality of evidence: d
## Summary of evidence
Despite the existence of multiple case reports and case series, there is no relevant high-level evidence.
## Commentary
Children with severe motor and intellectual disabilities caused by factors such as chromosomal abnormalities, multiple abnormality syndromes, and neonatal asphyxia (cerebral hypoxia) are estimated to occur in approximately 0.3 out of 1000 live births. Factors such as severe asphyxia and infection frequently cause acute kidney injury (AKI) in neonates. Neonates with AKI necessitating blood purification often present comorbid serious brain injury. Children with severe motor and intellectual disabilities that correspond to grades 1-4 of Oshima's classification have a high risk of developing severe infections, and frequently require renal replacement therapy (RRT) for AKI. However, most past reports of RRT in children with severe impairments, mostly from Japan, have involved the issues of chronic dialysis. Out of a total of 23 reports (37 patients), 20 of them (32 patients) described the initiation (or scheduled initiation) of peritoneal dialysis (PD), two (4 patients) described the initiation of chronic hemodialysis (HD), and one (1 patient) described PD and continuous hemodiafiltration (CHDF) for AKI. In another report, the patient was treated without initiating dialysis. Many of these reports have suggested that a multidisciplinary health care team should consider the patient's case and should ultimately decide what to do after consulting the patient's family. Meanwhile, reports from outside Japan have stated that the frequency of peritonitis in PD for children with psychomotor retardation is the same as in children without psychomotor retardation if dedicated cooperation and support are provided. There have also been reports of dialysis initiation in children with chromosomal abnormalities [bib_ref] Chronic peritoneal dialysis treatment in a pediatric patient with Down syndrome, Yavascan [/bib_ref] [bib_ref] Chronic peritoneal dialysis in a child with Down syndrome, Kupferman [/bib_ref] [bib_ref] Renal replacement therapy in Down's syndrome, Webb [/bib_ref]. These reports have demonstrated that RRT can be performed relatively safely in children with severe motor and intellectual disabilities. However, the medical staff experience a great physical and psychological burden; therefore, the health care team also needs support.
There are no definitive criteria upon which to determine the indication for RRT in children with severe impairments; thus, it must be considered on a case-by-case basis. The health care team should decide on a therapeutic strategy after considering the patient's present status and long-term survival prognosis amongst themselves, explaining the nature of the treatments to the patient's family, and presenting the respective advantages and disadvantages of treatment versus no treatment. Various guidelines can be referred as well. This concept is called shared decision-making; essentially, health care professionals must share information with the patient's family and decide on a therapeutic strategy together. The process is described below.
## Therapeutic strategy discussion amongst the health care team
Before providing information to the patient's family, the health care staff must gather information and share it amongst themselves in order to determine the patient's present status. Discussions should not only include the attending physician's department, but also intensive care specialists, neonatal intensive care specialists, and nurses; when necessary, clinical psychologists, a palliative care team, medical social workers, and other departments and disciplines should also be included. Based on these discussions, conceivable treatments should be identified as options, and the problems and invasiveness of each option should be abstracted (for example, for acute blood purification, these include complications associated with catheter insertion, the risk of hypotension associated with dialysis initiation, blood transfusion, etc.). Suitable strategies are then examined based on a prediction of the patient's prognosis (survival prognosis and sequelae) and on the consideration of the advantages and disadvantages of the potential treatments.
## 3
When considering withholding or discontinuing treatment, the relevant facility's institutional review board may be convened, or a conference may be held to discuss ethical issues.
## Explanation to the patient's family
When explaining therapeutic strategies to the patient's family, the parents must always be present; other individuals may attend the explanation if requested by the parents (grandparents, etc.). The name of the child's illness, its disease condition, the respective advantages and disadvantages of treatments such as blood purification (including their complications) versus no treatment, and the prognosis (sequelae and survival prognosis) should be explained comprehensively in a way that is easy to understand. Important information should be provided in writing. Moreover, even when acute blood purification is to be performed, it must be explained that permanent RRT may be necessary, thereby placing a burden on the patient and their family (which also requires explanation). In addition, the family must be informed that even after a strategy is decided, it can be reconsidered if they change their minds.
The content of this explanation, the way it is explained, and the course by which a strategy is chosen must be written in the patient's medical record. In particular, when treatment is withheld, it is important to record the course and content of the discussion that led to the treatment withdrawal. When the patient's family and the health care team cannot agree on a strategy, advice should be sought from a committee comprising the institutional review board and many other experts.
## Subsequent follow-up and reconsideration of the treatment strategy
Even after a strategy is decided, the patient's family will require continuous mental support. After blood purification is initiated, the patient's impairment may progress irreversibly, thereby requiring discontinuation of the treatment. On the other hand, even if the patient's family initially decides not to perform treatment, treatment may later be performed if they change their minds (or for other reasons). These reconsiderations of the therapeutic strategies require a new round of discussion. Moreover, when changing the therapeutic strategy, a consensus must be obtained among the health care team as appropriate.
If the patient's family wishes to discontinue dialysis, it is necessary to confirm that this is not based on temporary emotion, but on a careful consideration and sufficient understanding of the child's status. The patient may also die shortly after discontinuing treatment; therefore, when deciding to do so, the timing of the discontinuation must also be discussed.
The above procedure is also followed for comorbid severe brain injury associated with acquired causes, such as acute encephalitis/encephalopathy and head trauma. When the patient him/herself is evidently conscious and is capable of expressing their will but has a poor survival prognosis (such as in the case of older children with terminal malignancy), the patient's own will must be respected and prioritized above all else. In such cases, the question of how much medical information to convey to the patient must first be discussed with the patient's family and agreed in advance.
## Literature review
PubMed and Ichushi-Web (Japanese language) were searched for relevant studies published up to , and papers related to the present CQ were identified from the search results. References in Japanese are not shown in this article.
## Chapter 10: aki in the elderly and ethical aspects
Aging as a risk factor for AKI occurrence As Japan has become a super-aged society, it is increasingly crucial to understand the pathologies in which age is a risk factor and to take preemptive measures to prevent these pathologies in order to tackle diseases with no established treatments. A typical example of these pathologies is acute kidney injury (AKI). Elderly people account for a large and constantly increasing percentage of AKI patients [bib_ref] Community-based incidence of acute renal failure, Hsu [/bib_ref]. In addition, many observational studies published in the last 25 years have found aging to be a significant risk factor for AKI onset [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] [bib_ref] The clinical features and outcome of crush patients with acute kidney injury..., Zhang [/bib_ref].
Pre-AKI renal impairment is a risk factor for AKI; chronic kidney disease (CKD) patients are at a high risk of developing AKI. With the base of hypertensive nephrosclerosis, aging is associated with a reduced glomerular filtration rate (GFR); therefore, aging is conceivably an underlying factor of CKD, which in turn can be considered a universal risk factor for AKI [bib_ref] The association between age and nephrosclerosis on renal biopsy among healthy adults, Rule [/bib_ref] [bib_ref] A meta-analysis of the association of estimated GFR, albuminuria, age, race, and..., Grams [/bib_ref]. In the present guideline's examination of the risk factors for individual AKI, age was considered to be an independent risk factor for the onset of AKI in cardiac surgery (CQ3-1), acute heart failure (CQ3-3), and sepsis (CQ3-4). Although it is not covered by any CQ in the present guideline, dehydration-induced pre-renal AKI, which is an important aspect of community-acquired AKI, restricts the renal blood flow in elderly people due to their already low fluid volume and to arteriosclerosis; therefore, elderly people are at a high risk of developing dehydration-induced AKI [bib_ref] Renal disease in the elderly, Samiy [/bib_ref]. Drugs such as renin-angiotensin-aldosterone system inhibitors, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), and vitamin D preparations (which cause hypercalcemia)-the latter two of which are often used by elderly people-are involved in the increase in AKI among the elderly [bib_ref] Acute kidney injury in elderly patients with chronic kidney disease: do angiotensin-converting..., Chaumont [/bib_ref]. Elderly people are also known to be at a high risk of drug-induced AKI (contrast agents, aminoglycosides, etc.) [bib_ref] A simple risk score for prediction of contrastinduced nephropathy after percutaneous coronary..., Mehran [/bib_ref] [bib_ref] Risk factors for acute kidney injury in older adults with critical illness:..., Sl [/bib_ref]. Therefore, in order to prevent AKI, elderly people's exposure to these drugs must be minimized. Urinary tract obstructive kidney injury and ANCA-associated, vasculitis-induced rapidly progressive glomerulonephritis (RPGN) are also common causes of AKI in the elderly.
The present guideline recommends the use of the KDIGO criteria for the diagnosis of AKI; however, caution is necessary in applying these criteria to elderly patients. Although the KDIGO diagnostic criteria for AKI depend on the baseline renal function, it is often unknown in clinical settings; therefore, it is permissible to use the serum creatinine (sCr) as back-calculated from the MDRD formula by assuming an estimated glomerular filtration rate (eGFR) of 75 (or from the sCr-eGFR predictive equation for Japanese people). However, a standard eGFR of 75 often overestimates the renal function in elderly people; consequently, the sCr as back-calculated from eGFR formulas is underestimated, which causes an increase in false positives in the AKI diagnosis (overdiagnosis). Due to their diminished capacity for renal recovery, AKI easily progresses to a severe state in elderly people. Because of the physical frailty and of cardiovascular complications, it is highly likely that the survival and renal outcomes predicted for adults do not apply to elderly people. Based on the above, elderly people, who are at a high risk of developing AKI, require highly accurate AKI diagnoses; therefore, the development of dedicated AKI diagnostic criteria for elderly people may be needed.
## Blood purification in elderly aki patients
Aging is an evident high-risk factor for AKI development [bib_ref] Acute renal failure in critically ill patients: a multinational, multicenter study, Uchino [/bib_ref] [bib_ref] The clinical features and outcome of crush patients with acute kidney injury..., Zhang [/bib_ref]. In Japan and other developed nations, the incidence of AKI has been increasing as the population ages; this trend is particularly pronounced in men [bib_ref] Community-based incidence of acute renal failure, Hsu [/bib_ref] [bib_ref] Changes of etiology, incidence and outcomes of severe acute kidney injury during..., Skarupskiene [/bib_ref] [bib_ref] Very old patients admitted to intensive care in Australia and New Zealand:..., Bagshaw [/bib_ref]. Blood purification is more often required in elderly patients (particularly those aged over 75) [bib_ref] Dialysis-requiring acute kidney injury in Denmark 2000-2012: time trends of incidence and..., Carlson [/bib_ref]. In a Turkish observational study, blood purification was performed in 43 of 193 patients (22%) with a mean age of 79.99 years who were diagnosed with AKI as defined by the KDIGO classification; when including the 16 patients (12.7%) who required blood purification after discharge, a total of 37.7% of the patients required blood purification [bib_ref] Acute kidney injury in the elderly hospitalized patients, Kayatas [/bib_ref].
In AKI patients-including elderly ones-whose AKI progresses to an advanced stage and presents uremic symptoms, blood purification undoubtedly improves the survival outcomes [bib_ref] Renal replacement therapy in acute kidney injury, Palevsky [/bib_ref]. However, there have been no randomized controlled trials (RCTs) that enrolled elderly patients with advanced AKI with the survival outcome as the primary endpoint; nor have there been any relevant systematic reviews. However, there has been a retrospective cohort study of elderly AKI patients. Liu et al. examined the factors that affected the survival outcomes of 41 elderly AKI patients aged 80-100 years who required continuous renal replacement therapy (CRRT) in Beijing, China [bib_ref] Application of continuous renal replacement therapy for acute kidney injury in elderly..., Liu [/bib_ref]. In the AKI patients who underwent CRRT, the APACHE II score was the factor most strongly associated with the survival outcomes; the number of involved organs and hypoalbuminemia were also indicated to be important, while the age itself was unrelated to the survival outcomes. These results are not limited to elderly patients, but are relatively common to all AKI patients; they may indicate that if AKI has reached an advanced stage, blood purification should be considered even in elderly patients. However, in a similar study by Kayatas et al. involving patients within a slightly broader age range (≥ 65 years), a reduced blood pressure, and high CRP levels, low hemoglobin (Hb), aging was also found to be associated with the AKI outcomes [bib_ref] Acute kidney injury in the elderly hospitalized patients, Kayatas [/bib_ref]. Moreover, several studies have noted racial differences in the outcomes; among elderly ICU patients who required blood purification, the outcomes were worse for non-Caucasian patients [bib_ref] the impact of race on intensity of care provided to older adults..., Chima-Melton [/bib_ref] [bib_ref] Dialysis versus nondialysis in patients with AKI: a propensity-matched cohort study, Wilson [/bib_ref].
In elderly AKI patients, the outcomes are often affected not only by AKI, but also by existing comorbidities. This is also observed in maintenance hemodialysis (HD) patients and elderly people in general [bib_ref] High cost and low survival rate in high comorbidity incident elderly hemodialysis..., Lin [/bib_ref]. Elderly AKI patients in ICUs are reported to commonly exhibit evident dementia and symptoms of delirium [bib_ref] the impact of race on intensity of care provided to older adults..., Chima-Melton [/bib_ref]. In addition, the AKI morbidity is high in frail elderly people; the latter are highly likely to require blood purification, and their activities of daily living are reported to decline progressively [bib_ref] Dialysis versus nondialysis in patients with AKI: a propensity-matched cohort study, Wilson [/bib_ref] [bib_ref] Acute kidney injury in the elderly, Abdel-Kader [/bib_ref]. Therefore, when considering whether to perform blood purification in an elderly AKI patient, the chronological age alone is not sufficient; the severity of the AKI, the speed of its progression, and details of the patient's pre-AKI health status may also be necessary. The above has also been stated in a limited number of studies. However, in elderly AKI patients who did not demonstrate any major health problems before developing AKI, we do not recommend the needless avoidance of blood purification simply because of age. Conversely, AKI patients with multiple comorbidities and low activities of daily living before developing AKI are highly likely to have a poor renal and survival prognosis, which makes it necessary to consider whether blood purification should be performed or not [bib_ref] Acute kidney injury in the elderly, Abdel-Kader [/bib_ref]. Giving a definitive answer to this question would require prospective RCTs involving large numbers of elderly AKI patients, as well as sub-analyses to determine the effective groups. Coca at Yale University recommends that such RCTs involving elderly AKI patients should be conducted [bib_ref] Acute kidney injury in elderly persons, Coca [/bib_ref].
On the patient's side, medical economic factors would normally be the greatest determinants of whether to undergo blood purification; however, since Japan has abundant public health insurance, medical economic aspects (burdens of expenses) do not have a major impact on patients' decisions. Therefore, the decision whether to undergo blood purification is considered with social factors on the patient's side, medical perspectives, and the medical institution's treatment capacity on the medical side.
## Progression from aki to ckd in elderly patients
The renal outcomes of AKI are not favorable. Observational studies have shown that 20-50% of AKI survivors progress to CKD. AKI is not only involved in the de novo development of CKD, but it may also accelerate existing CKD. When AKI develops in a person with a previously normal renal function, if the renal function does not recover to pre-AKI status, one of the following three pathways will unfold.
(1) progression to end-stage kidney disease (ESKD) after the onset of AKI (AKI to ESKD), (2) incomplete recovery of the renal function from AKI and progression to CKD (AKI to CKD), and (3) temporary recovery of the renal function from AKI, but subsequent progression to CKD (AKI to subclinical CKD). Furthermore, it has been shown that 30% of AKI patients have underlying CKD. This represents a fourth pathway: AKI to worsening CKD.
The prevalence of CKD in adults is estimated to be ≥ 10%. As the renal function declines with age, the prevalence of CKD is higher in the elderly; CKD affects 30-40% of people aged ≥ 65 years. Aging has been identified as a risk factor for post-AKI progression to CKD, along with diabetes, hypertension, heart failure, renal impairment, and hypoalbuminemia. The differences in the AKI incidence and the renal function outcomes of elderly and non-elderly people have not been examined in sufficient detail. However, in light of the high prevalence of CKD in the elderly and of the involvement of aging itself in the risk of progression from AKI to CKD, it is rather unlikely that the post-AKI renal function outcomes would be more favorable in elderly people than in non-elderly people. It is necessary to pay attention for the prevention and early detection of AKI, and its progression to a severe state.
The renal outcomes of AKI in elderly people were analyzed in a study of people enrolled in Medicare, the American health insurance system for the elderly (aged ≥ 65 years) [bib_ref] Acute kidney injury increases risk of ESRD among elderly, Ishani [/bib_ref]. Of the more than 230,000 people examined, CKD was present in 12%, while AKI had developed in 3.1%. Of the people who had developed AKI, 34% had prior CKD (AKI + CKD). The post-AKI survival rates of AKI + CKD patients were worse than those of patients with AKI alone. This study also analyzed the risks of progression to ESKD within 2 years of discharge; the hazard ratios for the development of ESKD in AKI + CKD, AKI only, and CKD only were 41.19, 13.0, and 8.43, respectively. These results indicated that elderly people with CKD who develop subsequent AKI experience poor renal outcomes.
The severity and frequency of AKI have also been reported to be independently involved in the risk of progression to CKD. One study retrospectively analyzed the relationship between the post-hospitalization development of AKI and the prognosis in a cohort of elderly people hospitalized for myocardial infarction who were Medicare beneficiaries [bib_ref] Long-term risk of mortality and end-stage renal disease among the elderly after..., Newsome [/bib_ref]. In the analysis-in which the patients were divided into four quartiles based on sCr increases of 0.1-3.0 mg/dl-the quartile of patients with the largest percentage increase in sCr demonstrated high rates of preexisting diabetes, hypertension, myocardial infarction, congestive heart failure, and cerebrovascular injury, as well as a reduced renal function. After adjusting for these factors, the percentage increase in the sCr demonstrated significant correlations with the percentage of post-AKI progression to end-stage renal failure and death. In elderly patients, the AKI severity was associated with the renal and survival outcomes. An association was also observed between the number of AKI episodes and the rate of progression to CKD. In a study of American veterans with comorbid diabetes, patients with multiple AKI episodes demonstrated a higher rate of progression to stage G4 CKD than those with a single AKI episode [bib_ref] Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus, Thakar [/bib_ref]. Given that a high percentage of elderly people have CKD and that the post-AKI renal function outcomes are poor in patients with comorbid CKD, practitioners should be cautious about the development of AKI in non-elderly and older people.
## Ethical considerations relevant to aki treatment in elderly people
Elderly people are at a high risk of AKI and have poorer renal and survival outcomes than young people. This point has already been discussed in the present guideline, and it has also been covered in many studies [bib_ref] Acute kidney injury in the elderly, Abdel-Kader [/bib_ref] [bib_ref] Acute kidney injury increases risk of ESRD among elderly, Ishani [/bib_ref] [bib_ref] Healthcare intensity at initiation of chronic dialysis among older adults, Wong [/bib_ref]. In a study comparing dialyzed AKI patients with not-yetdialyzed AKI patients, Wilson et al. concluded that dialysis causes more harm than no dialysis when the sCr is below 3.8 mg/dl; the authors' opinion was that dialysis is harmful in the presence of a decreased muscle mass, i.e. in frail patients [bib_ref] Dialysis versus nondialysis in patients with AKI: a propensity-matched cohort study, Wilson [/bib_ref]. The message of these findings is that in elderly patients, AKI must be recognized not as a transient disease condition that can be cured, but rather as a serious status that leads to prolonged hospitalization, more complications, and a higher risk of death. Moreover, the decision to initiate dialysis in elderly AKI patients must be understood not only in terms of its effects on the prognosis (i.e. the survival prognosis, progression to chronic dialysis, etc.), but also of its major effects on the patient's quality of life (QOL).
## Points of note in relation to elderly aki patients' treatment
Crews et al. demonstrated that in elderly AKI patients, earlier dialysis initiation may in fact cause harm. The implementation of shared decision-making (as described below) for dialysis initiation enables more patient-centered care, and the elderly who participate in this process tend to forgo dialysis initiation [bib_ref] Predialysis health, dialysis timing, and outcomes among older United States adults, Crews [/bib_ref]. When deciding whether to initiate dialysis in an elderly AKI patient, it is importance to make a comprehensive determination of the indication based on more than the disease condition, and to obtain consent from the patient (or their guardian) by dialoguing with them. This process, which is called "shared decision-making", is described in a guideline published by the Renal Physicians Association in the United States entitled "Shared Decision Making in the Appropriate Initiation of and Withdrawal from Dialysis, 2nd Edition". We present here a proposed "Dialysis assessment form for elderly AKI patients", which is based on a modification of the above guideline. Another potentially helpful resource is a process notebook that was developed in Japan to consider the initiation of dialysis in elderly patients with the patient's cooperation. Going forward, we hope that this perspective will lend further momentum to shared decision-making in the consideration of elderly AKI patients' treatment.
## The aging of society, and the consequent increase in social welfare expenses
Japanese society has been aging at a rate that is unparalleled in the world, and this trend is predicted to continue. In the 2014 fiscal year (FY), the aging rate in Japan reached 26.0%; specifically, individuals aged 65-74 years accounted for 13.4% of the overall population, while those aged ≥ 75 years represented 12.5% of the population. The aging rate is predicted to exceed 30% by 2025. In FY 2012, Japan's total social welfare expenditure reached ¥108.5568 trillion (~ $977 billion), its highest level ever. The percentage of national income spent on social welfare expenses has risen from 5.8% in 1970 to 30.9%, and the benefits paid to the elderly accounted for 68.3% of these expenses in FY 2012. Of the approximately ¥45 trillion (~$405 billion) spent on national health care in FY 2012, approximately ¥18 trillion (~ $162 billion; 44%) were spent on late-stage elderly people (age ≥ 75 years, 12.5% of the overall population). It must be recognized that these medical economic factors may also have a considerable influence on the treatment of AKI in elderly patients.
[fig] Figure 1: In-hospital mortality in CA-AKI versus HA-AKI. CA-AKI community-acquired acute kidney injury, HA-AKI hospital-acquired acute kidney injuryFig. 2 Rate of AKI stage in CA-AKI versus HA-AKI. CA-AKI community-acquired acute kidney injury, HA-AKI hospitalacquired acute kidney injury [/fig]
[fig] Figure 3: In-hospital mortality in septic AKI versus non-septic AKI 1 3 [/fig]
[fig] CQ6- 2: Are loop diuretics recommended for the prevention and treatment of AKI?Recommendation: We do not recommend loop diuretics for the prevention of AKI. We also suggest that loop diuretics should not be administered for the treatment of AKI, except to correct fluid overload. [/fig]
[fig] Figure 5: Meta-analysis for early initiation of blood purification (28-or 30-day mortality) [/fig]
[fig] Figure 6: Blood purification for pediatric patients [/fig]
[table] Table 1: RIFLE criteriaGFR glomerular filtration rate, sCr serum creatinine, ESKD end-stage kidney disease, UO urine output [/table]
[table] Table 3: KDIGO criteria sCr serum creatinine, UO urine output, RRT renal replacement therapy [/table]
[table] Table 4: Estimation of unknown baseline serum creatinine sCr serum creatinine, GFR glomerular filtration rate, CKD chronic kidney disease [/table]
[table] Table 5: Risk factors for AKI development in cardiac surgery ○: risk, △: risk without significance, ×: not risk, -: not evaluated [/table]
[table] Table 6: Risk factors for AKI development in heart failure [/table]
[table] Table 8: Differences between CA-AKI and HA-AKI [/table]
[table] Table 9: Urinary NGAL for early AKI diagnosis sCr serum creatinine, UO urine output, RRT renal replacement therapy, AUC area under the curve, 95% CI 95% confidence interval, NR: not reported References CohortAll case (n) AKI case AKI definition also peak within a relatively short period and then decline. Therefore, if the timing of the AKI development is unknown, it is necessary to consider whether the testing was performed at the appropriate time for measurement.PubMed was searched for relevant studies published up to August 2015, and papers related to the present CQ were identified from the search results. Search query: ((("acute kidney injury"[MeSH Terms] OR "acute kidney injury"[tw] OR "acute renal failure"[tw]) AND ("biological markers"[MeSH Terms] OR "biological markers"[All Fields] OR "biomarker"[All Fields])) AND ("diagnosis"[Subheading] OR "diagnosis"[All Fields] OR "diagnosis"[MeSH Terms])) AND (Meta-Analysis[PT] OR systematic[SB]). [/table]
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AGO Austria recommendation on screening and diagnosis of Lynch syndrome (LS)
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AGO Austria recommendation on screening and diagnosis of Lynch syndrome (LS)
Purpose This manuscript reports the consensus recommendations on screening and diagnosis of Lynch syndrome (LS) in patients with endometrial or ovarian cancer as well as on possible preventive measures in effectively LS-diagnosed women. The recommendations are issued by the Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) of the Ö sterreichischen Gesellschaft für Gynäkologie und Geburtshilfe (OEGGG) after consultation of the most recent and relevant literature and following deliberation by the Genetic Task-Force convoked May, 2015 by the AGO Council. Results and conclusion The Austrian AGO recommends immunohistochemical tissue screening for type-I and type-II endometrial cancers in all patients below the age of 70 years, and for all endometrioid and clear-cell ovarian cancers independently of the patient's age. If needed immunohistochemistry should be complemented by tissue MLH1 promotor hypermethylation testing and/or microsatellite instability (MSI) analysis. The diagnosis LS requires confirmation through identification of a germline mutation by a molecular genetic examination in the mismatch repair genes using the patient's blood. This should be performed without preceding tissue screening when in LS-associated cancer patients the family history fulfills the Amsterdam II or the revised Bethesda criteria. In LS-diagnosed women, the age for prophylactic surgery should be set flexibly based on an informed consent. Regarding the monitoring of these women, chemo-preventive measures as well as screening procedures either to avoid or to early detect LSrelated tumors are discussed with a special light on their specific limitations.
# Introduction
The autosomal dominant inherited tumor disposition syndrome first described by Henry Lynch in 1966 is caused by heterozygous (only one allele is affected) inactivating germline mutation in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. LS may also be due to a germline deletion of the 3 0 end of the EPCAM gene, which causes epigenetic inactivation of the neighboring MSH2 gene. Somatic loss of the second allele in neoplastic cells either, through monoallelic promotor hypermethylation, gene sequence alteration, a large deletion or another genetic alteration leading to loss of the heterozygosity (LOH) causes expression loss of the respective MMR protein and, consequently, DNA MMR deficiency. Intratumoral loss of one of these repair proteins is detected with immunohistochemistry (IHC) and the molecular correlate of MMR deficiency is microsatellite instability (MSI). Microsatellites are DNA sequences spread throughout the genome; their repetitive sequence structure makes them susceptible for replication errors that can only be repaired with a functioning MMR system. Changes in microsatellites consequently serve as markers for a non-functioning MMR system in LS.
However, loss of MMR function is also observed in some non-LS-related, sporadic endometrial cancers and is most frequently caused by loss of the MLH1 protein due to biallelic somatic hypermethylation of the MLH1 promotor.
Individuals with LS have, depending on which MMR gene is mutated, a lifetime risk of 20-75% of developing a colorectal carcinoma. That is why the syndrome previously was called hereditary nonpolyposis colorectal cancer (HNPCC). Women have an almost equally high lifetime risk for developing endometrial cancer [bib_ref] Lynch syndrome: an updated review, Sehgal [/bib_ref]. The endometrial carcinoma is frequently observed in women as an initial malignancy (so-called sentinel malignancy) that precedes a colorectal carcinoma diagnosis [bib_ref] Testing women with endometrial cancer for lynch syndrome: should we test all?, Ma [/bib_ref]. Women with LS also have a life-long risk of up to 12% for developing ovarian cancer, which may occur either alone or synchronously with another LS-associated malignancy. LS-related ovarian carcinomas are endometrioid or clearcell carcinomas or histological mixed forms with predominance of the two mentioned histological components. Purely serous or mucinous histological subtypes are not to be expected. In addition, individuals with LS also have a higher risk for other malignancies such as those of the stomach, small intestine, hepatobiliary epithelium, urothelium and brain. Thus, it is essential to obtain a detailed patient and family history for all cancer patients.
Of all diagnosed endometrial carcinomas, between 1.8 and 3% are associated with LS, while this is the case for 2.8% of colorectal carcinomas. Median age at diagnosis of LS-associated endometrial carcinoma is between 47 and 55 years, depending on the studied cohort. However, a notably high percentage of [30% of cases in women are diagnosed after the age of 60. Especially MSH6-associated endometrial carcinomas occur comparatively later [bib_ref] Lynch syndrome: an updated review, Sehgal [/bib_ref] [bib_ref] Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with..., Buchanan [/bib_ref] [bib_ref] Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact..., Hendriks [/bib_ref]. In addition, 8-20% of all endometrioid or clear-cell ovarian carcinomas exhibit microsatellite instability [bib_ref] The histomorphology of Lynch syndrome-associated ovarian carcinomas: toward a subtype-specific screening strategy, Chui [/bib_ref] and are LS associated. They generally occur at a younger age (median age 47 years) compared to non-LS-associated ovarian cancers [bib_ref] Lynch syndrome in patients with clear cell and endometrioid cancers of the..., Vierkoetter [/bib_ref].
## Diagnosis of ls
Suspicion for LS may derive from the patient's and her family's cancer history or from specific tumor characteristics. International criteria based on the personal or the family history have been established to select individuals who are at high risk for LS. The Amsterdam I (1991) and Amsterdam II (1999) criteria primarily refer to the frequent occurrence of LS-typical carcinomas in several closely related members of a family (at least three LS patients in at least two generations, age at diagnosis\50 years in at least one person) [fig_ref] Table 1: Amsterdam II criteria [/fig_ref] [bib_ref] New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed..., Vasen [/bib_ref]. The Bethesda criteria revised in 2002 give recommendations on the specific analysis of the tumor tissue for particular constellations (age at diagnosis, histology, multiple tumors, etc.) [fig_ref] Table 2: Revised Bethesda guidelines Colorectal cancer with the MSI-high histology b diagnosed in... [/fig_ref] [bib_ref] Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite..., Umar [/bib_ref]. However, historically the main focus of these recommendations was the prevention of colorectal carcinomas [bib_ref] Lynch syndrome: an updated review, Sehgal [/bib_ref]. Retrospective evaluations have shown that precisely in the case of LSassociated endometrial carcinomas the mentioned criteria often do not permit proper risk assessment and women at increased risk of endometrial cancer do not consistently fulfill selection criteria [bib_ref] Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with..., Buchanan [/bib_ref]. There are two tumor tissue-based specific screening procedures for raising strong suspicion of LS from:
- Immunohistochemical detection of the absence of one of the four relevant MMR proteins MLH1, MSH2, MSH6 or PMS2 in tumor tissue. - Identification of MSI by analyzing five defined microsatellites with RT-PCR from tumor DNA; two or more positive markers indicate a very strong suspicion of LS.
In case of immunohistochemical absence of either MLH1 or PMS2 [bib_ref] Isolated loss of PMS2 immunohistochemical expression is frequently caused by heterogenous MLH1..., Kato [/bib_ref] , or demonstrated microsatellite instability, tumor tissue should be tested for biallelic hypermethylation of the MLH1 promotor, which is indicative for sporadic non-LS-associated cancers. In 25% of all diagnosed endometrial cancers, MLH1 is missing on immunohistochemistry, and in 75% of these cases this is due to biallelic hypermethylation of the MLH1 promotor. In the less frequent cases of isolated loss of PMS2 immunostaining (2.5%), also MLH1 promotor hypermethylation is causative in 50% of the cases [bib_ref] Isolated loss of PMS2 immunohistochemical expression is frequently caused by heterogenous MLH1..., Kato [/bib_ref]. Therefore, methylation status of MLH1 promotor should also be tested in these cancers [fig_ref] Figure 1: Flow chart for Lynch syndrome work- [/fig_ref].
However, in patients with a manifest LS-associated carcinoma and a positive family anamnesis according to the Amsterdam II or the revised Bethesda 2002 criteria the mentioned screening procedure should be skipped and a germline analysis should be offered immediately.
The diagnosis ''Lynch syndrome'' requires confirmation through identification of a germline mutation by means of a molecular genetic examination of the MMR gene(s) using the patient's blood. Gene-targeted molecular germline testing is based usually on the immunohistochemical results of missing proteins. For this selective testing, it should be emphasized that it is important to include deletion of the 3 0 end of the EPCAM gene if there is a loss of MSH2 protein expression. Furthermore, MLH1 germline mutation was identified in 23% of cancers with isolated immunohistochemical PMS2 loss. Therefore, analysis of the MLH1 mutational status should be advocated in addition to that of PMS2 in these cases [bib_ref] Germline MLH1 mutations are frequently identified in Lynch syndrome patients with colorectal..., Dudley [/bib_ref]. However, massive parallel sequencing techniques presently allow analysis of all relevant MMR genes simultaneously with the highest cost effectiveness [fig_ref] Figure 1: Flow chart for Lynch syndrome work- [/fig_ref].
In Austria, all molecular genetic testing for germline mutations requires written informed consent following detailed genetic counseling according to § 69, of the Austrian Gentechnik-Gesetz.
Currently, evidence of LS has no direct therapeutic consequences but serves to predict the risk for synchronous and metachronous LS-associated malignancies in the patient herself or in her direct relatives. In the near future, a therapeutic consequence may arise from the MMR status in ovarian and endometrial cancers. Better response to immunotherapy with checkpoint inhibitors (e.g., PD1 antibodies) has been demonstrated in LS-associated colon carcinomas as compared with microsatellite-stable cancers and this may also prove true for other LS-associated tumors [bib_ref] PD-1 blockade in tumors with mismatch-repair deficiency, Le [/bib_ref].
## Ago austria recommendations
In agreement with the NCCN guidelines 2014 [bib_ref] Uterine neoplasms, version 1, Koh [/bib_ref] , the AGO Austria recommends for all women with endometrial carcinoma (types I and II) below age of 70 years that tumor tissue is tested for LS. The recommended method is immunohistochemical analysis for the MMR proteins MLH1, MSH2, MSH6 and PMS2 in a first step. If immunohistochemistry is unremarkable (nuclear expression of all MMR proteins), but the patient's personal or family history is suggestive for LS (i.e., one first-degree relative with an LS-associated malignancy or another LSassociated malignancy in the patient's own history), LS screening should be expanded to microsatellite instability analysis as some mutations may give rise to stable nonfunctioning proteins that are missed by immunohistochemistry [bib_ref] Lynch syndrome: an updated review, Sehgal [/bib_ref]. In addition, AGO Austria recommends that these analyses should also be conducted irrespective of age at diagnosis for endometrioid and clear-cell ovarian cancers.
If one or more of the relevant MMR proteins cannot be identified, or microsatellite instability is demonstrated after exclusion of MLH1 promotor hypermethylation, molecular genetic testing for germline mutation should be offered after previous genetic counseling according to § 69, of the Austrian Gentechnik-Gesetz. Even if all screening results are negative but the family history is nevertheless strongly suggestive for LS (i.e., Amsterdam II or revised Bethesda criteria are met) molecular genetic testing of all known LS-relevant genes should be considered [bib_ref] Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with..., Buchanan [/bib_ref] [bib_ref] Uterine neoplasms, version 1, Koh [/bib_ref].
With regard to cancer prophylaxis and early detection in women with proven LS, AGO Austria in agreement with other medical societies recommends:
1. Prophylactic total hysterectomy with bilateral salpingo-oophorectomy from age 35 years or after completed family planning [bib_ref] Management of extracolonic tumours in patients with Lynch syndrome, Koornstra [/bib_ref] should be discussed. The patient is to be informed that bilateral salpingectomy alone is not sufficient with regard to the histological subtypes of ovarian cancers, which could be expected. The age limit for prophylactic surgery should be set flexibly on the basis of a personalized decision made with the patient under consideration of the earliest age at diagnosis in the family history and her own endocrinological preferences. For orientation in this purpose, the following key parameters from the observational study by Schmeler et al. can be used [bib_ref] Uterine neoplasms, version 1, Koh [/bib_ref]. In the non-interventional, i.e., only observed subgroup of LS women, endometrial cancer occurred in 33% and the median age at diagnosis was 46 (range 30-60) years. However, 6% of these women (corresponding to 2% of all LS women of the noninterventional subgroup) were of age 35 or younger at diagnosis, and 18% (i.e., 6% of the non-interventional subgroup) were of age 40 or younger at diagnosis. In the non-interventional group, ovarian cancer was less frequently diagnosed (5.5%), and the median age at diagnosis was 42 (range 31-48) years. Of these patients, 17% (i.e., 1% of the non-interventional subgroup) were of age 35 or younger and 37% (i.e., 2.3% of the entire non-interventional subgroup) were 40 years or younger [bib_ref] Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch..., Schmeler [/bib_ref].
Of special note is that according to the current state of the art, hormone replacement therapy can be offered to these women following salpingo-oophorectomy.
2. Women who wish to avoid the risks of surgery and premature menopause and who understand the risk of ovarian-and endometrial cancer and the lack of efficient screening for early detection of both cancers might nevertheless choose observation. As an alternative, the patient should be offered the possibility of an annual endometrium biopsy (pipelle eventually complemented by an office-hysteroscopy) together with transvaginal ultrasound examination from age 30/35 years [bib_ref] Uterine neoplasms, version 1, Koh [/bib_ref] [bib_ref] Management of extracolonic tumours in patients with Lynch syndrome, Koornstra [/bib_ref] [bib_ref] Recommendations for the care of individuals with an inherited predisposition to Lynch..., Lindor [/bib_ref]. 3. To prevent colorectal cancer: regular colonoscopy at intervals of 1-2 years from age 20/25 years, or 10 years before the earliest occurrence of a colorectal carcinoma in the family anamnesis, should be performed.
Moreover, chemoprevention by means of NSRA or acetylsalicylic acid can prevent the occurrence of colorectal carcinomas [bib_ref] Chemoprevention of colorectal neoplasia, Wakeman [/bib_ref]. [bib_ref] Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with..., Buchanan [/bib_ref]. Regular medical examinations for early detection for other LS-relevant tumors. 5. Inform the patient about the symptoms of the mentioned malignancies and the need to explore such symptoms earliest if they occur. 6. Chemoprevention using oral contraceptives can be considered for young women, even though there are no prospective studies that demonstrate their efficacy for women with LS in particular. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://crea tivecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
[fig] Figure 1: Flow chart for Lynch syndrome work- [/fig]
[table] Table 1: Amsterdam II criteria [/table]
[table] Table 2: Revised Bethesda guidelines Colorectal cancer with the MSI-high histology b diagnosed in a patient who is younger than 60 years of age 4. Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor a , with one of the cancers being diagnosed before age 50 years 5. Colorectal cancer diagnosed in two or more first-or seconddegree relatives with HNPCC-related tumors, regardless of age Umar et al.[9] a HNPCC-related tumors include colorectal, endometrial, gastric, ovarian, pancreatic, ureter/renal pelvis, biliary tract and brain (usually glioblastoma as seen in Turcot syndrome) tumors, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel b Presence of tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation or medullary growth pattern [/table]
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Transition from childhood to adulthood in coeliac disease: the Prague consensus report
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Transition from childhood to adulthood in coeliac disease: the Prague consensus report
# Abstract
The process of transition from childhood to adulthood is characterised by physical, mental and psychosocial development. Data on the transition and transfer of care in adolescents/young adults with coeliac disease (CD) are scarce. In this paper, 17 physicians from 10 countries (Sweden, Italy, the USA, Germany, Norway, the Netherlands, Australia, Britain, Israel and Denmark) and two representatives from patient organisations (Association of European Coeliac Societies and the US Celiac Disease Foundation) examined the literature on transition from childhood to adulthood in CD. Medline (Ovid) and EMBASE were searched between 1900 and September 2015. Evidence in retrieved reports was evaluated using the Grading of Recommendation Assessment, Development and Evaluation method. The current consensus report aims to help healthcare personnel manage CD in the adolescent and young adult and provide optimal care and transition into adult healthcare for patients with this disease. In adolescence, patients with CD should gradually assume exclusive responsibility for their care, although parental support is still important. Dietary adherence and consequences of non-adherence should be discussed during transition. In most adolescents and young adults, routine small intestinal biopsy is not needed to reconfirm a childhood diagnosis of CD based on European Society for Pediatric Gastroenterology, Hepatology and Nutrition or North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) criteria, but a biopsy may be considered where paediatric diagnostic criteria have not been fulfilled, such as, in a patient without biopsy at diagnosis, additional serology (endomysium antibody) has not been performed to confirm 10-fold positivity of tissue transglutaminase antibodies or when a no biopsy strategy has been adopted in an asymptomatic child.
# Introduction
The Child and Adolescent Health Measurement Initiative estimates that one million US children with special health needs make the transition to adult care every year.A large proportion of adolescents/young adults, however, have not been sufficiently prepared for the transfer to adult care. Coeliac disease (CD) [bib_ref] The Oslo definitions for coeliac disease and related terms, Ludvigsson [/bib_ref] is one of the most common chronic disorders in childhood, and children with CD make up an important part of transition healthcare in the Western world. The overall prevalence of CD varies from 0.71% in the USA [bib_ref] The prevalence of celiac disease in the United States, Rubio-Tapia [/bib_ref] to as high as 2.9% in certain age groups in Sweden. [bib_ref] Celiac disease revealed in 3% of Swedish 12-year-olds born during an epidemic, Myléus [/bib_ref] Data also suggest that both diagnostic rates and incidence of undiagnosed and diagnosed CD 9 10 are increasing.
Generally, the transition from paediatric to adult care should be a collaborative process involving patients, their parents or caregivers, the physician and the dietician. [bib_ref] American Academy of Family Physicians; American College of Physicians; Transitions Clinical Report..., Cooley [/bib_ref] This transition has also been made a top 10 priority by the American Academy of Pediatrics 11 with dedicated programmes for patients and professionals (eg, the Bright Future Programme). There are several transition recommendations for chronic disease, but very few for CD, [bib_ref] Transition of gastroenterological patients from paediatric to adult care: A position statement..., Elli [/bib_ref] and without comment on CD-specific aspects of different recommendations for diagnostics in childhood [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] and adulthood. In this consensus report, we propose recommendations for the management of CD in adolescents and young adults, and how to facilitate the transition to adult healthcare for patients with CD.
# Methods
Seventeen physicians from 10 countries (Sweden, Israel, Italy, the USA, Germany, Norway, the Netherlands, Australia, Britain and Denmark) and 2 representatives from patient organisations (Association of European Coeliac Societies and the US Celiac Disease Foundation) examined the available literature on the transition from childhood to adulthood CD.
## Intent and levels of evidence
We carefully weighed all aspects of the childhood to adulthood transition in relation to CD diagnosis and management. In conjunction with librarians at the Karolinska Institute, Sweden, we searched Medline (Ovid) and EMBASE between 1900 and September 2015 to identify the most relevant information for this review. The following search algorithm was used ("transition of care" or "transition of management" or "continuity of care") AND ("adolescence" or "pediatrics") AND ("celiac disease" or "coeliac disease") and identified 190 references. We also explored the literature on transitional issues in other paediatric fields and additional relevant literature. The working groups developed initial recommendations and rated the quality of evidence and strength according to the Grading of Recommendation Assessment, Development and Evaluation method. The quality of evidence for each statement was graded as high, moderate or low (A, B, C). [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] Our consensus group consisted of paediatricians , two general practitioners (LA, APH), one histopathologist (MMW) and two representatives from a patient organisation (MGG, TK).
After an initial review of the literature, we formed working groups focusing on different topics (see online supplementary appendix). Each working group worked independently prior to a first draft created by JFL. All data and opinions were discussed among all coauthors to reach consensus. The content of this report was discussed through teleconferencing and at two gastroenterology meetings (Prague, June 2015; Barcelona, October 2015). All authors agreed on the conclusions of the report.
# Results
Transfer of responsibility for self-care from the paediatric to the adolescent patient with CD Paediatric patients with CD are usually seen by their general paediatrician and in a specialised centre by a team comprising a paediatric gastroenterologist, a specialised nurse, a dietician and, if needed, a social worker or psychologist. In children, the delivery of care is fundamentally family-centred, whereas in adulthood, responsibility becomes autonomous and dependent upon the needs of individuals. [bib_ref] Between two worlds: bridging the cultures of child health and adult medicine, Rosen [/bib_ref] Adolescents typically start to seek independence as part of a structured family environment, but as adults they leave home, learn how to live with others and assume various responsibilities (eg, work and societal and financial commitments). [bib_ref] Transition from paediatric to adult care: psychological principles, Bryon [/bib_ref] The transition process should gradually parallel this evolution of becoming an adult and include an incremental increase in shifting knowledge and decisions to the adolescent patient with CD. [bib_ref] Between two worlds: bridging the cultures of child health and adult medicine, Rosen [/bib_ref] The actual transfer may also be triggered by non-age-related factors, such as pregnancy, marriage, poor dietary adherence, substance abuse or dropping out from school. While none of these factors may signal maturity, they may draw the family's attention (and that of the family doctor) to the fact that the adolescent is entering adulthood. The physical, mental and psychosocial development when becoming an adolescent and ultimately an adult is central to transition. This development varies between individuals of the same age, and of note, children with a chronic disease may develop autonomy later than their peers. [bib_ref] Young adult patients with a history of pediatric disease: impact on course..., Stam [/bib_ref] Both the family and the adolescent patient should be at the centre of transition, and the function of the clinician is to balance the parents' authority and the need for autonomy in the adolescent. Many adolescents/young adults have to work hard to overcome their reliance on their parents. To parents, this means stepping back and allowing their adolescent children to make independent decisions. Both overprotection and insufficient support of the child are undesirable.
In a joint statement, 11 three physician organisations suggest that the physician starts a discussion about transition when the adolescent is 12-13 years old, develop a transition plan when the child is 14-15, with the actual transfer taking place at ≥18 years of age. We agree with this timeline, although cultural and social differences as well as individual patient preferences mean variations may occur. Transition is a complex process, and specific aims for transition in adolescents and young adults are listed in box 1.
Statement: The transition process should gradually parallel evolution of child to adult and include an incremental increase in transferring responsibility for self-care to the adolescent patient with CD. (C)
Recommendation: We recommend to gradually transfer responsibility of medical care to the adolescent patient with CD.
## Growth and puberty
Growth impairment is a known consequence of untreated or undertreated CD though many children with short stature diagnosed with CD in childhood demonstrate good catch-up growth. [bib_ref] Short stature and catch-up growth in celiac disease, Troncone [/bib_ref] However, catch-up growth may occur more predictably for those with a delayed bone age at diagnosis and where growth velocity acceleration during the first year of treatment for CD is apparent. [bib_ref] Growth and adult height in atypical coeliac patients, with or without growth..., Salardi [/bib_ref] Untreated CD, or CD diagnosed after attainment of adult height, results in shorter adult height than seen in healthy controls, particularly among men. While the precise pathophysiology may currently be poorly understood, some adolescents and young adults with CD will experience a delay in pubertal development [bib_ref] Two cases presenting with pubertal delay and diagnosed as Celiac disease, Abaci [/bib_ref] and may continue to grow and sexually mature beyond the expected age of pubertal completion. [bib_ref] The teenage coeliac: follow up study of 102 patients, Kumar [/bib_ref] This may have implications for emotional maturity, sexual health and menstrual regularity. At the time when transition is anticipated, the paediatric provider should provide data regarding the patient's history of physical development and should note to the adult provider whether the patient has achieved his or her final adult height. For those patients who have experienced significant pubertal delay where the paediatric provider may be better suited to provide guidance, it may be advisable to coordinate transition to an adult provider at the completion of puberty, particularly where other paediatric specialists such as endocrinologists continue to care for the patient to manage growth failure. A bone age X-ray may be done for cases of observed pubertal delay to inform growth expectations and timing of transition.
## Barriers to a successful transition in cd
Several factors inhibit a successful transition; among them is having an adult healthcare provider without experience of the Box 1 Specific aims for transition to adult care in adolescents and young adults with coeliac disease ▸ Encourage maturation of communication and decision-making skills. ▸ Allow patients to take responsibility for medical self-management. ▸ Education and counselling of the adolescent/young adult to manage a gluten-free diet and consequences of non-adherence. ▸ Recognition and treatment of psychological problems: discouragement, feeling overwhelmed, anxiety about the future and complications such as depression and eating disorders. ▸ Show patients how to become familiar with the healthcare system, including environmental changes when they legally become an adult. ▸ Increase disease knowledge and its potential complications. ▸ Help the patient develop good health habits and self-care skills that encourage autonomy and establish good health habits. ▸ Address the family's anxieties or questions. relevant disease. The paediatric healthcare provider should therefore help the adolescent identify a concerned and capable caregiver for adults. [bib_ref] Health care transition: youth, family, and provider perspectives, Reiss [/bib_ref] A transition programme can only be successful if organised with the active participation and interest of the adult healthcarers, 20 who may be a gastroenterologist or a general practitioner.
One inherent barrier impeding an adolescent's communication with a health provider is the fear of being judged. Out of the fear of being judged by the adult physician, adolescents may be less likely to ask questions that could reveal a history of nonadherence with medical recommendations. [bib_ref] Chronically ill adolescents' experiences of communicating with doctors: a qualitative study, Beresford [/bib_ref] The key here is to establish a regular communication channel between the adolescent/young adult and the adult physician.
The patients' impression of their provider influences the likelihood of effective communication of health information and patient concerns. Unsurprisingly, conflict with the healthcare provider has a negative impact on adherence to therapeutic regimens. Cultural distinctions between paediatric and adult providers have been noted, where departure from a child to an adult environment with a greater expectation of patient independence may deter some families. Families of young adults with a variety of chronic conditions report relative decrease in support and availability for advice from their new adult provider. [bib_ref] Health care transition: youth, family, and provider perspectives, Reiss [/bib_ref] Some patients and parents, therefore, prefer to remain with their paediatrician. Ensuring that no adolescent drops out at transfer of care is crucial. Statement: The patients' impression of their provider influences the adherence and communication of health information and patient concerns. (C)
Recommendation: Healthcare providers are advised to consider that their demeanour is likely to influence patient concerns as well as the effectiveness of health information.
## The actual transfer of care
There are differences between CD and other chronic diseases. For example, patients do not depend on particular medications with prescriptions and thus visits to a physician are not obligatory. In fact, many patients believe they have mastered the gluten-free diet (GFD) and have minimal contact with healthcare. In addition, non-adherence to diet may not cause symptoms for years, giving a false sense of security. Therefore, adolescents/young adults with CD are at risk of 'medical' dropout prior to and during transfer. [bib_ref] American Academy of Family Physicians; American College of Physicians; Transitions Clinical Report..., Cooley [/bib_ref] Meanwhile, adult services expect that their adult patients will be able to care for themselves and be capable of negotiating the hospital clinical system. So, clearly there is a need to bridge the gap between the paediatric and adult services. [bib_ref] Transition from paediatric to adult care. Bridging the gaps or passing the..., Viner [/bib_ref] For adult gastroenterologists, CD is also often perceived as a less serious disease compared with GI cancer or IBD and knowledge may be limited with respect to complications, diet, inheritance, extraintestinal manifestations and how to monitor patients.
The actual transfer can take many forms. In some settings, the paediatric and adult gastroenterologists see the patient at the same visit; in others, paediatric and adult gastroenterologists meet annually to discuss patients in transition. Optimally, joint transition clinics with paediatric and adult service clinicians can be established for information delivery and generating trust in the new physician. [bib_ref] Transition of patients with inflammatory bowel disease from pediatric to adult care, Dabadie [/bib_ref] Structured transitional models and targeted education are important and in other chronic diseases [bib_ref] Transition of management in adolescents with IBD, Zeisler [/bib_ref] [bib_ref] Transitioning health care responsibility from caregivers to patient: a pilot study aiming..., Annunziato [/bib_ref] [bib_ref] Transition to adult care for youths with diabetes mellitus: findings from a..., Nakhla [/bib_ref] [bib_ref] The impact of a coordinated transitional care programme on adolescents with juvenile..., Mcdonagh [/bib_ref] [bib_ref] Improving the transition between paediatric and adult healthcare: a systematic review, Crowley [/bib_ref] have been linked to improved care, better health outcome and improved health-related quality of life (QoL). One path to facilitate transition and transfer of care is to create a 'transition document', which would allow a smooth transfer of individual medical care data 36 (see online supplementary appendix). Such a transition document should be created by the paediatrician prior to transfer, and at the minimum, contain details of the basis for the coeliac diagnosis and information during follow-up such as serology, anthropometric data, comorbidities and dietary compliance.
Recommendation: We recommend that the actual transfer from paediatric to adult care should be structured and include as the minimum written information on the base of diagnosis, follow-up, anthropometric data, comorbidities and dietary compliance.
Communicating with the adolescent/young adult Adolescents and young adults may have difficulty communicating with health providers for many reasons. Consequently, providers should be flexible in their communication styles when working with young adult patients. At a face-to-face encounter, it is unclear whether the presence of a parent at the medical visit may be detrimental or supportive to adolescent/young adult communication with the provider. [bib_ref] Chronically ill adolescents' experiences of communicating with doctors: a qualitative study, Beresford [/bib_ref] The presence of a parent can be helpful if the adolescent has not been prepared for independent visits.
Traditional medical care for coeliac patients consists of regular physician visits to evaluate their health, including weight and height measurements (in children), dietary adherence and CD-specific serum antibodies. [bib_ref] ACG clinical guidelines: diagnosis and management of celiac disease, Rubio-Tapia [/bib_ref] Although important, these measures can be time-consuming. In addition, many patients do not visit their physician for regular CD follow-up. Young patients may also have difficulty expressing sensitive concerns in person to a provider, but may do so more readily by email. [bib_ref] Health communication and adolescents: what do their emails tell us?, Harvey [/bib_ref] Other types of electronic communication, including videoconferencing, SMS messaging, and online consultations, have also been tested in paediatric groups with some success. [bib_ref] Health information technology to facilitate communication involving health care providers, caregivers, and..., Gentles [/bib_ref] Another option can be a self-management e-health coeliac follow-up independent from time and place limitations.
Research in other disease areas shows that e-health selfmanagement encourages patients to manage their disease and improve their physical and psychosocial well-being. [bib_ref] Information and communication technology-enabled person-centered care for the "big five" chronic conditions:..., Wildevuur [/bib_ref] Issues that need to be discussed during transition/transfer Several issues may be discussed during the transition period 47 (box 2). Some adolescents/young adults may question their diagnosis and feel the transition period is a natural point for discussing how the diagnosis was made and whether re-evaluation is appropriate. During transition, patients may also realise that they have a long-term condition that requires monitoring throughout adult life. They may also become aware that CD is linked to increased mortality and comorbidity though the excess risks are generally seen in the first 1-2 years after diagnosis. [bib_ref] Small-intestinal histopathology and mortality risk in celiac disease, Ludvigsson [/bib_ref] [bib_ref] Nationwide cohort study of risk of ischemic heart disease in patients with..., Ludvigsson [/bib_ref] [bib_ref] Risk of thyroid disease in individuals with celiac disease, Elfström [/bib_ref] Of special importance to the adolescent and young adult with CD is adherence to a GFD. In Europe, adherence to a GFD by children and adolescents varies from 44% to 97%, 51-55 and accidental transgressions are common. [bib_ref] Swedish children with celiac disease comply well with a gluten-free diet, and..., Tapsas [/bib_ref] At an early age, a GFD may have been prescriptively provided by carers at home, with some involvement of the school. In adolescence, the responsibility of keeping a GFD must be shared by the child and his or her parents. Adherence to a GFD can be very difficult, particularly as the children face new challenges: peer pressure and the stigma of 'being different', school trips and increasing independence from their parents. Adolescence is recognised to be a period when adherence is poor and thus potential risk factors for poor adherence should be recognised. [bib_ref] Celiac disease: predictors of compliance with a gluten-free diet in adolescents and..., Errichiello [/bib_ref] The little (and historic) data that are available reveal that increasing adherence can be maintained by regular follow-up. [bib_ref] Need for follow up in coeliac disease, Bardella [/bib_ref] Adolescents report lower adherence than younger children, particularly at social events. [bib_ref] Factors affecting adherence to a gluten-free diet in children with celiac disease, Macculloch [/bib_ref] Dietary non-adherence in adolescents is associated with increased disease burden, poorer QoL and increased physical symptoms. [bib_ref] Quality of life in adolescents with treated coeliac disease: influence of compliance..., Wagner [/bib_ref] Most young people with CD think that avoiding cancer is the most important reason to adhere to a GFD. However, the risk for cancer in CD is much lower than previously presumed, [bib_ref] European multi-centre study on coeliac disease and non-Hodgkin lymphoma, Mearin [/bib_ref] [bib_ref] Risk of Lymphoproliferative Malignancy in Relation to Small Intestinal Histopathology Among Patients..., Elfström [/bib_ref] [bib_ref] Low risk of gastrointestinal cancer among patients with celiac disease, inflammation, or..., Elfström [/bib_ref] and instead, the risk of osteoporosis [bib_ref] Persistent mucosal damage and risk of fracture in celiac disease, Lebwohl [/bib_ref] and adverse pregnancy outcome may be bigger issues in individuals with poor adherence. Refractory CD is very rare in children. Undiagnosed patients with CD may adopt a high-energy diet because of malabsorption. If they continue their eating behaviour after diagnosis, they risk obesity and metabolic syndrome, especially the first year after diagnosis. [bib_ref] Metabolic syndrome in patients with coeliac disease on a gluten-free diet, Tortora [/bib_ref] Mariani et al 61 reported that 72% of Italian adolescents with CD who strictly adhered to the diet were overweight and consumed an unbalanced diet rich in fat and protein, poor in carbohydrate and deficient in calcium, iron and fibre.
After moving away from home, adolescents/young adults with CD are responsible for purchasing food and cooking, activities previously provided by their parents. Financial issues for the more expensive gluten-free products become more relevant for adolescents/young adults who now live on a limited budget. Adolescents attending college or university face both the difficulty of an abrupt transition from home to a dining room situation with variable provisions for a GFD by their respective institutions and social pressures in adhering to the diet. [bib_ref] Navigating the gluten-free diet in college, Panzer [/bib_ref] Statement: Dietary adherence and consequences of nonadherence are key components for discussion in a transition setting. (C)
Recommendation: We recommend that dietary adherence and consequences of non-adherence are key components for discussion in a transition setting.
## Current guidelines for coeliac diagnosis
Recently, several guidelines have appeared for CD diagnosis reflecting the development in diagnosis of CD (eg, better quality of serological tests and the increased awareness of CD). The NASPGHAN guidelines (USA) from 2005 73 clearly address the questions who to test and how to test using transglutaminase 2 IgA antibody (TG2-IgA) combined with total IgA as a screening tool, followed by referral to a paediatric gastroenterologist and biopsy, with the diagnosis based on a histological analysis. More recently, the ESPGHAN guidelines, [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] as well as the British Society for Paediatric Gastroenterology guidelines for the diagnosis of CD, 74 advocate TG2-IgA with total IgA (and IgG-based tests in case of IgA deficiency) as a screening tool. Furthermore, based on an evidence report, [bib_ref] Accuracy of diagnostic antibody tests for coeliac disease in children: summary of..., Giersiepen [/bib_ref] in cases with symptoms and very high TG2-IgA levels (>10× the upper limit of normal (ULN)), which gives a high likelihood for concurrent enteropathy, [bib_ref] Coeliac disease: a biopsy is not always necessary for diagnosis, Hill [/bib_ref] current ESPGHAN guidelines suggest that in carefully selected cases a biopsy avoidance strategy may be employed by undertaking further supportive tests (HLA-DQ2 and DQ8 determination may rule out CD, and the endomysial antibodies (EMAs) test has a high specificity). If these investigations are consistent with the suspicion of CD, the diagnosis may be established without a biopsy after careful discussion with a paediatric gastroenterologist. Conversely, the adult guidelines from Europe 16 and the USA 17 recommend a diagnosis of CD based on TG2-IgA and with biopsy. The US guidelines [bib_ref] ACG clinical guidelines: diagnosis and management of celiac disease, Rubio-Tapia [/bib_ref] consider the pre-test probability and recommend in populations with high pre-test probability to use biopsy in conjunction with TG2-IgA. In populations with a lower pre-test probability, the guidelines suggest waiting for the TG2-IgA results before performing a biopsy. The British guidelines in addition use the EMA test for strengthening the suspicion of CD.
There are good reasons to perform an upper endoscopy with biopsies in adults with suspected CD (box 3). However, some of these issues may not apply in children/adolescence. A further complexity of the CD diagnosis is that the histological analysis may show variability between histopathologists, [bib_ref] Variability in small bowel histopathology reporting between different pathology practice settings: impact..., Arguelles-Grande [/bib_ref] and use as the reference standard for the diagnosis of CD has been challenged. Therefore, it is important, as recommended by all guidelines, to take serology, histology and HLA status into account when there are uncertainties in diagnosis. [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] Use of biopsy, CD serology and genetic testing in transition to adulthood While duodenal biopsies have been the reference standard for diagnosis of CD, recently, a selective no biopsy policy has been Box 2 Topics that may be discussed during transition in coeliac disease (CD)
▸ Education on the risk of developing complications despite being asymptomatic (there can be a long interval between gluten exposure and the return of symptomatic disease). ▸ A preventive care plan to increase adolescent/young adult health, even for factors not directly related to CD, [bib_ref] Is HEADS in our heads? Health risk behavior is not routinely discussed..., Boisen [/bib_ref] such as education about smoking, [bib_ref] Longitudinal examination of predictors of smoking cessation in a national sample of..., Walker [/bib_ref] alcohol and drug abuse, [bib_ref] Understanding young adult physical activity, alcohol and tobacco use in community colleges..., Vankim [/bib_ref] and the importance of physical exercise. [bib_ref] Bone mass in women with celiac disease: role of exercise and gluten-free..., Passananti [/bib_ref] Dietary education that is aimed to avoid deficiencies and to control weight. 126 ▸ Medical monitoring with laboratory tests and healthcare visits according to the management of all chronic conditions. 11 ▸ Allocating time and space to discuss with experts about psychological aspects as CD may influence self-image and self-esteem [bib_ref] Best practices in managing transition to adulthood for adolescents with congenital heart..., Sable [/bib_ref] and interfere with school, education and work. [bib_ref] Disease characteristics as determinants of the labour market position of adolescents and..., Calsbeek [/bib_ref] 128 ▸ Sexuality and fertility. Dietary adherence is especially important before conception and during pregnancy as women with untreated CD are more likely to suffer an adverse pregnancy outcome. Several large studies have, however, shown that lifetime fertility is similar in individuals with and without CD. 129-131 ▸ The gluten-free diet (see text).
proposed for some children. In comparison, the policy adopted by gastroenterologists who care for adult patients uniformly requires a biopsy for diagnosis and frequently a follow-up biopsy to document healing for management and prognostic information. The no biopsy policy was adopted by ESPGHAN, but it is not widely accepted in the USA or Australia. This difference between paediatric and adult gastroenterologists may present a topic for discussion in the transition from paediatric to adult care. Both parties will be interested in the quality of the diagnosis of CD to attain the best quality of care. All diagnostic test results must be available to the accepting physician. Of importance to recognise is that the respective guidelines may not have been followed by the physician who made the initial CD diagnosis. The main themes are as follows: [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] Review of the symptoms, results of serology, HLA status and response to GFD. For levels of TG2-IgA <10× ULN, biopsy data must be available. Different scenarios may be envisaged: 1. The child was symptomatic at diagnosis with malabsorption and the diagnosis based on a TG2-IgA >10× ULN, appropriate HLA, positive EMA on a second blood draw and a good response to a GFD. This diagnosis appears to be of high quality that should prompt continuing management with a strict GFD. 2. The child was asymptomatic with, for example, type 1 diabetes mellitus (T1DM) and TG2-IgA >10× ULN, appropriate HLA and no biopsy. A single positive tTG IgA test may have been obtained without a second blood draw, confirming a positive tTG or EMA. In this setting, it is necessary to consider whether there may be a temporary coeliac autoimmunity as has been seen in children and adults. The 2012 ESPGHAN criteria are not met in that these criteria do not accept a definitive diagnosis of CD without a biopsy in asymptomatic at-risk groups (a biopsy may be suggested after a gluten load). We urge caution in accepting a diagnosis where diagnostic criteria, as outlined by paediatric guidelines in Europe or North America, have not been fulfilled.
The serological diagnosis of CD is dependent on the quality of the assay employed. For TG2-IgA, the majority of the tests are based on ELISA and eminently suited for assay quality control measures. EMA testing is based on immune fluorescence and with an operator-dependent read-out with possibilities for variability. Yet, EMA testing is the assay with the highest specificity. [bib_ref] Accuracy of diagnostic antibody tests for coeliac disease in children: summary of..., Giersiepen [/bib_ref] As stated in the ESPGHAN diagnostic guideline, to rely on serology, the tests have to be subject to continuous participation in control measures (such as the National External Quality Assurance Scheme (NEQUAS) initiative in Europe). In non-European countries, significant laboratory variability may occur and whether these cut-offs are valid in countries such as the USA are yet to be confirmed. A diagnosis made according to the ESPGHAN guidelines outside of Europe should be considered in the context of this potential uncertainty. [bib_ref] Evaluation of the ESPGHAN Celiac Guidelines in a North American Pediatric Population, Gidrewicz [/bib_ref] The histological evaluation may also be indeterminate and transition into adult care could be a convenient time for re-evaluation, even when the initial diagnosis is definitive. is an overview of differences in the use of histology for diagnostic purposes in children and adults.
Persistent mucosal lesions are common in adults with CD, despite normalisation of serologies. [bib_ref] Predictors of persistent villous atrophy in coeliac disease: a population-based study, Lebwohl [/bib_ref] Concomitant with these lesions are augmented risks of morbidity such as lymphoma [bib_ref] Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based..., Lebwohl [/bib_ref] and certain fractures. [bib_ref] Persistent mucosal damage and risk of fracture in celiac disease, Lebwohl [/bib_ref] Whereas these risks may be lower in children, [bib_ref] Follow-up of pediatric celiac disease: value of antibodies in predicting mucosal healing,..., Vécsei [/bib_ref] and refractory CD and consequently enteropathy associated t-cell lymphoma (EATL) is extremely rare in subjects with CD diagnosed in and treated since childhood, adolescents and young adults with CD may have greater difficulty with dietary adherence, whether accidental or intentional. Early identification of such risks may thwart future adverse outcomes and identify those in need of greater surveillance.
Also important is the procedure adopted for transitional follow-up. If the existing diagnostic guidelines have not been met and the diagnosis needs re-evaluation, a new diagnostic approach should be instituted. Serology and histology may be part of this approach. [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] However, undertaking duodenal biopsies while on a GFD may be uninformative, except for ruling out differential diagnosis and to confirm mucosal healing. After transition, care will be determined dependent upon the results of nutritional, serological, genetic and dietary assessment. [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] There are four indications for performing a biopsy before or after transition to adult care in some settings with a gluten challenge: Histology in children and adults with suspected coeliac disease (CD)
## Children adults
Is a biopsy necessary for diagnosis?
Dependent on TG2 level, HLA status-if anti-TG2 titres are high (>10 times the upper limit of normal), the ESPGHAN guidelines have an option to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] Recommendation for biopsy-all guidelines emphasise the combined use of biopsy and serological analyses for diagnosis. [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] However, in low-resource countries, a positive TG2 with symptom improvement on a GFD may be considered sufficient for diagnosis. How many biopsies? And where from? 4-6 including 2 from bulb, as focality was present in 18%, patchiness in 53% and at least 1 normal biopsy fragment was present in 36% of the cases. Sometimes, changes compatible with CD are only seen in the bulb, 140 11% of patients show only duodenal bulb involvement, and also bulb sparing, so both should be taken. [bib_ref] Importance of duodenal bulb biopsies in children for diagnosis of celiac disease..., Rashid [/bib_ref] At least four, including bulb biopsy. Adherence to guidelines for biopsy?
In those without histological evidence of CD, fewer biopsies are obtained with none documented from the bulb. Failure to take the recommended number of biopsies could result in some missed cases of CD. [bib_ref] Adherence to Endoscopy Biopsy Guidelines for Celiac Disease, Ofei [/bib_ref] Adherence to submitting ≥4 specimens is low in the USA. Adherence yields a doubling of the diagnostic rate of CD. [bib_ref] Adherence to biopsy guidelines increases celiac disease diagnosis, Lebwohl [/bib_ref] Intraepithelial lymphocytes/100 enterocytes. What is the cut-off count?
Normal architecture with increased IELs is considered non-specific in paediatric guidelines. [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] Normal architecture with ≥25 IELs/100 enterocytes has been validated as a cut-off point in adults. GFD, gluten-free diet; IEL, intraepithelial lymphocyte; TG2, transglutaminase 2.
1. if the existing guidelines have not been met; 2. the adolescent has ceased a GFD because he or she doubts the diagnosis; 3. the patient or the physician requires documentation of healing; 4. the presence of symptoms suggests active CD or another diagnosis. The potential contribution of genetics in ruling out CD in suspect or insufficiently diagnosed cases is important. CD is strongly associated with the HLA-DQ2 and HLA-DQ8 genotypes. [bib_ref] Genetic background of celiac disease and its clinical implications, Wolters [/bib_ref] While HLA-DQ2 or DQ8 occurs in >99% of people with CD, it is found in ∼30% of the general population, and therefore, a positive genetic test does not confirm a CD diagnosis. [bib_ref] Systematic review: noncoeliac gluten sensitivity, Molina-Infante [/bib_ref] Statement: In adolescents and young adults, biopsy to reconfirm a childhood diagnosis of CD may be considered when the 10-fold positive tissue transglutaminase antibody result has not been confirmed by positive EMA in a second serology at the time of diagnosis or when the ESPGHAN diagnostic criteria have not been met in a child without duodenal biopsies. Biopsies may also be relevant when the adolescent has ceased a GFD because he or she doubts the diagnosis; the patient or the physician requires documentation of healing; and the presence of symptoms suggests active CD. (C)
Recommendation: We recommend that in adolescents and young adults, routine small intestinal biopsy is not required to reconfirm a childhood diagnosis of CD when the diagnosis has been made according to ESPGHAN or NASPGHAN criteria.
Statement: HLA testing can be used to rule out CD in unclear cases. (B)
Recommendation: We recommend testing for HLA-DQ2 and HLA-DQ8 genotypes in unclear cases.
## The gluten challenge
A gluten challenge after transfer to adult care is normally not needed if diagnostic criteria have been followed, including children diagnosed younger than 2 years of age. [bib_ref] Diagnosis of coeliac disease in children younger than 2 years, Misak [/bib_ref] A gluten challenge is indicated when the primary diagnosis of CD was not performed according to standards and guidelines. [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] A second circumstance when a gluten challenge is applicable is when the patient requests proof of the diagnosis, even though the initial diagnosis was performed according to the current standards.
There are no well-established rules in a gluten challenge. The clinical tolerability and the time to relapse vary between patients, but traditionally a 3 months' challenge with moderate to high amounts of gluten has been advocated, [bib_ref] Standardised approach to gluten challenge in diagnosing childhood coeliac disease, Rolles [/bib_ref] keeping in mind that an enteropathy may occur after an extended period of time. [bib_ref] Postpubertal gluten challenge in coeliac disease, Mäki [/bib_ref] Before gluten challenge, serology for CD-specific autoantibodies should be performed (duodenal biopsies should preferentially be obtained as well). An increase in CD-specific serum autoantibodies follows histological change. Therefore, if the patient remains asymptomatic, the biopsies should be performed when serology is positive.
## Non-coeliac gluten sensitivity in children
Non-coeliac gluten sensitivity (NCGS) is a differential diagnosis to consider in patients with symptoms of CD, but TG2-IgA and EMA are negative and the histology is normal or near normal (only lymphocytic duodenosis is accepted [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref]. The genotypes HLA-DQ2/DQ8 may or may not be present. The distinction between wheat allergies with negative IgE antibodies may be difficult. In children, circumstantial evidence suggests that a proportion of children suspected of CD, but with the characteristics mentioned above, may have NCGS. [bib_ref] Clinical, serologic, and histologic features of gluten sensitivity in children, Francavilla [/bib_ref] However, to our knowledge, no study of blinded, placebocontrolled food challenges has been performed in children with gastroenterological symptoms of NCGS. The prevalence of NCGS in children is still unclear, and further studies are needed. Statement: There is as yet no reliable prevalence data on NCGS in children. Recommendation: We recommend that the diagnosis of NCGS in children/adolescents is not made on a regular basis, but awaits further documentation.
## Follow-up
Follow-up of patients with CD is advocated to ensure dietary adherence, prevent or detect complications or associated conditions including autoimmune thyroid disease, and promote optimal health. [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] Data, though limited, suggest continued follow-up improves dietary adherence, whereas lack of regular follow-up seems to be a particular problem for the phase of transition between paediatric and adult care. [bib_ref] Follow-up of children with celiac disease-lost in translation?, Mozer-Glassberg [/bib_ref] Based on expert opinion, all paediatric patients should be seen at 3-6-month intervals for the first year after diagnosis. Once symptoms have resolved and serological tests for CD have normalised, an annual follow-up visit is recommended. This recommendation is in line with that for adult patients with CD. [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] CD is associated with fracture risk, predominantly before treatment or in the setting of non-adherence to GFD. [bib_ref] Risk of fractures in celiac disease patients: a cross-sectional, case-control study, Vasquez [/bib_ref] Bone mineral density is frequently depressed in both children [bib_ref] Bone mineral density and importance of a gluten-free diet in patients with..., Kalayci [/bib_ref] and adults [bib_ref] Osteoporosis in adult patients with celiac disease, Kemppainen [/bib_ref] with CD at the time of diagnosis, and deficits have been shown to correlate with degree of histological severity. [bib_ref] Bone mineral content deficits of the spine and whole body in children..., Jatla [/bib_ref] The vast majority of children recover from bone mineral density abnormalities following appropriate therapy. [bib_ref] Bone density and bone metabolism are normal after long-term gluten-free diet in..., Mora [/bib_ref] Thus, dual-energy X-ray absorptiometry should only be considered for young adults at high risk (eg, known history of low-energy bone fractures, dietary non-adherence, established persistent villous atrophy or low body mass index (<20 kg/m 2 )).
A subset of patients with CD suffer from other diseases of autoimmune pathogenesis such as T1DM 108 and thyroid disease. [bib_ref] Risk of thyroid disease in individuals with celiac disease, Elfström [/bib_ref] CD is more often seen in patients with Down's syndrome. [bib_ref] Down syndrome is associated with elevated risk of celiac disease: a nationwide..., Marild [/bib_ref] Some of these patients may present specific problems in the transition phase and guidelines have been published on transition in T1DM and Down's syndrome. As far as CD is concerned, in patients with T1DM, the GFD may represent a special challenge as diet is already an issue in patients with T1DM.
Dermatitis herpetiformis is a pruritic skin condition strongly linked to CD. Adolescents and young adults with dermatitis herpetiformis should be aware that medical treatment with dapsone will remedy itch but will have no influence on small intestinal inflammation. Hence, a strict GFD is crucial for this group of patients.
## Primary care involvement
In many countries, adolescents leaving paediatric care are often cared for by a general practitioner rather than by an adult gastroenterologist. Primary care physicians (PCPs) are then also responsible for the healthcare during and after transition. In adults, PCPs may take a major role in care, dependent upon management care programmes and the availability of skilled personnel and local practice. Some adolescent/young adult patients are also referred to primary care when they are considered healthy after diagnostic work-up information and initial follow-up in secondary care (either with a paediatrician or an adult gastroenterologist). Primary care may also be a suitable care provider if adequate resources in terms of personnel skills and laboratory facilities are sufficient for long-term follow-up. In settings where the PCP has access to upper endoscopies with biopsies, the adolescent/young adult be solely cared for by the PCP, provided that relevant skills, a dietician with expertise is available, and that the care results in good self-reported health and normalised laboratory data. Whenever the patient's follow-up is in primary care, a management plan should be followed. [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] When seeing an adolescent/young adult with CD, the PCP also has to consider an increased risk for other autoimmune diseases. [bib_ref] Risk of thyroid disease in individuals with celiac disease, Elfström [/bib_ref] Statement: The PCP is often the care provider who is closest to the adult patient with CD. (C)
Recommendation: Primary care may be a suitable care provider if adequate personnel skills and laboratory facilities are sufficient for long-term follow-up, and this may depend on local practice.
## Economic issues
The cost of gluten-free products is often substantially higher than that of gluten-containing products. [bib_ref] Gluten-free and regular foods: a cost comparison, Stevens [/bib_ref] [bib_ref] The economics of coeliac disease: a population-based study, Long [/bib_ref] [bib_ref] Limited availability and higher cost of gluten-free foods, Singh [/bib_ref] Different economic models are used to compensate patients with CD, with tax deduction used in parts of Europe (eg, Germany) and North America, [bib_ref] Tax-deductible provisions for gluten-free diet in Canada compared with systems for gluten-free..., Pinto-Sanchez [/bib_ref] and prescriptions for GFD in many European countries. Prescriptions may, however, only apply to children and in, for example, Austria, Estonia, Finland, Hungary, Spain and Ukraine, adults with CD receive no government support for extra costs ( personal communication, T Koltai, 17 February 2016). While in Italy there are no requirements for the quality of food prescribed, the coeliac society in the UK restricts the prescribed list to essential products, excluding gluten-free foods considered 'unhealthy' such as gluten-free snacks and desserts. In those countries where prescription and rebates on GFD are restricted to children, becoming an adult will incur extra costs of GFD, potentially having a negative impact on dietary adherence.
The cost of healthcare in the transitional period between adolescence and adulthood will vary according to the country of residence. Indeed, in some countries one in three young adults has unmet health needs because of cost. [bib_ref] Access to health care for young adults with disabling chronic conditions, Callahan [/bib_ref] Special issues arise in the USA with its hybrid healthcare system. Poor children may be covered by Medicaid or Children's Health Insurance Program. In the USA, the Patient Protection and Affordable Care Act (2010) included a provision for a child to remain under his or her parents' insurance plan until age 26. This act also prevented denial of coverage based on the presence of a chronic condition. However, the parents' insurance may be inadequate to make the needed care affordable.
# Discussion
Seventeen physicians and two representatives from CD patient organisations wrote this consensus report after reviewing the literature on the transition of CD care from childhood to adulthood.
The strengths of our paper lie in the systematic literature search and the involvement of patient organisation representatives. However, we acknowledge several weaknesses, including a low level of evidence, and we are not aware of any randomised trials on transition in CD. Despite the lack of CD-specific evidence, we have tried to make statements and recommendations, sometimes based on inference from data in other chronic diseases and sometimes on our own pooled clinical experience. We have listed several recommendations of care adding to more general recommendations of diagnostics and management in CD. [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] [bib_ref] Diagnosis and management of adult coeliac disease: guidelines from the British Society..., Ludvigsson [/bib_ref] [bib_ref] ACG clinical guidelines: diagnosis and management of celiac disease, Rubio-Tapia [/bib_ref] Still, we understand that countries, and thereby the conditions for care of delivery, differ. We also recognise that resource limitations will hinder some providers from offering joint clinics and follow-up as suggested.
We believe that we offer a working approach to adolescents and young adults who were once diagnosed without a small intestinal biopsy [bib_ref] European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis..., Husby [/bib_ref] and now enter adult healthcare where biopsy is still generally recommended to diagnose the condition. That said, we recognise that there is international variation of practice based on social practice and that individual patient preferences may also influence the transition process.
We recommend that the diagnosis be re-evaluated only when made outside current ESPGHAN or NASPGHAN recommendations or when the patient questions his/her diagnosis. That does not mean that a paediatric CD diagnosis is more erroneous than a diagnosis made by an adult gastroenterologist.
The implementation of a systematic transition policy in CD has been limited by a lack of clinical guidelines based on outcome-related research and clear and consistent definitions. [bib_ref] The Oslo definitions for coeliac disease and related terms, Ludvigsson [/bib_ref] In the absence of solid evidence, different models of transition will be likely developed locally. We still do not know if a standardised protocol-driven transition process is superior to a process that varies both nationally and internally. These differences will contribute to the differences that exist between the different healthcare systems. Models of transition 42 will eventually need to be evaluated in randomised controlled trials with clear patient outcome measures. It is crucial to know to what extent a wellstructured and planned transition will influence adherence to a GFD, which in CD is imperative for restoration of health and well-being. This aspect will depend on the prevalence and quality of complications, as well as on health-related QoL. Socio-economic effectiveness and outcomes of care of the different models should also be carefully evaluated. Further studies are needed to identify and remove barriers 20 to transition.
Correction notice This article has been corrected since it published Online First. An Open Access licence has been added.
## Twitter follow marilyn geller at @ceoatcdf
Contributors JFL and SH initiated the study on the suggestion of JAM. JFL coordinated the study and wrote the first draft. All authors contributed to the literature searches, contributed to the writing of the manuscript and approved the final version of the manuscript.
Funding JFL was supported by the Swedish Research Council (522-2A09-195) and the Swedish Society of Medicine while writing the draft of this paper. DSS received an educational grant from Biocard and Simtomax to undertake an investigator-led research study on point of care tests, an educational grant from Dr Schär (a gluten-free food manufacturer) to undertake an investigator-led research study on gluten sensitivity. SH received unconditional grants from the NovoNordiskFonden, the Health Research Funds of the Region of Southern Denmark, the Odense University Hospital.
Competing interests PHRG: scientific advisory board of Alvine Pharmaceuticals and ImmusanT. JAM: consultant for Alba Pharmaceuticals, Alvine Therapeutics, Flamentera, 2GPharma Boeringer-Ingelheim and ImmusanT. KEAL: ImmusanT, Regeneron and Alvine Pharmaceuticals. DSS: has received an educational grant from Coeliac UK, Biocard, Simtomax and Dr Schär (a gluten-free food manufacturer) to undertake an investigator-led research study on CD and/or gluten sensitivity. IH: Abbvie Scientific Advisory Group Member. RS: consultant to Bioline. SK: Received funding for a CD-related research projects from Nestle, R-Biopharm, Schär, Phadia-ThermoFisher, Eurospital, Euroimmun, Inova. NR: clinical advisory board for ImmusanT. SH: educational grant from Thermo-Fisher, advisory board for Simtomax.
Provenance and peer review Not commissioned; externally peer reviewed.
Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/
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The process of transition from childhood to adulthood is characterised by physical, mental and psychosocial development. Data on the transition and transfer of care in adolescents/young adults with coeliac disease (CD) are scarce. In this paper, 17 physicians from 10 countries (Sweden, Italy, the USA, Germany, Norway, the Netherlands, Australia, Britain, Israel and Denmark) and two representatives from patient organisations (Association of European Coeliac Societies and the US Celiac Disease Foundation) examined the literature on transition from childhood to adulthood in CD. Medline (Ovid) and EMBASE were searched between 1900 and September 2015. Evidence in retrieved reports was evaluated using the Grading of Recommendation Assessment, Development and Evaluation method. The current consensus report aims to help healthcare personnel manage CD in the adolescent and young adult and provide optimal care and transition into adult healthcare for patients with this disease. In adolescence, patients with CD should gradually assume exclusive responsibility for their care, although parental support is still important. Dietary adherence and consequences of non-adherence should be discussed during transition. In most adolescents and young adults, routine small intestinal biopsy is not needed to reconfirm a childhood diagnosis of CD based on European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) or North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) criteria, but a biopsy may be considered where paediatric diagnostic criteria have not been fulfilled, such as, in a patient without biopsy at diagnosis, additional serology (endomysium antibody) has not been performed to confirm 10-fold positivity of tissue transglutaminase antibodies or when a no biopsy strategy has been adopted in an asymptomatic child.
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Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis
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Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis
Objectives To develop recommendations for the management of adult and paediatric lupus nephritis (LN). Methods The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.
# Introduction
Approximately 50% of patients with systemic lupus erythematosus (SLE) will develop lupus nephritis (LN), which increases the risks for renal failure, cardiovascular disease and death. In 2008, we published the first European League Against Rheumatism (EULAR) recommendations on the management of SLE. [bib_ref] Report of a Task Force of the EULAR Standing Committee for International..., Bertsias [/bib_ref] Since then, several controlled trials have been published upon which updated recommendations can be based. The realisation that in the care of patients with LN internists/ rheumatologists and nephrologists are involved, prompted us to develop recommendations for LN under the joint auspices of the EULAR and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), with experts from both disciplines. The panel was enriched with renal pathologists and paediatricians with expertise on LN.
# Methods
We followed the EULAR standardised operating procedures 2 and the Appraisal of Guidelines Research and Evaluation instrument. We selected a list of questions by a modified Delphi method further edited for literature search, followed by a systematic search of the PubMed database (web-only appendix tables 1 and 2); all English language publications up to December 2011 were considered. We further refined retrieved items based on abstract and/or full-text content, and the number of patients (requiring n≥30 for diagnosis, monitoring, prognosis; n ≥ 10 for treatment). A detailed presentation of the literature review is provided in web-only appendix table 3. Evidence was categorised based on the design and validity of available studies and the strength of the statements was graded. After discussions, the committee arrived at 28 final statements rated individually by each member (tables 1 and 2).
## Indications for first renal biopsy in sle
Any sign of renal involvement-in particular, urinary findings such as reproducible proteinuria ≥0.5 g/24 h especially with glomerular haematuria and/or cellular casts-should be an indication for renal biopsy. Renal biopsy is indispensable since in most cases, clinical, serological or laboratory tests cannot accurately predict renal biopsy findings. [bib_ref] Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease..., Reich [/bib_ref].7 (0. [bib_ref] Lupus nephritis: clinical and pathological correlation, Leaker [/bib_ref] 10 (1) 2. Pathological assessment of kidney biopsy The use of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification system is recommended with assessment of active and chronic glomerular and tubulointerstitial changes, and of vascular lesions associated with anti-phospholipid antibodies/ syndrome 9.6 (0. [bib_ref] Association between serum total cholesterol level and renal outcome in systemic lupus..., Tisseverasinghe [/bib_ref] 10 (1) 3. Indications and goals of immunosuppressive treatment in lupus nephritis (LN) 3.1. Initiation of immunosuppressive treatment should be guided by a diagnostic renal biopsy. Immunosuppressive agents are recommended in class III A or III A/C (±V) and IV A or IV A/C (±V) nephritis, and also in pure class V nephritis if proteinuria exceeds 1 g/24 h despite the optimal use of renin-angiotensin-aldosterone system blockers 9.4 (0. [bib_ref] Association between serum total cholesterol level and renal outcome in systemic lupus..., Tisseverasinghe [/bib_ref] 10 (1) 3.2. The ultimate goals of treatment in LN are long-term preservation of renal function, prevention of disease flares, avoidance of treatment-related harms, and improved quality of life and survival. Treatment should aim for complete renal response with UPCR <50 mg/mol and normal or near-normal (within 10% of normal GFR if previously abnormal) renal function. Partial renal response, defined as ≥50% reduction in proteinuria to subnephrotic levels and normal or near-normal renal function, should be achieved preferably by 6 months but no later than 12 months following initiation of treatment 9.6 (0. [bib_ref] Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than..., Grootscholten [/bib_ref] 10 (1) 4. Treatment of adult LN Initial treatment 4.1. For patients with class III A or III A/C (±V) and class IV A or IV A/C (±V) LN, mycophenolic acid (MPA) (mycophenolate mofetil (MMF) target dose: 3 g/day for 6 months, or MPA sodium at equivalent dose) or low-dose intravenous cyclophosphamide (CY) (total dose 3 g over 3 months) in combination with glucocorticoids, are recommended as initial treatment as they have the best efficacy/toxicity ratio 9.3 (0.8) 9 (1) 4.2. In patients with adverse prognostic factors (acute deterioration in renal function, substantial cellular crescents and/or fibrinoid necrosis), similar regimens may be used but CY can also be prescribed monthly at higher doses (0.75-1 g/m 2 ) for 6 months or orally (2-2.5 mg/kg/day) for 3 months
[formula] 8.8 (1.3) 9 (2) 4.3. [/formula]
To increase efficacy and reduce cumulative glucocorticoid doses, treatment regimens should be combined initially with three consecutive pulses of intravenous methylprednisolone 500-750 mg, followed by oral prednisone 0.5 mg/kg/day for 4 weeks, reducing to ≤10 mg/day by 4-6 months 9.0 (1.1) 9 (2) 4.4. In pure class V nephritis with nephrotic-range proteinuria, MPA (MMF target dose 3 g/day for 6 months) in combination with oral prednisone (0.5 mg/kg/day) may be used as initial treatment based on better efficacy/toxicity ratio. CY or calcineurin inhibitors (ciclosporin, tacrolimus) or rituximab are recommended as alternative options or for non-responders.
[formula] 8.9 (1.2) 9 (2) [/formula]
4.5. Azathioprine (AZA) (2 mg/kg/day) may be considered as an alternative to MPA or CY in selected patients without adverse prognostic factors (as defined in 4.2), or when these drugs are contraindicated, not tolerated or unavailable. Azathioprine use is associated with a higher flare risk.
8.6 (1.3) 9 (2) Subsequent treatment 4.6. In patients improving after initial treatment, subsequent immunosuppression is recommended with either MPA at lower doses (initial target MMF dose 2 g/day) or AZA (2 mg/kg/day) for at least 3 years, in combination with low dose prednisone (5-7.5 mg/day). Gradual drug withdrawal, glucocorticoids first, can then be attempted. 6. Monitoring and prognosis of LN 6.1. Active LN should be regularly monitored by determining at each visit body weight, blood pressure, serum creatinine and eGFR, serum albumin, proteinuria, urinary sediment (microscopic evaluation), serum C3 and C4, serum anti-dsDNA antibody levels and complete blood cell count. Anti-phospholipid antibodies and lipid profile should be measured at baseline and monitored intermittently. 6.4. Repeat renal biopsy may be used in selected cases, such as worsening or refractoriness to immunosuppressive or biological treatment (failure to decrease proteinuria by ≥50%, persistent proteinuria beyond 1 year and/or worsening of GFR), or at relapse, to demonstrate change or progression in histological class, change in biopsy chronicity and activity indices, to provide prognostic information, and detect other pathologies 9.2 (1.4) 10 (1)
## Continued
## Results and discussion indications for first renal biopsy in sle
Because of the potentially aggressive nature of LN, the thresholds for performing a renal biopsy should be low. Any sign of renal involvement-in particular, reproducible proteinuria ≥0.5 g/24 h especially with glomerular haematuria and/or cellular casts-can be an indication for biopsy. Clinical, serological or laboratory tests cannot accurately predict histological findings.
Although clinically relevant biopsy findings are more common in the presence of significant proteinuria, a biopsy may also be considered in cases of persisting isolated glomerular haematuria, isolated leucocyturia (after other causes, such as infection or drugs are excluded), and the rare occurrence of unexplained renal insufficiency with normal urinary findings. Lower glomerular filtration rate (GFR) is associated with chronic histological lesions and faster rate of decline in GFR. [bib_ref] Lupus nephritis: clinical and pathological correlation, Leaker [/bib_ref] [bib_ref] Contribution of renal biopsy data in predicting outcome in lupus nephritis. Analysis..., Nossent [/bib_ref] [bib_ref] Association between serum total cholesterol level and renal outcome in systemic lupus..., Tisseverasinghe [/bib_ref] [bib_ref] Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than..., Grootscholten [/bib_ref] [bib_ref] Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease..., Reich [/bib_ref] Methods for estimating GFR such as the Cockcroft-Gault and the Modification of Diet in Renal Disease equations in adults or the Schwartz formula in children, although not fully validated in SLE, are acceptable in clinical practice. For GFR <30 ml/min the decision for biopsy should be based on normal kidney size (>9 cm length in adults) and/or evidence of renal disease activity, in particular proteinuria and active urinary sediment (dysmorphic red blood cells (glomerular haematuria), white blood cells and/or cellular casts). Biopsy should be performed within the first month after disease onset, preferably before the institution of immunosuppressive treatment, unless contraindicated. [bib_ref] The clinical and renal biopsy predictors of long-term outcome in lupus nephritis:..., Esdaile [/bib_ref] [bib_ref] Withdrawal of therapy in patients with proliferative lupus nephritis: long-term follow-up, Moroni [/bib_ref] [bib_ref] Prognostic factors in lupus nephritis: diagnostic and therapeutic delay increases the risk..., Faurschou [/bib_ref] Treatment with high-dose glucocorticoids should not be delayed if a renal biopsy cannot be readily performed.
## Pathological assessment of renal biopsy
We recommend using the International Society of Nephrology/ Renal Pathology Society 2003 classification system [bib_ref] The classification of glomerulonephritis in systemic lupus erythematosus revisited, Weening [/bib_ref] [bib_ref] Interobserver reproducibility and application of the ISN/RPS classification of lupus nephritis-a UK-wide..., Furness [/bib_ref] [bib_ref] Interobserver agreement of scoring of histopathological characteristics and classification of lupus nephritis, Grootscholten [/bib_ref] with assessment of active and chronic glomerular and tubulointerstitial changes, [bib_ref] Tubulointerstitial renal disease in systemic lupus erythematosus, O'dell [/bib_ref] [bib_ref] Predictors of one year outcome in lupus nephritis: the importance of renal..., Esdaile [/bib_ref] [bib_ref] High-risk features of lupus nephritis: importance of race and clinical and histological..., Austin [/bib_ref] [bib_ref] A new morphologic index for the evaluation of renal biopsies in lupus..., Hill [/bib_ref] and of vascular lesions associated with antiphospholipid antibodies/syndrome. An adequate sample of ≥8 glomeruli should be examined under light microscopy with haematoxylin and eosin, periodic acid-Schiff, Masson's trichrome and silver stain. Immunofluorescence or immunohistochemistry for immunoglobulin and complement deposits (IgG, IgA, IgM, C3, C1q, κ and λ light chains) is recommended. [bib_ref] The clinical and renal biopsy predictors of long-term outcome in lupus nephritis:..., Esdaile [/bib_ref] Electron microscopy facilitates the recognition of proliferative and membranous lesions and should be performed if possible. Indications and goals of immunosuppressive treatment in LN Ultimate goals of treatment are long-term preservation of renal function, prevention of flares, avoidance of treatment-related harms, and improved quality of life and survival. Treatment must be based on a shared decision between patient and doctor. Immunosuppressive treatment is generally not indicated in classes I and VI LN, unless necessitated by extra-renal lupus activity. [bib_ref] Long-term mortality and renal outcome in a cohort of 100 patients with..., Faurschou [/bib_ref] [bib_ref] Minimal mesangial lupus nephritis: a systematic review, Mok [/bib_ref] [bib_ref] Revised classification of lupus nephritis is valuable in predicting renal outcome with..., Hiramatsu [/bib_ref] Treatment should aim for complete renal response, defined as urine protein:creatinine ratio (UPCR) <50 mg/mmol (roughly equivalent to proteinuria <0.5 g/24 h) and normal or nearnormal (within 10% of normal GFR if previously abnormal) GFR. Partial renal response, defined as ≥50% reduction in proteinuria to subnephrotic levels and normal or near-normal GFR, should be achieved preferably by 6 months and no later than 12 months following treatment initiation. 9 33-35 Improvement includes any reduction in proteinuria and normalisation or stabilisation of GFR. Although partial response carries worse prognosis than complete response, [bib_ref] Renal flares are common in patients with severe proliferative lupus nephritis treated..., Illei [/bib_ref] it may be an acceptable outcome when all treatments have been exhausted or cannot be used due to high individual risks for toxicity. Following response, patients may experience nephritic or proteinuric flares, the former having more adverse impact on renal outcomes. Nephritic flares include reproducible increase of serum creatinine by ≥30% (or, decrease in GFR by ≥10%) and active urine sediment with increase in glomerular haematuria by ≥10 red blood cells per high power field, irrespective of changes in proteinuria; proteinuric flares include reproducible doubling of UPCR to >100 mg/mmol after complete response or reproducible doubling of UPCR to >200 mg/mmol after partial response. [bib_ref] Renal flares are common in patients with severe proliferative lupus nephritis treated..., Illei [/bib_ref] 1. All methods of renal replacement treatment can be used in patients with lupus, but there may be increased risk of infections in patients on peritoneal dialysis still on immunosuppressive agents and vascular access thrombosis in patients with anti-phospholipid antibodies 9.5 (0. [bib_ref] Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than..., Grootscholten [/bib_ref] 10 (1) 7.2. Transplantation should be performed when lupus activity has been absent, or at a low level, for at least 3-6 months, with superior results obtained with living donor and pre-emptive transplantation. Anti-phospholipid antibodies should be sought during transplant preparation because they are associated with an increased risk of vascular events in the transplanted kidney. 9.4 (0.9)
10 (1) 8. Anti-phospholipid syndrome-associated nephropathy in SLE In patients with lupus and anti-phospholipid syndrome (APS)-associated nephropathy (APSN), hydroxychloroquine and/or antiplatelet/ anticoagulant treatment should be considered 9.0 (1.4) 9 (2) 9. LN and pregnancy 9.1. Pregnancy may be planned in stable patients with inactive lupus and UPCR <50 mg/mmol, for the preceding 6 months, with GFR that should preferably be >50 ml/min. Acceptable medications include hydroxychloroquine, and where needed, low dose prednisone, azathioprine and/or calcineurin inhibitors. The intensity of treatment should not be reduced in anticipation of pregnancy. During pregnancy, acetylsalicylic acid should be considered to reduce the risk of pre-eclampsia. Patients should be assessed at least every 4 weeks, preferably by a specialist physician and obstetrician. Compared to adult-onset disease, LN in children is more severe with increased damage accrual and more common at presentation but the diagnosis, management and monitoring is similar to that of adults. A coordinated transition programme to adult specialists is important in assessing concordance to treatments and optimising long-term outcomes. 9.6 (0.7)
10 (1) *Numbers are mean (SD) and median (IQR) agreement level among experts. A score of 10 represents the highest level of agreement. GFR, glomerular filtration rate; UPCR, urine protein:creatinine ratio. Better outcome when lupus activity is absent or at a low level for 3-6 months 3 C Better outcome with living versus cadaveric donor 2 B Better outcome with pre-emptive transplantation 3 C Increased risk for vascular events in patients with anti-phospholipid antibodies 2 B 8. Treatment of anti-phospholipid syndrome (APS)-associated nephropathy (APSN) Hydroxychloroquine -C Antiplatelet/anticoagulation treatment -C 9. LN and pregnancy Safe in inactive SLE with UPCR <50 mg/mmol for the preceding 6 months 2 B GFR preferably above 50 ml/min -C Safety and efficacy of the following medications Hydroxychloroquine 3 B Low-dose prednisone 4 C Azathioprine 4 C Calcineurin inhibitors 4 C Intensity of treatment should not be reduced in anticipation of pregnancy -C Acetylsalicylic acid to reduce the risk of pre-eclampsia 3 C Assessment every 4 weeks, preferably by a specialist physician and obstetrician -C Flare of nephritis can be treated with same acceptable medications but also with calcineurin inhibitors, intravenous immunoglobulin, immunoadsorption and plasma exchange -C 10. Paediatric LN More common at presentation compared to adult-onset SLE 1 A More severe with increased damage accrual compared to adult-onset disease 2 B Similar monitoring with adults 3 C Similar treatment with adults 3 C Importance of coordinated transition programme to adult specialists -C *Quality of evidence was graded 1-4 and the strength of statements was graded A-C (refer to web-only appendix table 1 for details). †MPA refers to either mycophenolate mofetil (MMF) or enteric-coated MPA sodium at equivalent dose based on evidence for comparable efficacy of the two regimens. MMF has been used in most controlled trials in LN. dsDNA, double-stranded DNA; GFR, glomerular filtration rate; UPCR, urine protein:creatinine ratio.
## Treatment of adult ln initial treatment
Patients with LN should be managed, if possible, in experienced centres. [bib_ref] Hospital experience and mortality in patients with systemic lupus erythematosus: which patients..., Ward [/bib_ref] Early trials of immunosuppressive agents have highlighted the importance of long-term (beyond 5 years) follow-up in demonstrating differences in 'hard' outcomes such as doubling of serum creatinine, end-stage renal disease (ESRD) and death. [bib_ref] Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs, Austin [/bib_ref] [bib_ref] Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a..., Wang [/bib_ref] [bib_ref] Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome..., Illei [/bib_ref] Such outcomes, however, are not frequent and may occur late in the course of LN. Intermediate outcome measures, such as renal response and flares, occurring in the majority of patients within the first 2 years after treatment initiation, correlate with hard outcomes in studies with long-term follow-up and are commonly used as endpoints in trials. Correlation does not guarantee surrogacy of these outcomes for all patients, some of whom may still have hard outcomes diverging from their intermediate outcomes.
To date, long-term data are not available for MPA (box 1). Nonetheless, the publication of the Aspreva Lupus Management Study (ALMS) trial, [bib_ref] Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis, Appel [/bib_ref] the largest trial in LN showing comparable response rates between MPA (target mycophenolate mofetil (MMF) dose 3 g/day) and intravenous cyclophosphamide (CY) (monthly pulses 0.5-1 g/m 2 ), both administered for 6 months, together with the ease of administration and the more favourable gonadal toxicity profile of the former, 46-48 formed the basis for recommending MPA as initial treatment for most cases of class III-IV LN. Evidence from transplantation medicine and a single randomised controlled trial (RCT) in LN [bib_ref] Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid..., Zeher [/bib_ref] suggests that MMF and entericcoated mycophenolic acid sodium (eMPA) are likely to be equally efficacious. To this end, and while awaiting further validation, the Committee felt that either MPA formulation can be used in treatment of LN, with 720 mg dose eMPA roughly equivalent to 1 g dose of MMF. We also recommend low-dose intravenous CY (total dose 3 g over 3 months) in combination with glucocorticoids (0.5 mg/kg/day) as initial treatment of class III-IV (±V) LN in Caucasians based on better efficacy/ toxicity ratio than high-dose intravenous CY. A single RCT in patients with pure class V LN demonstrated that the combination of glucocorticoids with intravenous CY (6 bimonthly pulses 0.5-1 g/m 2 ) was more efficacious than glucocorticoids alone; the combination of glucocorticoids with ciclosporin was also efficacious but was associated with significantly more relapses of nephrotic syndrome than CY. [bib_ref] Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy, Austin [/bib_ref] Moreover, combined analysis of two other RCTs in the subgroup of patients with pure class V LN showed a comparable antiproteinuric effect of MPA versus high-dose intravenous CY. [bib_ref] Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class..., Radhakrishnan [/bib_ref] By extrapolation from these studies, and based on the more favourable gonadal toxicity profile of MPA compared to CY, we recommend MPA as initial treatment for most cases of class V LN and nephrotic-range proteinuria. The low-dose CY regimen has not been tested in pure class V LN.
Subgroup analysis suggests that MPA may have greater efficacy in patients of African descent; further confirmation is needed before issuing a recommendation favouring MPA in these patients. Post hoc analysis in 32 patients in ALMS with baseline GFR<30 ml/min/1.73 m 2 , [bib_ref] Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis, Appel [/bib_ref] and evidence from 2 controlled studies in severe histological forms of LN, support the use of MPA in patients with impaired renal function or crescents. Only high-dose intravenous CY has demonstrated efficacy in a RCT specifically designed to include severe nephritic cases with GFR 25-80 ml/min or with crescents/necrosis in >25% of glomeruli. [bib_ref] Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in..., Boumpas [/bib_ref] Data from a RCT 59 and the 10-year follow-up 60 suggest that azathioprine can be used in class III-IV LN albeit at an increased risk for renal relapse (HR 4.5), thus the committee recommends it for milder cases ( preserved renal function and no adverse histological findings).
Intravenous methylprednisolone (MP) pulses are recommended as part of the initial treatment regimen by extrapolation from controlled studies, to decrease cumulative glucocorticoid dose and associated harms. Higher initial glucocorticoid dose (oral prednisone 0.7-1 mg/kg/day) may be used in severe renal or extra-renal lupus, or when intravenous MP treatment is not feasible. Clinical experience suggests that a further course of three intravenous MP pulses can be considered in patients failing to improve within the first 3 months.
For class II LN with proteinuria >1 g/24 h despite renin-angiotensin-aldosterone system (RAAS) blockade, especially in the presence of glomerular haematuria, we recommend low-to-moderate doses of glucocorticoids ( prednisone 0.25-0.5 mg/kg/day) alone or in combination with azathioprine (1-2 mg/kg/day), if needed, as steroid-sparing agent. Glucocorticoids alone or in combination with immunosuppressive agents may also be considered in cases of class I LN with podocytopathy on the electron microscopy (minimal change disease) or interstitial nephritis.
## Subsequent treatment
For patients improving after initial treatment, we recommend subsequent immunosuppression to consolidate renal response and prevent flares. Although among patients from European ancestries azathioprine and MPA were equivalent after initial treatment with low-dose intravenous CY, 67 a larger RCT suggested a difference between the two drugs in favour of MPA after initial response to either MPA or intravenous CY (monthly pulses 0.5-1 g/m 2 ). [bib_ref] Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis, Dooley [/bib_ref] In this trial, sequential use of azathioprine after MPA resulted in more treatment failures as compared to
## Box 1 research agenda
- Special training sessions for renal pathologists to improve the interpretation of renal biopsy findings in lupus nephritis (LN) and enhance interobserver agreement - Development and validation of biomarkers which will better reflect kidney biopsy findings and renal disease activity and severity - Long-term (beyond 5 years) efficacy and safety data for mycophenolic acid - Provide data to guide duration of immunosuppressive treatment beyond 3 years - Define the role of adding calcineurin inhibitors, rituximab or belimumab to standard immunosuppressive treatment in cases with residual renal disease - Need for more data on switching regimens in cases of treatment failure - Larger studies with extended follow-up are needed to assess the prognostic significance of anti-phospholipid syndrome (APS)-associated nephropathy (APSN) and coexistence of anti-phospholipid antibodies in LN - Need for controlled trials to assess the role of antiplatelet/ anticoagulant regimes in APSN - Need for randomised controlled trials (RCTs) in paediatric LN and the need to have very long follow-up (beyond 10-15 years) to fully assess the impact of the various treatment strategies and modalities in children MPA followed by MPA. The committee therefore recommends continuation of MPA if the drug was successful as initial treatment. Calcineurin inhibitors can be considered in selected cases with preserved renal function based on evidence from RCTs. [bib_ref] A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in..., Moroni [/bib_ref] [bib_ref] Cyclosporine treatment of lupus membranous nephropathy, Radhakrishnan [/bib_ref] [bib_ref] Irreproducibility of the activity and chronicity indices limits their utility in the..., Schwartz [/bib_ref] Intravenous CY, pulsed every 3 months, may be used in selected cases but exposure to CY should be minimised, especially in women at risk for amenorrhoea and infertility 73 or men planning to father children.
There is no data to guide duration of treatment beyond 3 years; continuing treatment for longer time periods should be individualised with an effort first to withdraw glucocorticoids before immunosuppressive agents. Gradual drug dosage titration may be attempted to ensure the best possible efficacy/toxicity ratio. MPA dose often needs titration to reduce toxicity (doses 1-2 g/day can be effective for long-term treatment). Monitoring MPA blood levels to minimise harm and increase efficacy is under investigation [bib_ref] Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children, Filler [/bib_ref] [bib_ref] Pharmacokinetics of mycophenolic acid in severe lupus nephritis, Lertdumrongluk [/bib_ref] [bib_ref] Mycophenolic acid area under the curve correlates with disease activity in lupus..., Zahr [/bib_ref] but it should be considered in cases with GFR <30 ml/min.
## Refractory disease
Complete renal response can take up to 2 years to reach with <30% to 40% of patients achieving this outcome within the first 6 months of treatment. Switching to an alternative agent is recommended for patients who fail to improve within 3-4 months, or do not achieve partial response after 6-12 months, or complete response after 2 years of treatment. For patients not responding to MPA or CY, evidence from uncontrolled studies suggests that treatment may be switched from MPA to CY, from CY to MPA, or that rituximab (anti-CD20 mAb) may be given either as add-on treatment or as monotherapy. Additional options include calcineurin inhibitors (ciclosporin A, tacrolimus), [bib_ref] Long-term outcomesmycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for..., Cortes-Hernandez [/bib_ref] [bib_ref] Tacrolimus is an alternative therapeutic option for the treatment of refractory lupus..., Lee [/bib_ref] [bib_ref] Cyclophosphamide in lupus nephritis: a controlled trial, Steinberg [/bib_ref] intravenous immunoglobulin, [bib_ref] Intravenous immunoglobulin treatment of lupus nephritis, Levy [/bib_ref] plasma exchange for rapidly progressive glomerulonephritis, or immunoadsorption for patients who have failed or cannot tolerate other treatments. Data on leflunomide are limited. [bib_ref] Safety and efficacy of leflunomide in the treatment of lupus nephritis refractory..., Tam [/bib_ref]
## Adjunctive treatment in patients with ln
We recommend control of cardiovascular disease risk factors in a manner similar to patients who do not have SLE with chronic kidney disease, although benefit has not been demonstrated specifically in SLE.Complications of chronic renal insufficiency (anaemia, cardiovascular disease, metabolic bone disease) should also be managed as in patients who do not have SLE. RAAS blockers are recommended as preferred treatment in all patients who are not pregnant with significant proteinuria or hypertension, based on: (a) evidence for their antihypertensive, antiproteinuric and renoprotective effect, [bib_ref] Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated..., Duran-Barragan [/bib_ref] [bib_ref] Antiproteinuric effect of ARB in lupus nephritis patients with persistent proteinuria despite..., Kanda [/bib_ref] [bib_ref] Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus..., Tse [/bib_ref] and, (b) lack of data on the comparative efficacy of other classes of antihypertensive agents in LN. Their dose is titrated for maximum antiproteinuric effect while monitoring blood pressure (target level <130/80 mm Hg), serum potassium and GFR levels. Epidemiological studies and the follow-up of a controlled trial 95 demonstrate that hydroxychloroquine use is associated with higher rates of renal response, fewer renal relapses and reduced accrual of renal damage. Hydroxychloroquine (6.5 mg/kg/day or 400 mg/day, whichever is lower) is generally safe in patients with normal baseline ophthalmological examination; dose adjustments may be necessary in patients with GFR <30 ml/min. Annual ophthalmological screening begins after 5 years of treatment or sooner if there are risk factors for retinal damage. [bib_ref] Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy, Marmor [/bib_ref] Patients should also be immunised with non-live vaccines according to the EULAR recommendations. Monitoring and prognosis of LN Patients should be monitored regularly according to EULAR recommendations, [bib_ref] European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus..., Mosca [/bib_ref] including annual examination of cervicovaginal smear in women and measurement of serum immunoglobulins at baseline and then annually in patients who receive immunosuppressive treatment to assess risk of infection. Monitoring of body weight, blood pressure, serum creatinine and estimated GFR, serum albumin, proteinuria, urinary sediment (microscopic evaluation), serum C3/C4, serum anti-dsDNA antibody levels and complete blood cell count are used to define activity and evaluate response to treatment although their individual predictive value for hard outcomes at particular time points is modest.
Spot UPCR measured on first morning void urine sample is a valid and conveniently repeatable measure for measuring proteinuria in children and monitoring within-patient changes in adults. [bib_ref] A prospective study of protein excretion using short-interval timed urine collections in..., Fine [/bib_ref] [bib_ref] Random spot urine protein/ creatinine ratio is unreliable for estimating 24-hour proteinuria..., Hebert [/bib_ref] [bib_ref] Urine protein-to-creatinine ratio in an untimed urine collection is a reliable measure..., Leung [/bib_ref] Timed (12 h or 24 h) urine collections may also be considered at baseline and when major therapeutic changes are considered. Reappearance of urine cellular casts has >80% sensitivity and specificity for renal flares. [bib_ref] Relationship between appearance of urinary red blood cell/white blood cell casts and..., Hebert [/bib_ref] Although serum C3 has generally higher sensitivity than serum C4 (72% to 85% vs 28% to 74%), both tests have modest specificity for active LN. The diagnostic accuracy of serum anti-dsDNA is also modest with positive and negative likelihood ratios ranging from 1.5-4.8 and 0.3-0.8, respectively. Farr and ELISA methods are both acceptable, although the former yields higher sensitivity and specificity rates. Anti-C1q and anti-nucleosome 112-114 antibodies have higher sensitivity and specificity for active nephritis but further standardisation and validation are required. Changes in serological tests are more important predictors of concurrent or impending LN flare than their absolute levels but should be repeated no more than monthly. In the absence of proteinuria, active serology (decreasing C3/C4 and/or increasing anti-dsDNA) and/or urine sediment is not an indication for pre-emptive treatment but dictates closer monitoring of patients. Repeat renal biopsy provides additional prognostic information [bib_ref] A double-blind controlled trial comparing cyclophosphamide, azathioprine and placebo in the treatment..., Steinberg [/bib_ref] [bib_ref] Predictive power of the second renal biopsy in lupus nephritis: significance of..., Hill [/bib_ref] [bib_ref] Outcome of relapse in lupus nephritis: roles of reversal of renal fibrosis..., Hill [/bib_ref] [bib_ref] Clinical and prognostic value of serial renal biopsies in lupus nephritis, Moroni [/bib_ref] and can assist therapeutic decisions in patients with relapse of nephritis after complete renal response, or with refractory disease. It can also be used in the context of a clinical trial to monitor treatment efficacy and changes in chronicity scores.
## Management of esrd in ln
Despite immunosuppressive treatment, 10% to 30% of patients with LN will progress to ESRD within 15 years of diagnosis. Infections (including peritonitis) may occur in patients with active disease still on immunosuppressive treatment, and contribute to morbidity and mortality. [bib_ref] Why do patients with lupus nephritis die, Correia [/bib_ref] [bib_ref] Thrombotic microangiopathy in United States long-term dialysis patients, Perkins [/bib_ref] [bib_ref] Clinical outcomes of systemic lupus erythematosus patients undergoing continuous ambulatory peritoneal dialysis, Siu [/bib_ref] [bib_ref] Peritoneal dialysis and hemodialysis in systemic lupus erythematosus patients: comparison of clinical..., Weng [/bib_ref] Although clinical and serological activity tend to subside in most patients with ESRD on dialysis, flares of renal or extra-renal lupus can occur. [bib_ref] Factors associated with active systemic lupus erythematosus after endstage renal disease, Szeto [/bib_ref] [bib_ref] Analysis of lupus activity in end-stage renal disease treated by hemodialysis, Okano [/bib_ref] [bib_ref] Poor prognosis in end-stage lupus nephritis due to nonautologous vascular access site..., Sires [/bib_ref] [bib_ref] Renal replacement therapy in lupus nephritis, Rietveld [/bib_ref] Comparative studies and cases series support that patients with SLE are good candidates for renal transplantation performed when clinical (and ideally, serological) lupus activity is absent, or at a low level, for at least 3-6 months 135 ; best results are obtained with living donor [bib_ref] Recurrence of lupus nephritis after kidney transplantation, Contreras [/bib_ref] [bib_ref] Outcome of renal transplantation in systemic lupus erythematosus, Stone [/bib_ref] [bib_ref] Factors affecting kidney-transplant outcome in recipients with lupus nephritis, Tang [/bib_ref] and pre-emptive transplantation. [bib_ref] Preemptive kidney transplantation in systemic lupus erythematosus, Naveed [/bib_ref] Patients with moderate to high titres of antiphospholipid antibodies are at increased risk for thrombotic complications and may receive anticoagulants perioperatively. [bib_ref] The long-term prognosis of renal transplantation in patients with lupus nephritis, Moroni [/bib_ref] [bib_ref] Antiphospholipid antibody syndrome in renal transplantation: occurrence of clinical events in 96..., Stone [/bib_ref] [bib_ref] Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with..., Vaidya [/bib_ref] [bib_ref] Relative risk of post-transplant renal thrombosis in patients with antiphospholipid antibodies, Vaidya [/bib_ref] Post-transplantation recurrent LN, although difficult to treat, is a rare cause of renal allograft loss. [bib_ref] Recurrence of lupus nephritis after kidney transplantation, Contreras [/bib_ref] Anti-phospholipid syndrome (APS)-associated nephropathy (APSN) in SLE Anti-phospholipid antibodies (anti-cardiolipin antibodies, anti-β2-glycoprotein I antibodies, lupus anticoagulant) may be associated with a distinct type of vascular nephropathy (APSN) with adverse prognostic factors such as hypertension, impaired renal function and interstitial fibrosis. [bib_ref] Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies:..., Tektonidou [/bib_ref] [bib_ref] Immunohistochemical detection of intravascular platelet microthrombi in patients with lupus nephritis and..., Galindo [/bib_ref] [bib_ref] IgA antiphospholipid antibodies are an independent risk factor for thromboses, Shen [/bib_ref] [bib_ref] Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study..., Zheng [/bib_ref] Histological lesions of APSN are present in 20% to 30% of patients with SLE and include thrombotic microangiopathy and chronic lesions such as fibrous intimal hyperplasia, organising thrombi with recanalisation, focal cortical atrophy and fibrous occlusions of arteries/arterioles, thus, need to be distinguished from thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome and malignant hypertension. In spite of lack of evidence from controlled studies, hydroxychloroquine and/or antiplatelet/anticoagulant treatment can be considered in combination with immunosuppressive treatment if nephritis is present. Patients with definite APS should receive anticoagulation treatment. [bib_ref] Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid..., Ruiz-Irastorza [/bib_ref]
## Ln and pregnancy
Pregnancy may be planned in patients with inactive lupus and UPCR <50 mg/mmol for the preceding 6 months, with GFR that should preferably be >50 ml/min. Patients with LN who are pregnant should ideally be followed by a multidisciplinary team. Stable renal disease is treated with the same drugs that are recommended as acceptable during prepregnancy counselling (hydroxychloroquine, prednisone, azathioprine). Hydroxychloroquine should be continued or even instituted if immunosuppressive agents need to be stopped. MPA or CY should not be used in the last 3 months, and biological agents for at least 4 months-dependent upon the agent used before conception. Blood pressure should be controlled without RAAS blockers at the time of conception if possible, due to their potential teratogenic effect during the first trimester, or with switching to other agents such as nifedipine or labetalol as soon as pregnancy is confirmed. Acetyl-salicylic acid is recommended to reduce the risk for pre-eclampsia. [bib_ref] Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and maternal..., Imbasciati [/bib_ref] Patients with APS are at increased risk for adverse pregnancy outcomes and should be considered for anticoagulation with low-molecular-weight heparin and/or acetyl-salicylic acid depending on their history of obstetric and/or thrombotic events. [bib_ref] Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid..., Ruiz-Irastorza [/bib_ref] Warfarin must be discontinued as soon as pregnancy is confirmed. Patients with nephrotic-range proteinuria are also candidates for anticoagulation.
For monitoring, any fall in serum C3/C4 is significant given than levels usually rise during pregnancy; 159 additional investigation may be needed to rule out pre-eclampsia before diagnosing exacerbation of renal disease. [bib_ref] Pregnancy in past or present lupus nephritis: a study of 32 pregnancies..., Huong [/bib_ref] For active disease or pre-eclampsia, combined care with obstetricians is recommended. [bib_ref] A systematic review and meta-analysis of pregnancy outcomes in patients with systemic..., Smyth [/bib_ref] Close surveillance for renal flare post partum is essential. In addition to acceptable medications used in stable LN, refractory cases can also be treated with calcineurin inhibitors, intravenous immunoglobulin, immunoadsorption and possibly plasma exchange, according to disease severity. Management of paediatric LN Children are at increased risk for renal involvement compared to adults with SLE (OR 1.5-2.4), and nephritis often is a presenting feature of paediatric SLE. Together with elevated blood pressure, fever, lymphadenopathy, skin and joint manifestations, [bib_ref] Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis, Livingston [/bib_ref] children with LN tend to have more active disease over time, receive more intensive immunosuppressive treatment and accrue more damage, often related to glucocorticoid toxicity, compared to adults. [bib_ref] Risk factors for hypercreatinemia in patients with systemic lupus erythematosus, Rzany [/bib_ref] [bib_ref] Assessment of damage in juvenile-onset systemic lupus erythematosus: a multicenter cohort study, Ravelli [/bib_ref] [bib_ref] Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus, Brunner [/bib_ref] [bib_ref] Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus:..., Hiraki [/bib_ref] [bib_ref] Differences in long-term disease activity and treatment of adult patients with childhood-and..., Hersh [/bib_ref] [bib_ref] Prognostic impact of atypical presentation in pediatric systemic lupus erythematosus: results from..., Taddio [/bib_ref] The diagnosis, management and monitoring is based on extrapolation from evidence in adults, and on the limited, non-randomised, evidence in children with LN. [bib_ref] Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell..., Traynor [/bib_ref] [bib_ref] Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus..., Fu [/bib_ref] [bib_ref] Induction therapy for pediatric focal proliferative lupus nephritis: cyclophosphamide versus mycophenolate mofetil, Lau [/bib_ref] [bib_ref] Outcomes in patients with active lupus nephritis requiring immunosuppressives who never received..., Urowitz [/bib_ref] Additional considerations include the negative effect of disease activity and glucocorticoids on linear growth, and the modification of body image induced by treatment. This may represent major psychological burden especially in adolescents building their self-esteem and affecting treatment compliance.
[fig] .: Flare of LN during pregnancy can be treated with acceptable medications stated above depending on severity of [/fig]
[table] Table 1: Recommendations for the management of patients with systemic lupus erythematosus (SLE) with renal involvement [/table]
[table] Table 2: Category of evidence and strength of statements* Indications for first renal biopsy Diagnostic value of urinary findings (proteinuria ≥0.5 g/24 h especially with glomerular haematuria and/or cellular casts) 2 C Clinical, serological or laboratory tests correlate modestly with renal biopsy findings 2 B 2. Pathological assessment of kidney biopsy International Society of Nephrology/Renal Pathology Society (ISN/RPS) Immunosuppression for class III A or III A/C (±V) and IV A or IV A/C (±V) nephritis 1 A Immunosuppression for class V nephritis if proteinuria >1 g/24 h 4 C Target: preservation of renal function, prevention of disease flares, avoidance of treatment-related harms and improved quality of life and survival [/table]
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https://ard.bmj.com/content/annrheumdis/71/11/1771.full.pdf
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Objectives To develop recommendations for the management of adult and paediatric lupus nephritis (LN). Methods The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. Results Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III–IVA or A/C (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. Conclusions Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.
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Conditional Recommendations for Specific Dietary Ingredients as an Approach to Chronic Musculoskeletal Pain: Evidence-Based Decision Aid for Health Care Providers, Participants, and Policy Makers
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Conditional Recommendations for Specific Dietary Ingredients as an Approach to Chronic Musculoskeletal Pain: Evidence-Based Decision Aid for Health Care Providers, Participants, and Policy Makers
Objective. Approximately 55-76% of Service members use dietary supplements for various reasons; although such use has become popular for a wide range of pain conditions, decisions to use supplements are often driven by information that is not evidence-based. This work evaluates whether the current research on dietary ingredients for chronic musculoskeletal pain provides sufficient evidence to inform decisions for practice and self-care, specifically for Special Operations Forces personnel. Methods. A steering committee convened to develop research questions and factors required for decision-making. Key databases were searched through August 2016. Eligible systematic reviews and randomized controlled trials were assessed for methodological quality. Meta-analysis was applied where feasible. GRADE was used to determine confidence in the effect estimates. A decision table was constructed to make evidence-informed judgments across factors required for decision-making, and recommendations were made for practice and self-care use. Results. Nineteen dietary ingredients were included. Conditional evidence-based recommendations were made for the use of avocado soybean unsaponifiables, capsaicin, curcuma, ginger, glucosamine, melatonin, polyunsaturated fatty acids, and vitamin D. In these cases, desirable effects outweighed undesirable effects, but there was uncertainty about the trade-offs, either because the evidence was low quality or because benefits and downsides were closely balanced. Conclusions. The evidence showed that certain dietary ingredients, when taken as part of a balanced diet and/or as a supplement (e.g., pill, tablet, capsule, cream), may alleviate musculoskeletal pain with no to minimal risk of harm. This finding emphasizes and reinforces the critical importance of shared decision-making between Operators and their health care providers.
# Introduction
Musculoskeletal (MSK) injuries are a leading cause of pain, medical encounters, lost duty time, and disability within the military due to the extreme demands of physical training and combat missions [bib_ref] Prevention of physical training-related injuries recommendations for the military and other active..., Bullock [/bib_ref] [bib_ref] Musculoskeletal injuries description of an under-recognized injury problem among military personnel, Hauret [/bib_ref]. Although MSK pain is typically treated with medications (e.g., nonsteroidal anti-inflammatories , injections, physical therapy, acupuncture, and other modalities, alternative approaches are needed. Dietary ingredients may be one such option. Dietary supplement use for a wide range of conditions, including pain, has become increasingly popular, with about 70-74% of the general adult population and 55-76% of Service members using dietary supplements for various reasons [bib_ref] A systematic review and meta-analysis on the prevalence of dietary supplement use..., Knapik [/bib_ref]. Despite their popularity, evidence for their use is unclear [bib_ref] Are active self-care complementary and integrative therapies effective for management of chronic..., Buckenmaier [/bib_ref] [bib_ref] Evidence for the efficacy of complementary and alternative medicines in the management..., Silva [/bib_ref] , and decisions to use these supplements may be driven by information that is not evidence-based (e.g., advice from peers, family members, and other sources). It is imperative that evidence-based research be used to inform decisions regarding such use to ensure safe and effective management of MSK pain.
As part of the US Special Operations Command's Preservation of the Force and Family Behavioral Health Program, this project sought to determine whether current research on dietary ingredients for chronic MSK pain could provide sufficient evidence to inform decisions for both practice and self-care use. To achieve this, stateof-the-science evidence methodologies were applied to provide clear, comprehensive, and unbiased information to the Special Operations community and enable key stakeholders and subject matter experts to make evidence-based recommendations to inform policy decisions regarding dietary ingredients for improving pain and pain-related (e.g., psychological health, quality of life) outcomes.
The aim of this article is to describe the resulting evidence-based recommendations made for the use of dietary supplements. This paper is the second in a series of articles [bib_ref] How Evidence-Based Recommendations May Direct Policy Decisions Regarding Appropriate Selection and Use..., Cota [/bib_ref] [bib_ref] Dietary Ingredients Requiring Further Research before Evidence-Based Recommendations Can be Made for..., Crawford [/bib_ref] [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref] that detail the methodological approach and relevance of this work to Special Operators, specific evidence-based recommendations, and implications for policy decisions. It is important to note that although formal processes were followed and recommendations made, this is not intended to serve as a formal clinical practice guideline.
# Methods
The project's full methodological approach is detailed within the first of this series of three articles (Supplementary Data: Detailed Methodology) [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref]. Briefly, 1) the authors followed the Institute of Medicine guidelines to ensure transparent processes were followed and mitigate any conflicts of interest to carefully select and recruit an unbiased group of key stakeholders and subject matter experts. The committee, named the Holistic Evidence Review Board (HERB), was convened to develop the criteria to inform the clinical question(s), definitions [bib_ref] Report of the Task Force on Research Standards for chronic low-back pain, Deyo [/bib_ref] , and factors required for decision-making (Supplementary Data: GRADE Grid); 2) a review team, independent of the HERB, then conducted a series of systematic reviews to assess the current state of the evidence and to explore the safety and efficacy of various dietary ingredients for treating pain and related outcomes (Supplementary Data: Summary Report); 3) the gathered evidence was integrated with the expertise of those subject matter experts; and 4) modified Delphi methods were used to develop evidence-based recommendations for the use of dietary ingredients and priority areas in need of future research following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref] [bib_ref] Consensus methods, clinical guidelines, and the RAND study of chiropractic, Coulter [/bib_ref] [bib_ref] Use of GRADE grid to reach decisions on clinical practice guidelines when..., Jaeschke [/bib_ref]. The series of systematic reviews used to inform recommendations are reported in the Supplementary Data: Summary Report.
Conditional recommendations were made when the desirable anticipated effects outweighed the undesirable effects but there was uncertainty about the trade-offs, either because the key evidence was of low quality or because the benefits and downsides were closely balanced. No recommendations were made either because the quality of the evidence was too low or trade-offs were so closely balanced that any recommendation would be too speculative. Recommendations against the current use of an ingredient, based on available evidence, were made when undesirable anticipated effects outweighed the desirable effects or the downsides clearly outweighed the benefits overall.
# Results
Nineteen dietary ingredients were identified and evaluated using systematic review methods (Supplementary Data: Detailed Methodology and Summary Report) [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref]. Integrating the evidence with the HERB clinical acumen across the factors required for decision-making, three types of recommendations were ultimately made for these dietary ingredients [fig_ref] Figure 1: Recommendations. [/fig_ref]. This article details dietary ingredients for which conditional, evidence-based recommendations were ultimately made; recommended ingredients include avocado soybean unsaponifiables (ASU) [bib_ref] Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis..., Blotman [/bib_ref] [bib_ref] Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double..., Appelboom [/bib_ref] [bib_ref] Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in..., Maheu [/bib_ref] [bib_ref] Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the..., Maheu [/bib_ref] [bib_ref] Efficacy and safety of piascledine 300 versus chondroitin sulfate in a 6..., Pavelka [/bib_ref] [bib_ref] Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of..., Lequesne [/bib_ref] , capsaicin [bib_ref] Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients, Casanueva [/bib_ref] [bib_ref] Efficacy of a 0.1% capsaicin hydrogel patch for myofascial neck pain: A..., Cho [/bib_ref] [bib_ref] Effectiveness and safety of topical capsaicin cream in the treatment of chronic..., Chrubasik [/bib_ref] [bib_ref] Topical treatment of chronic low back pain with a capsicum plaster, Frerick [/bib_ref] [bib_ref] Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus..., Kosuwon [/bib_ref] [bib_ref] High strength capsaicin cream for osteoarthritis pain: Rapid onset of action and..., Schnitzer [/bib_ref] [bib_ref] Capsicum pain plaster in chronic non-specific low back pain, Keitel [/bib_ref] [bib_ref] Capsaicin cream 0.025% as monotherapy for osteoarthritis: A double-blind study, Altman [/bib_ref] [bib_ref] Treatment of arthritis with topical capsaicin: A double-blind trial, Deal [/bib_ref] [bib_ref] Topical application of capsaicin for the treatment of localized pain in the..., Winocur [/bib_ref] [bib_ref] Systematic review of topical capsaicin for the treatment of chronic pain, Mason [/bib_ref] , curcuma [bib_ref] A randomized, pilot study to assess the efficacy and safety of curcumin..., Chandran [/bib_ref] [bib_ref] Curcuminoid treatment for knee osteoarthritis: A randomized double-blind placebo-controlled trial, Panahi [/bib_ref] [bib_ref] Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: A randomized, double-blind,..., Nakagawa [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts in patients with knee osteoarthritis, Kuptniratsaikul [/bib_ref] [bib_ref] Safety and efficacy of curcuma longa extract in the treatment of painful..., Madhu [/bib_ref] [bib_ref] The efficacy of Curcuma longa L. extract as an adjuvant therapy in..., Pinsornsak [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts compared with ibuprofen in patients..., Kuptniratsaikul [/bib_ref] [bib_ref] Treatment of osteoarthritis with a herbomineral formulation: A double-blind, placebocontrolled, cross-over study, Kulkarni [/bib_ref] [bib_ref] Clinical evaluation of a formulation containing curcuma longa and boswellia serrata extracts..., Kizhakkedath [/bib_ref] [bib_ref] Boswellia-curcumin preparation for treating knee osteoarthritis: A clinical evaluation, Badria [/bib_ref] , ginger [bib_ref] Evaluating the effects of ginger extract on knee pain, stiffness and difficulty..., Zakeri [/bib_ref] [bib_ref] Effects of a ginger extract on knee pain in patients with osteoarthritis, Altman [/bib_ref] [bib_ref] The efficacy of powdered ginger in osteoarthritis of the knee, Niempoog [/bib_ref] [bib_ref] The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis, Wigler [/bib_ref] [bib_ref] Comparing analgesic effects of a topical herbal mixed medicine with salicylate in..., Zahmatkash [/bib_ref] [bib_ref] A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis, Bliddal [/bib_ref] [bib_ref] Comparing the effects of ginger (Zingiber officinale) extract and ibuprofen on patients..., Haghighi [/bib_ref] [bib_ref] Influence of a specific ginger combination on gastropathy conditions in patients with..., Drozdov [/bib_ref] [bib_ref] Comparable efficacy of standardized ayurveda formulation and hydroxychloroquine sulfate (HCQS) in the..., Chopra [/bib_ref] [bib_ref] A commercialized dietary supplement alleviates joint pain in community adults: A double-blind,..., Nieman [/bib_ref] [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref] , glucosamine [bib_ref] Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: Results of..., Bruyere [/bib_ref] [bib_ref] Risk of bias and brand explain the observed inconsistency in trials on..., Eriksen [/bib_ref] [bib_ref] Efficacy and safety of glucosamine, diacerein, and NSAIDs in osteoarthritis knee: A..., Kongtharvonskul [/bib_ref] [bib_ref] Glucosamine therapy for treating osteoarthritis, Towheed [/bib_ref] [bib_ref] Effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib..., Zeng [/bib_ref] [bib_ref] OARSI recommendations for the management of hip and knee osteoarthritis: Part III:..., Zhang [/bib_ref] , melatonin [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] [bib_ref] Adjuvant use of melatonin for treatment of fibromyalgia, Hussain [/bib_ref] [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref] , polyunsaturated fatty acids (PUFA) [bib_ref] Polyunsaturated fatty acids and chronic pain: A systematic review and meta-analysis, Prego-Dominguez [/bib_ref] , and vitamin D [bib_ref] Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate..., Salesi [/bib_ref] [bib_ref] An evaluation of high-dose vitamin D for rheumatoid arthritis, Hansen [/bib_ref] [bib_ref] The effect of vitamin D on nonspecific low back pain, Sandoughi [/bib_ref] [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] [bib_ref] Diffuse musculoskeletal pain is not associated with low vitamin D levels or..., Warner [/bib_ref] [bib_ref] A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic..., Gendelman [/bib_ref] [bib_ref] Effect of vitamin D supplementation on progression of knee pain and cartilage..., Mcalindon [/bib_ref] [bib_ref] Effect of vitamin D supplementation on tibial cartilage volume and knee pain..., Jin [/bib_ref] [bib_ref] Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot..., Sanghi [/bib_ref] [bib_ref] Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind,..., Knutsen [/bib_ref] [bib_ref] Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: A randomized..., Schreuder [/bib_ref] [bib_ref] The effect of oral and parenteral vitamin D supplementation in the elderly:..., Sakalli [/bib_ref] [bib_ref] Effect of vitamin D supplementation on pain: A systematic review and meta-analysis, Wu [/bib_ref].
Although uncertainties remain, thereby precluding any strong recommendations for immediate use, these dietary ingredients, when taken as part of a balanced diet, applied as a cream, or administered as a supplement, may help alleviate pain from chronic MSK conditions and are suggested for use. In these cases, health care providers should be prepared to help individuals make decisions consistent with their own values, and Special Operators should be aware of the potential benefits and discuss the use of these ingredients with a provider. Because no strong recommendations were made to endorse an ingredient for immediate use without any caveats, there is a need to encourage discussion and debate among stakeholders before policy decisions are made. [fig_ref] Table 2: Summary of findings [/fig_ref] displays the ingredients where conditional recommendations were made, the graded evidence for efficacy as well as safety and other considerations examined when making recommendations. [fig_ref] Table 3: Judgments across factors for decision-making [/fig_ref] details the summary of judgments across factors and resulting recommendations.
## Conditional evidence-based recommendations
## Avocado soybean unsaponifiables
Avocado soybean unsaponifiables are a natural vegetable extract made from one-third avocado oil and two-thirds soybean oil. ASU are commonly used for osteoarthritis symptoms, as it is believed that they slow down disease progression [bib_ref] Management of osteoarthritis with avocado/soybean unsaponifiables, Christiansen [/bib_ref].
Six studies meeting the review's criteria compared ASU with placebo or chondroitin sulfate in knee and/or hip osteoarthritis populations [bib_ref] Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis..., Blotman [/bib_ref] [bib_ref] Symptoms modifying effect of avocado/soybean unsaponifiables (ASU) in knee osteoarthritis. A double..., Appelboom [/bib_ref] [bib_ref] Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in..., Maheu [/bib_ref] [bib_ref] Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the..., Maheu [/bib_ref] [bib_ref] Efficacy and safety of piascledine 300 versus chondroitin sulfate in a 6..., Pavelka [/bib_ref] [bib_ref] Structural effect of avocado/soybean unsaponifiables on joint space loss in osteoarthritis of..., Lequesne [/bib_ref]. Studies administered 300 or 600 mg/d of ASU for anywhere from three months to three years [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (75% weak, in favor; 12.5% none; 12.5% weak, against) for the use of PiascledineV R 300 (300-600 mg/d), a commercialized brand of ASU, as a dietary supplement for pain and related symptoms.
The low to moderate quality and certainty of the evidence suggests that Piascledine 300 or 600 mg/d is associated with a statistically significant reduction in pain (standardized mean difference [SMD] ¼ -0.60) and improvement in function (SMD ¼ -0.64) as compared with placebo at time points of three to six months' duration. (Supplementary Data: Summary Report). These desirable anticipated effects appeared to be moderate, whereas any undesirable effects, primarily gastrointestinal complaints noted across all treatment groups, were small to trivial. There was a high degree of statistically significant heterogeneity detected from the pooled studies, as well as risk of bias associated with some studies. Additionally, the small sample sizes reduced the certainty of the evidence evaluated.
Research trials to date appear to consistently report on the use of Piascledine 300, the majority of which are funded by the same entity that supplied the intervention. Although ASU appear to be available over the counter (OTC) and in combination with other "joint health" supplements, evidence to support their use in these formularies is unknown. Resources required for the use of ASU are highly dependent on the type of formulary. For . Focused PICOS used to define the narrowed research question: Are there dietary supplements/ingredients that can safely mitigate chronic pain in adults (18þ years old) with musculoskeletal disorders?
## Population
- Adults (18þ years) with chronic pain due to musculoskeletal disorders. - Chronic pain was defined as ongoing or recurrent pain, lasting beyond the usual course of acute illness or injury (i.e., >3 months and occurring at least half of the days over the past 6 months), and which adversely affects the individual's well-being [bib_ref] Report of the Task Force on Research Standards for chronic low-back pain, Deyo [/bib_ref]. - Musculoskeletal pain was defined as pain affecting the bones, muscles, ligaments, or disorders of the muscles, nerves, tendons, joints, and cartilage, and disorders of the nerves, tendons, muscles, and supporting structures of the upper and lower limbs, neck, and lower back that are caused, precipitated, or exacerbated by sudden exertion or prolonged exposure to physical factors such as repetition, force, vibration, or awkward posture. Note that headaches/ migraines and musculoskeletal pain conditions resulting from another disease or injury (e.g., fracture, contusion, abrasion, laceration) were excluded. Intervention
Any single or multiple (e.g., combination of ingredients) dietary ingredient(s)- Indicated for neuropathic pain as secondline treatment; may also be effective for musculoskeletal pain.
- Be aware of possible burning sensation upon application, especially at higher doses (0.25%).
- Invest in resources in dose response study to understand dose response curve.
vs other
## 2/194
Fibromyalgia, osteoarthritis Only one study compared capsaicin with another comparator (i.e., usual care). Both high (i.e., 0.25% capsaicin) and low (i.e., 0.025% capsaicin) doses were effective. Although a higher dose may produce more burning sensation, the application of the product may be required less frequently, and preliminary evidence suggests that pain relief occurs quicker at this higher dose.
(continued) - Already available in tea/food; no additional risk in obtaining ginger via food sources.
## Conditionally recommended dietary ingredients for pain
- Divergent opinions regarding feasibility, acceptability, and suitability.
- Invest more in research, specifically in larger trials.
vs other ¶
## 2/187
Osteoarthritis Two studies compared ginger with ibuprofen and reported mixed results. The higher the dose (e.g., 1,000 mg), the more likely a positive benefit for ginger only.
*Studies combining ginger (N ¼ 4) with other ingredients were heterogeneous. Overall, combination products showed positive benefit for reducing pain and possibly overall health/quality of life but not for improving function.
(continued) - Moderate-quality evidence supports the use of glucosamine in the form of pCGS at 1,500 mg/d and suggests that it has similar effects to ibuprofen but takes longer to obtain a response.
- Effects of pCGS combined with prescription chondroitin are still unknown.
- pCGS implementation requires obtaining a supplement with the same purity levels of the pCGS ingredients.
- OTC appears safe, but types and effects of formulations are unknown. Fibromyalgia Two studies showed that melatonin was effective, and in some cases more effective, than other comparators in improving pain, sleep, health-related quality of life, mood, and physical function.
## -
(continued) *Eight voting members judged factors to consider together to develop recommendations. A summary weight is provided for each ingredient ranking the desirable consequences to the unknown or undesirable consequences across factors, which was done anonymously. The quality was not assigned a weight, as this was used to determine the weight of the certainty of the evidence across all outcomes assessed, and as supplied by the evidence review independently (Supplementary Data: Summary Report). Although the accumulated judgments of all factors were used to inform the recommendations ultimately made and displayed using the GRADE Grid (Supplementary Data: GRADE Grid) visually, they were not assigned a weighted summary score. † Conditionally recommend use as a food source, not as a dietary supplement, at this time.
example, Piascledine 300 is made in France, and therefore the required resources are perhaps higher than other dietary ingredients. Because it is unknown what formularies might be beneficial beyond Piascledine 300, members had divergent opinions regarding ASU's required resources, acceptability to stakeholders, and feasibility of implementation.
Given that the desirable effects outweigh the undesirable, research should focus on understanding OTC formulations and conducting third-party evaluations before strong recommendations can be made. The purity of ASU ingredients should also be confirmed via United States Pharmacopeia (USP)-verified or NSF-certified products.
## Capsaicin
Capsaicin, one of the primary constituents of the Capsicum species, is an active component of chili peppers. Capsicum is grown worldwide and adds color, pungency (i.e., heat), and aroma to food. Capsaicin is used orally, topically, and intranasally for a variety of conditions. It is most commonly used topically for MSK conditions such as osteoarthritis, rheumatoid arthritis, neuralgias/neuropathies, back pain, fibromyalgia, and muscle spasms. In fact, both low-concentration OTC and Food and Drug Administration (FDA)-approved, high-concentration (i.e., Qutenza TM ) topical formulations are available.
Ten randomized controlled trials (RCTs) [bib_ref] Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients, Casanueva [/bib_ref] [bib_ref] Efficacy of a 0.1% capsaicin hydrogel patch for myofascial neck pain: A..., Cho [/bib_ref] [bib_ref] Effectiveness and safety of topical capsaicin cream in the treatment of chronic..., Chrubasik [/bib_ref] [bib_ref] Topical treatment of chronic low back pain with a capsicum plaster, Frerick [/bib_ref] [bib_ref] Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus..., Kosuwon [/bib_ref] [bib_ref] High strength capsaicin cream for osteoarthritis pain: Rapid onset of action and..., Schnitzer [/bib_ref] [bib_ref] Capsicum pain plaster in chronic non-specific low back pain, Keitel [/bib_ref] [bib_ref] Capsaicin cream 0.025% as monotherapy for osteoarthritis: A double-blind study, Altman [/bib_ref] [bib_ref] Treatment of arthritis with topical capsaicin: A double-blind trial, Deal [/bib_ref] [bib_ref] Topical application of capsaicin for the treatment of localized pain in the..., Winocur [/bib_ref] compared the effect of capsaicin with placebo, usual treatment, or other capsaicin products within a variety of populations, including those with osteoarthritis, rheumatoid arthritis, and other MSK conditions. Capsaicin was delivered topically either as a patch or gel/cream; capsaicin gels/creams were labeled as Capsika gelV R , ZostrixV R , Dolarac TM , FinalgonV R , or SensedolV R . Daily dosages of patches containing either 0.1% or 22-37.4 ug/cm 2 of capsaicin were applied at times ranging from four to 12 hours over three to four weeks, whereas dosages of creams containing 0.0125-0.25% capsaicin were applied at times ranging from twice to four times daily for three to 12 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (37.5% weak, in favor; 62.5% strong, in favor) for the use of capsaicin as a cream or patch for pain and related symptoms.
Current research shows high-quality evidence and certainty that capsaicin will produce a statistically significant reduction in pain (SMD ¼ -0.56) and the patient's global assessment of improvement (risk difference [RD] ¼ -0.21) compared with placebo at time points closest to four weeks (Supplementary Data: Summary Report). These desirable anticipated effects were judged to be moderate overall, and the undesirable anticipated effects, primarily associated with burning, itching, and irritation, were judged to be small to trivial. Most OTC creams contain 0.025-0.075% capsaicin and can be applied three to four times a day to the affected area. The application of higher OTC doses (i.e., 0.25%) is only recommended if the patient can tolerate the increased undesirable effects, an approach that can potentially provide quicker pain relief with less frequent applications.
Because the cost of capsaicin is highly dependent upon its dose and delivery system, it was challenging for members to judge the required resources based on the current evidence. Given the desirable vs undesirable anticipated effects, however, its use likely justifies the resource requirements and out-of-pocket expenses. Members agreed that capsaicin would likely be acceptable to stakeholders and feasible/suitable to implement for use as a cream or patch.
## Curcuma
Turmeric, commonly referred to by its Latin name, curcuma, is a plant related to ginger and is grown throughout India, parts of Asia, and Central America [89]. Curcuma is formulated into capsules, tablets, teas, extracts, and/or pastes and is used for inflammation, arthritis, stomach, skin, liver and gallbladder problems, cancer, and other conditions. Turmeric root and powder are available as grocery items for cooking.
The authors identified 10 RCTs [bib_ref] A randomized, pilot study to assess the efficacy and safety of curcumin..., Chandran [/bib_ref] [bib_ref] Curcuminoid treatment for knee osteoarthritis: A randomized double-blind placebo-controlled trial, Panahi [/bib_ref] [bib_ref] Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: A randomized, double-blind,..., Nakagawa [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts in patients with knee osteoarthritis, Kuptniratsaikul [/bib_ref] [bib_ref] Safety and efficacy of curcuma longa extract in the treatment of painful..., Madhu [/bib_ref] [bib_ref] The efficacy of Curcuma longa L. extract as an adjuvant therapy in..., Pinsornsak [/bib_ref] [bib_ref] Efficacy and safety of curcuma domestica extracts compared with ibuprofen in patients..., Kuptniratsaikul [/bib_ref] [bib_ref] Treatment of osteoarthritis with a herbomineral formulation: A double-blind, placebocontrolled, cross-over study, Kulkarni [/bib_ref] [bib_ref] Clinical evaluation of a formulation containing curcuma longa and boswellia serrata extracts..., Kizhakkedath [/bib_ref] [bib_ref] Boswellia-curcumin preparation for treating knee osteoarthritis: A clinical evaluation, Badria [/bib_ref] meeting the review's inclusion criteria. Studies compared curcuma, either alone (N ¼ 7) or combined with other ingredients , with other dietary ingredients, NSAIDs, or placebo in samples with osteoarthritis and/or rheumatoid arthritis. Doses ranged from 700 to 2,000 mg/d over 42 days to 12 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (75% weak in favor; 12.5% none; 12.5% weak, against) for the use of curcuma as a food source in daily diets at dose equivalents of 500 mg two to three times per day for pain and related symptoms. The HERB did not recommend curcuma as a dietary supplement at this time.
A large (SMD ¼ -1.05) and statistically significant desirable anticipated effect was noted for pain reduction, enhanced global function (SMD ¼ -0.87), and reduced medication use (RD ¼ -0.50), as compared with placebo at the time point closest to two months. The quality and certainty of the evidence are very low to low. Potential risk of bias across the pooled studies, small sample size, and statistically significant heterogeneity were reasons for downgrading (Supplementary Data: Summary Report).
Curcuma was rated as a high priority research area given that its potential desirable effects outweigh the minimal undesirable effects (e.g., minor gastrointestinal complaints). Until further research is conducted, curcuma is suggested as a useful dietary source but should not be used as a dietary supplement. Costs were rated as negligible to even moderate savings. There was some disagreement as to whether curcuma would be acceptable to stakeholders or feasible to implement. Once further research emerges, additional stakeholder debate would be required [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref].
## Ginger
Ginger is a tropical plant widely used as a flavoring or fragrance in foods, beverages, soaps, and cosmetics. Common forms include the fresh or dried root, tablets, capsules, liquid extracts, and teas. Ginger is currently used as a dietary ingredient for nausea, rheumatoid arthritis, and osteoarthritis.
Ten RCTs [bib_ref] Evaluating the effects of ginger extract on knee pain, stiffness and difficulty..., Zakeri [/bib_ref] [bib_ref] Effects of a ginger extract on knee pain in patients with osteoarthritis, Altman [/bib_ref] [bib_ref] The efficacy of powdered ginger in osteoarthritis of the knee, Niempoog [/bib_ref] [bib_ref] The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis, Wigler [/bib_ref] [bib_ref] Comparing analgesic effects of a topical herbal mixed medicine with salicylate in..., Zahmatkash [/bib_ref] [bib_ref] A randomized, placebo-controlled, cross-over study of ginger extracts and ibuprofen in osteoarthritis, Bliddal [/bib_ref] [bib_ref] Comparing the effects of ginger (Zingiber officinale) extract and ibuprofen on patients..., Haghighi [/bib_ref] [bib_ref] Influence of a specific ginger combination on gastropathy conditions in patients with..., Drozdov [/bib_ref] [bib_ref] Comparable efficacy of standardized ayurveda formulation and hydroxychloroquine sulfate (HCQS) in the..., Chopra [/bib_ref] [bib_ref] A commercialized dietary supplement alleviates joint pain in community adults: A double-blind,..., Nieman [/bib_ref] met the review's eligibility criteria, five of which were also included in Bartels et al.'s 2015 systematic review and meta-analysis [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref] on ginger for osteoarthritis. Studies compared ginger, either alone or combined with other ingredients, with herbal, pharmacologic, and placebo comparators in osteoarthritis, rheumatoid arthritis, and chronic joint pain populations. Dosages ranged from 250 to 1,000 mg/d (delivered as a capsule) and 6 g/d (delivered as an ointment) over anywhere from three to 12 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Whereas no recommendation was provided (37.5% weak, in favor; 37.5% none; 25% weak, against) for the use of ginger as a dietary supplement, members agreed that minimal adverse events have been noted and that the certainty and quality of the evidence for a small yet statistically significant reduction in pain (SMD ¼ -0.30) and disability (SMD ¼ -0.22) were moderate (Supplementary Data: Summary Report) [bib_ref] Dietary Ingredients Requiring Further Research before Evidence-Based Recommendations Can be Made for..., Crawford [/bib_ref] [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref]. The desirable anticipated effect was not as substantial as the other ingredients reported here; however, members agreed that it is already available in tea and food and, if readily available, could be suggested for use.
Although the critical threshold for a clinically relevant effect is debatable, the effect size of ginger does fall within the range of some other nutraceuticals/herbal medicines, and NSAIDs and may be beneficial to some individuals [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref]. The exact dose is not well established, but plausible dose responses associated with ginger in higher doses (i.e., 1,000 mg) appear to produce a larger effect than lower doses (i.e., 250 mg) [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref]. Risk of bias was detected across some studies evaluated. The cost appears negligible or even a moderate savings compared with other active pain medications, but members did not agree as to whether this would justify its use or out-ofpocket costs. Members mostly agreed that there are concerns over feasibility and suitability with ginger in mission planning and that it would likely not be acceptable to stakeholders for use.
## Glucosamine, prescription/over-the-counter
Glucosamine is an amino sugar naturally produced in the human body. It is required for the synthesis of glucoproteins, glyocolipids, and glucosaminoglycans found in the tendons, ligaments, cartilage, synovial fluid, mucous membranes, eye structures, blood vessels, and heart valves. It can also be derived from marine exoskeletons or produced synthetically [bib_ref] Glucosamine hydrochloride for the treatment of osteoarthritis symptoms, Fox [/bib_ref]. Glucosamine sulfate and glucosamine hydrochloride are delivered orally for many MSK conditions such as temporomandibular disorder, joint pain, osteoarthritis, knee pain, and back pain. Both are also commonly combined with each other or other products (e.g., chondroitin sulfate, N-acetyl glucosamine).
Controversy surrounds the reported effectiveness of glucosamine [bib_ref] Efficacy and safety of glucosamine sulfate in the management of osteoarthritis: Evidence..., Bruyere [/bib_ref] ; however, a Cochrane review recently confirmed that a particular glucosamine sulfate product (Dona, Rotta Pharmaceuticals), as opposed to other formulations, was effective in reducing osteoarthritic pain [bib_ref] Glucosamine therapy for treating osteoarthritis, Towheed [/bib_ref].
Conditional recommendations were made (62.5% weak; 37.5% strong, in favor) for the use of prescription patented Crystalized Glucosamine Sulfate (pCGS) at daily doses of 1,500 mg for pain and related symptoms. It is important to note that the controversy concerning the use of glucosamine sulfate and combination products containing glucosamine largely reflects the differing regulatory status, labeling, and availability of medications in separate countries and regions of the world. Hence, to date it appears that pCGS, as supplied by RottaPharm, is the only product with a well-documented pharmacological effect [bib_ref] Risk of bias and brand explain the observed inconsistency in trials on..., Eriksen [/bib_ref] [bib_ref] Glucosamine therapy for treating osteoarthritis, Towheed [/bib_ref].
There is moderate overall quality and certainty that this product will produce a statistically significant effect in reducing pain (SMD ¼ -0.27) compared with placebo [bib_ref] Risk of bias and brand explain the observed inconsistency in trials on..., Eriksen [/bib_ref] [bib_ref] OARSI recommendations for the management of hip and knee osteoarthritis: Part III:..., Zhang [/bib_ref]. pCGS appears to be well-tolerated, as associated undesirable effects (e.g., mild gastrointestinal complaints) are small to trivial. Although pCGS shows similar effects to ibuprofen, it does take longer to obtain a response. Members mostly agreed that the cost would be negligible to even a moderate savings compared with other active ingredients for pain relief. Moreover, they concurred that it would likely justify out-of-pocket expenses and be both acceptable to stakeholders and feasible/suitable to implement, provided that any implemented supplement had the same purity levels as the pCGS ingredients, as in the RottaPharm product.
Effects of pCGS combined with chondroitin remain unknown. OTC glucosamine is available, and although the certainty of the evidence was very low to low and the desirable effects likely small, the members believed that the undesirable effects would be small to trivial. Conditional recommendations were provided for OTC glucosamine (62.5% weak, in favor; 37.5% none), should pCGS not be available to a Special Operator.
## Melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone naturally produced by the pineal gland in the brain. This hormone plays a role in sleep, with production and release related to time of day (i.e., rising in the evening, falling in the morning) [bib_ref] Melatonin in humans, Brzezinski [/bib_ref]. Melatonin is commonly administered orally via capsule for sleep disorders but may be also used to manage neuropathies, headaches, cancers, or osteoporosis.
Three RCTs meeting the review's inclusion criteria compared the effect of melatonin with either a placebo [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref] or a pharmacological drug (i.e., fluoxetine [bib_ref] Adjuvant use of melatonin for treatment of fibromyalgia, Hussain [/bib_ref] or amitriptyline [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] in fibromyalgia [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] [bib_ref] Adjuvant use of melatonin for treatment of fibromyalgia, Hussain [/bib_ref] and myofascial temporomandibular disorder (TMJ) populations [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref]. Melatonin doses ranged from 3 to 10 mg/d across four to eight weeks [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref]. Baseline levels of melatonin were not reported by any study [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (75% weak, in favor; 12.5% none; 12.5% weak, against) for short-term use of low-dose (i.e., 3-5 mg/d) USP-verified or NSF-certified melatonin products as a dietary supplement for pain and related symptoms.
Preliminary evidence demonstrates that melatonin is superior to placebo [bib_ref] Analgesic and sedative effects of melatonin in temporomandibular disorders: A doubleblind, randomized,..., Vidor [/bib_ref] , and perhaps to amitryptline [bib_ref] Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system..., De Zanette [/bib_ref] , in reducing pain and reliance on other medications while improving sleep patterns. Little is known about how large these desirable anticipated effects may be or the potential adverse events that might be associated with long-term use. Nonrandomized trials have reported that drowsiness, headache, dizziness, and nausea are uncommon. The HERB agreed that higher doses of melatonin should be avoided until further long-term studies are conducted. Melatonin is a dietary ingredient already broadly used, acceptable to many stakeholders, and available as a sleep aid, so it is likely feasible to implement for pain and sleep improvement. Associated costs are viewed as negligible or even a moderate savings compared with other pain-relieving medications. The quality and certainty of the evidence were judged to be very low to low, with insufficient studies to conduct a meta-analysis.
## Polyunsaturated fatty acids
Fish oil comes from various species, including mackerel, herring, tuna, halibut, salmon, cod liver, and whale and seal blubber. Thus, these types of fish are dietary sources of omega-3 fatty acids, also known as n-3 fatty acids [bib_ref] Beyond the Mediterranean diet: The role of omega-3 fatty acids in the..., Harper [/bib_ref]. Omega-3 fatty acids are essential dietary ingredients and include alpha-linolenic acid (ALA), longchain omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Fish oil supplements contain varying amounts of EPA and DHA (18-51% and 12-32%, respectively). Although ALA is mainly found in green vegetables, canola oil, and soybeans, EPA and DHA almost exclusively come from fish oil and other seafood. ALA, EPA, and DHA are types of omega-3 fatty acids but may serve different functional roles and should subsequently not be considered interchangeable. Although proprietary prescription fish oil is FDAapproved to lower levels of triglycerides, nonprescription formulations of fish oil are also used for other conditions including chronic fatigue syndrome, cognitive function/ impairment, and MSK (e.g., rheumatoid arthritis, muscle strength, muscle soreness, osteoporosis, osteoarthritis, migraines) issues .
The authors relied upon evidence on PUFA for chronic pain presented in Prego-Dominguez et al.'s 2016 systematic review and meta-analysis [bib_ref] Polyunsaturated fatty acids and chronic pain: A systematic review and meta-analysis, Prego-Dominguez [/bib_ref]. The majority of examined studies compared various combinations of PUFA with placebo or other comparators for pain reduction in rheumatoid arthritis patients, with doses ranging from 300 to 9,600 mg for anywhere from four to 48 weeks [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report).
Conditional recommendations were made (50% weak; 50% strong, in favor) for the use of PUFA supplementation for pain and related symptoms, incorporated into the daily diet at 1,200 mg/d, and not to exceed 2 g/d. Whereas the undesirable effects appear to be small to trivial at low doses, >3 g/d is likely to increase the potential for adverse events (e.g., inhibition of platelet aggregation, risk of bleeding, and potentially hemorrhagic stroke at very high doses) (Supplementary Data: Summary Report).
Moderate-quality evidence suggests that the desirable anticipated effects for pain reduction (SMD ¼ -0.40 range) are statistically significant as compared with placebo [bib_ref] Polyunsaturated fatty acids and chronic pain: A systematic review and meta-analysis, Prego-Dominguez [/bib_ref]. Heterogeneity is noted across the assessed studies and is likely due to varying blends of omega-3/6 used. Although research points to the association between omega-3, rather than omega-6, and pain reduction, the exact ratio, dose, and duration of PUFA use are yet to be determined; most studies, however, report benefit between 1 and 2 g/d.
PUFA do have preventive benefits, are available in food, and should be considered as a dietary source. Nutrition education is critical, moreover, to ensure that the proper amounts are being obtained via food or supplementation to avoid excessive intake. Members mostly agreed that the certainty of the evidence is moderate and that cost is negligible, with even moderate savings compared with currently used pain medications. Subsequently, PUFA are likely acceptable, feasible, and suitable to implement as a dietary food source or supplement, preferably from a USP-verified or NSF-certified product.
Vitamin D Vitamin D is a fat-soluble vitamin obtained from sun exposure, food, and/or dietary supplements. Vitamin D promotes calcium absorption, is necessary for bone growth, and appears to also affect skeletal muscle, immune regulation, cardiovascular health, and metabolic activities [bib_ref] Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis..., Razzaque [/bib_ref]. Vitamin D deficiencies can result in thin, brittle, or misshapen bones, bone pain, muscle weakness, rickets, and osteomalacia [bib_ref] Vitamin D: Importance in the prevention of cancers, type 1 diabetes, heart..., Holick [/bib_ref]. Vitamin D is most commonly used for osteoporosis, osteomalacia, and falls and fractures in individuals at risk for osteoporosis.
The authors relied on the systematic review published by Wu et al. [bib_ref] Effect of vitamin D supplementation on pain: A systematic review and meta-analysis, Wu [/bib_ref] and individual RCTs examining populations with rheumatoid arthritis, chronic low back, fibromyalgia, chronic nonspecific MSK pain, and knee osteoarthritis [bib_ref] Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate..., Salesi [/bib_ref] [bib_ref] An evaluation of high-dose vitamin D for rheumatoid arthritis, Hansen [/bib_ref] [bib_ref] The effect of vitamin D on nonspecific low back pain, Sandoughi [/bib_ref] [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] [bib_ref] Diffuse musculoskeletal pain is not associated with low vitamin D levels or..., Warner [/bib_ref] [bib_ref] A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic..., Gendelman [/bib_ref] [bib_ref] Effect of vitamin D supplementation on progression of knee pain and cartilage..., Mcalindon [/bib_ref] [bib_ref] Effect of vitamin D supplementation on tibial cartilage volume and knee pain..., Jin [/bib_ref] [bib_ref] Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot..., Sanghi [/bib_ref] [bib_ref] Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind,..., Knutsen [/bib_ref] [bib_ref] Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: A randomized..., Schreuder [/bib_ref] [bib_ref] The effect of oral and parenteral vitamin D supplementation in the elderly:..., Sakalli [/bib_ref] to evaluate and present the evidence on vitamin D for chronic MSK pain. Ingredients were labeled calcifediol [bib_ref] Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate..., Salesi [/bib_ref] [bib_ref] The effect of vitamin D on nonspecific low back pain, Sandoughi [/bib_ref] , vitamin D 2 [bib_ref] An evaluation of high-dose vitamin D for rheumatoid arthritis, Hansen [/bib_ref] [bib_ref] Diffuse musculoskeletal pain is not associated with low vitamin D levels or..., Warner [/bib_ref] , vitamin D 3 [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] [bib_ref] A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic..., Gendelman [/bib_ref] [bib_ref] Effect of vitamin D supplementation on progression of knee pain and cartilage..., Mcalindon [/bib_ref] [bib_ref] Does vitamin D improve osteoarthritis of the knee: A randomized controlled pilot..., Sanghi [/bib_ref] [bib_ref] Effect of vitamin D on musculoskeletal pain and headache: A randomized, double-blind,..., Knutsen [/bib_ref] [bib_ref] Vitamin D supplementation for nonspecific musculoskeletal pain in non-Western immigrants: A randomized..., Schreuder [/bib_ref] , and vitamin D [bib_ref] The effect of oral and parenteral vitamin D supplementation in the elderly:..., Sakalli [/bib_ref]. Baseline vitamin D levels ranged from 12.8 6 8.7 to 42.9 6 11.3 ng/mL in the vitamin D group and 15.0 6 3.0 to 37.3 6 13.2 ng/mL in the comparator arm. Dosages ranged from 400 IU to 300,000 IU/d for anywhere from a single dose to a course of two years. All studies except one [bib_ref] Effects of vitamin D on patients with fibromyalgia syndrome: A randomized placebo-controlled..., Wepner [/bib_ref] that included a triglyceride solution compared vitamin D with placebo [fig_ref] Table 2: Summary of findings [/fig_ref] Supplementary Data: Summary Report).
Following a strict methodological approach and using evidence to guide judgments [bib_ref] Dietary Ingredients as an Alternative Approach for Mitigating Chronic Musculoskeletal Pain: Evidence-based..., Crawford [/bib_ref] , conditional recommendations (100% weak, in favor) were made for the use of vitamin D supplementation for pain and related symptoms at doses of 2,000 IU/d, not to exceed 4000 IU/d. Higher doses should only be used for short-term treatment of vitamin D deficiency and when instructed by a health care provider. Recent evidence suggests that individuals who consume high doses of vitamin D could be at risk of vitamin D intoxication, dysregulation of calcium and phosphorous metabolism, hypercalcemia, hypercalciuria, and hyperphosphatemia. Current approaches to assessing serum levels of 25 hydroxyvitamin D do not necessarily reflect current intake or stores of vitamin D [bib_ref] Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis..., Razzaque [/bib_ref] [bib_ref] Association between calium or vitamin D supplementation and fracture incidence in community-dwelling..., Zhao [/bib_ref].
Based on the evidence, the HERB judged the desirable anticipated effects for pain reduction to be moderate in size (SMD ¼ -0.55) at final follow-up, and results were statistically significant compared with placebo when used at low doses [bib_ref] Effect of vitamin D supplementation on pain: A systematic review and meta-analysis, Wu [/bib_ref]. Undesirable effects were judged to be small to trivial. This research is of low quality, primarily due to concerns over heterogeneity, varying populations with potentially different baseline vitamin D levels, and varying doses and durations of intake, which make interpretation challenging (Supplementary Data: Summary Report). Members judged the certainty of the evidence to be low and agreed that cost was negligible compared with ibuprofen 2400 mg/d.
Because the desirable effects likely outweigh the undesirable, resource requirements may justify vitamin D use. Members agreed that vitamin D up to 2,000 IU per day would probably be feasible and acceptable to stakeholders when the product was produced by reputable manufacturers and sold by trusted vendors. Only some vitamin D products sold are on the United States Pharmacopeia National Formulary (USP-NF) verified product list. Although vitamin D can be obtained via food and sun exposure, the HERB members agreed that Special Operators may not receive adequate exposure to sunlight due to wearing long-sleeved clothing/tactical gear and being outside during nighttime operations.
# Discussion
Evidence-based conditional recommendations have been made for various dietary ingredients, which suggests that they could be used in support of managing chronic MSK pain, specifically for Special Operations Forces (SOF). Nineteen dietary ingredients [fig_ref] Figure 1: Recommendations. [/fig_ref] had sufficient scientific evidence available to evaluate the state-of-the-science and evidence for any desirable and undesirable anticipated effects on chronic MSK pain, function, and related outcomes through systematic review and meta-analysis techniques. The GRADE approach was used to determine the quality of that evidence by examining the risk of bias, inconsistency, imprecision, and indirectness from the pooled studies. Subject matter experts and key stakeholders evaluated the certainty of the overall evidence, weighed the desirable to undesirable anticipated effects, and considered resource requirements, acceptability, and feasibility/suitability to determine the strength and direction of evidence-based recommendations that could be practical/useful to SOF [fig_ref] Table 3: Judgments across factors for decision-making [/fig_ref].
ASU, capsaicin, curcuma, ginger, glucosamine, melatonin, PUFA, and vitamin D are recommended and may help alleviate chronic MSK pain. They are suggested for use when taken either as part of a balanced diet and/or as a supplement or applied as a cream. Individuals should discuss options with a health care provider before initiating use of any dietary ingredient. Individuals should also select USP-verified products when possible as they 1) contain the ingredients listed on the label in the declared potency and amounts, 2) contain no harmful levels of specified contaminants, 3) break down and release into the body within a specified amount of time, and 4) have been made according to FDA current Good Manufacturing Practices by using sanitary and wellcontrolled procedures. Operators can also consider NSF Certified for Sportproducts and refer to Operation Supplement Safety, a Department of Defense dietary supplement resource [bib_ref] Usefulness of a risk assessment tool to risk stratify dietary supplements, Attipoe [/bib_ref] , to verify safety.
Because recommendations were only conditional and did not strongly endorse an ingredient for immediate use, discussion and debate among stakeholders before policy decisions are made surrounding these dietary ingredients and future efforts worthy of further investigation are encouraged.
## Weighing the desirable and undesirable effects
The HERB members weighed desirable and undesirable anticipated effects based on the evidence supplied through systematic review and meta-analysis. Each conditionally recommended ingredient showed an improvement in pain over time compared with placebo or other active comparators. The quality of that evidence varied among the dietary ingredients evaluated. For example, evidence for pain reduction via capsaicin and PUFA is high and moderate, respectively; conversely, the evidence that vitamin D will produce a statistically significant reduction in pain associated with chronic MSK pain is of low quality. Further, although curcuma shows the largest estimated effect for decreasing pain and improving global function, and perhaps decreasing medication use, the quality of the evidence is very low to low. Some ingredients showed improvement in other pain-related outcomes, but how these ingredients affect such outcomes overall and whether they influence outcomes beyond those in [fig_ref] Table 2: Summary of findings [/fig_ref] are unknown.
In addition, how substantial these reported desirable effects might be for any one individual may vary significantly. What is considered a clinically meaningful improvement in pain, as well as other outcomes, is under considerable debate and is a point of discussion by the HERB members. , compared the SMD from their meta-analysis with other SMDs noted from other interventions, stating,
The SMD of 0.30 for ginger compared with placebo corresponds to an effect size for pain which is only slightly above the critical threshold limit for a relevant SMD in osteoarthritis, and it is comparable, although a little higher, to the SMD of 0.21 seen with intake of acetaminophen [bib_ref] Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised..., Zhang [/bib_ref]. The observed pain reducing effect for ginger is in the same range as SMD previously reported for other nutraceuticals/herbal medicines like diacerein with an SMD of 0.24 [bib_ref] Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: A..., Bartels [/bib_ref] , ASU with an SMD of 0.39 [bib_ref] Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: A..., Bartels [/bib_ref] , and rose hip powder of 0.37 [bib_ref] Does the rose hip powder of rosa canina (rosehip) reduce pain in..., Christensen [/bib_ref] , all in comparison with placebo. Compared to the effect of NSAIDs, the SMD for ginger has an effect size in the middle of the NSAID range of 0.17 to 0.66, all when compared to placebo [bib_ref] Efficacy of etoricoxib, celecoxib, lumiracoxib, non-selective NSAIDs, and acetaminophen in osteoarthritis: A..., Stam [/bib_ref] [bib_ref] Influence of flare design on symptomatic efficacy of non-steroidal anti-inflammatory drugs in..., Trijau [/bib_ref] [bib_ref] Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: Meta-analysis of..., Bjordal [/bib_ref].
The HERB used the effect of high-dose ibuprofen, 2,400 mg/d, reported as SMD ¼ -0.41 compared with placebo [bib_ref] Efficacy of etoricoxib, celecoxib, lumiracoxib, non-selective NSAIDs, and acetaminophen in osteoarthritis: A..., Stam [/bib_ref] , as a reference point. To date, comparative effectiveness trials across dietary ingredients are heterogeneous and challenging to pool in meta-analysis in any meaningful way. Further research is needed for comparing ingredients with placebo and other standards of care.
Undesirable anticipated effects, as reported in the evaluated studies, primarily consisted of minor gastrointestinal complaints. Given their nonserious and infrequent nature, members judged that the desirable effects outweighed the undesired across all dietary ingredients. Currently data from published studies showing how these ingredients directly compare with other active comparators in terms of varying adverse events are insufficient. There is concern that when used at higher doses, more and additional adverse events, beyond gastrointestinal issues, may occur. For example, extremely high doses of PUFA may increase the risk of both ischemic and hemorrhagic stroke [bib_ref] Fish consumption and stroke: A community case-control study in Asturias, Spain, Caicoya [/bib_ref] , and extremely high doses of vitamin D could lead to intoxication [bib_ref] Vitamin D intoxication associated with an over-the-counter supplement, Koutkia [/bib_ref]. Other adverse events, though relatively mild (e.g., "bad taste" associated with ginger and PUFA) can cause some individuals to discontinue use [bib_ref] Efficacy and safety of ginger in osteoarthritis patients: A meta-analysis of randomized..., Bartels [/bib_ref] [bib_ref] Effects of new fish oil derivative on fatty acid phospholipidmembrane pattern in..., Belluzzi [/bib_ref] [bib_ref] Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease, Kris-Etherton [/bib_ref].
## Certainty of the evidence
Although the quality of the evidence was determined using the GRADE approach and was specific to each outcome evaluated, the certainty of the evidence was judged based on reviewing the evidence of effects across all outcomes where it was feasible to pool results into a metaanalysis [fig_ref] Table 2: Summary of findings [/fig_ref] ; Supplementary Data: Summary Report.) Members judged the certainty of the overall evidence for PUFA and ginger as moderate and for curcuma and vitamin D as very low to low. Further research is needed to address gaps of ingredients with low-quality studies and uncertain evidence. In some circumstances, the use of ingredients with some evidence suggesting desirable effect can be suggested when the risk of using the ingredient is minimal. In all cases, discussions with a health care provider are recommended to consider ingredient use and an approach to shared decision-making.
## Justification of resource requirements/cost
Cost is an essential factor required for decision-making that affects all individuals at some level. On average, given the doses reported in the studies, the cost associated with any of these ingredients was considered negligible to moderate savings compared with commonly used pain relievers (e.g., ibuprofen 2,400 mg, estimated at approximately $1/d to serve as a reference point for comparison). As such, most members agreed that resource requirements and out-of-pocket costs were justified.
## Other considerations: feasibility, acceptability, suitability
The HERB members agreed that capsaicin, pCGS, melatonin, PUFA, and vitamin D would probably be acceptable to stakeholders and feasible/suitable to implement as a policy of practice, whereas there was more debate concerning ginger, curcuma, and ASU. Although ginger and curcuma should both be considered a dietary food (e.g., teas, cooking ingredient) and may have the potential to pre-emptively mitigate pain, there was insufficient strong research for recommending their use as a supplement. The overall effect of ginger was relatively small, and although curcuma produced a large effect, the authors were less confident in that effect estimate. It is possible that these ingredients could be inserted into a mission planning process and added to a nutrition checklist by mission dietitians. Whether it would be feasible for Special Operators to obtain ginger and curcuma during specific operational missions is unknown.
Research on ASU evaluated by the authors was confined to the commercialized French product Piascledine. The quality of the evidence for its effects on pain reduction is moderate, diminished by potential bias of being funded by the manufacturer. Third-party evaluations of Piascledine are needed. In addition, Piascledine 300 costs more than the other dietary ingredients and other products that claim to be made with ASU. HERB member opinions regarding Piascledine or other ASU products' (that lack rigorous clinical evidence) acceptability and feasibility were diverse.
## Remarks on the methodological approach
Systematic reviews provide essential information to lay the foundation for evidence-based practice but are often insufficient for making well-informed decisions. Stakeholders can easily judge the appropriateness of an intervention or treatment when high-quality evidence supports substantial desirable anticipated effects and there are minimal to no undesirable anticipated effects. In these cases, treatments are recommended with little need for further debate. Little debate is needed when treatments are judged to be inappropriate and risks clearly outweigh benefits. In between these two judgments is a massive gray area where the evidence is of low, indeterminate, or equivocal quality. Importantly, dietary ingredients are not intended to treat any particular health condition. If a particular ingredient or combination of ingredients were identified as potentially useful for mitigating or treating MSK pain, then the ingredient would be classified as a drug and required to go through the FDA Investigational New Drug Applications process. Despite this, many dietary supplements are marketed for pain relief. A casual search of the National Institutes of Health's Office of Dietary Supplement's Dietary Supplement Label Database (https://www.dsld. nlm.nih.gov/dsld/index.jsp) yielded a total of 272 products when the terms "pain" and "muscle" were used to search for label statements or health claims. Thus, caution is urged, and obtaining ingredients through food is always preferred, unless the evidence of safety and efficacy is clear and manufactures' production processes are verified or certified by trusted third parties.
A framework for decision-making is essential. The authors involved diverse subject matter experts and key stakeholders proactively to develop key questions and to drive the direction of evidence evaluation that illuminated critical outcomes and factors important to them. This evaluation, conducted by a third party, used processes and procedures designed to minimize bias. Factors required for decision-making for this project were adapted from the GRADE framework and specific to the Special Operations environment. The integration of systematic review results into the GRADE Evidence to Decision Framework and the use of a modified Delphi voting process seeking points of convergence and divergence enable all voices to be heard. Subsequently, recommendations about practice, policy, and next steps for research that are useful to the diversity of end users can be developed. A limitation in all research is wide generalizability, and the framework used here can be adapted to different contexts, settings, and stakeholders to consider other essential factors important for decisionmaking.
# Conclusions
Conditional, evidence-based recommendations were made for the use of vitamin D (2,000 mg/d), PUFA (1,200 mg/d), curcuma and ginger (as food sources), melatonin (3-5 mg/d), a proprietary brand of ASU (300-600 mg/d), capsaicin (as a cream, 0.025-0.075% applied 3-4/d), and prescription glucosamine (pCGS, 1,500 mg/d) as alternative or supplemental approaches for mitigating pain and related symptoms associated with chronic MSK pain. These recommendations were based upon rigorous evidence evaluation and integrated with expert clinical acumen by using strict methodological criteria and processes designed and practiced to minimize bias. The process allowed for all voices to be heard with regard to reaching the greatest spread of end user impact. Caveats exist, and in some cases the quality and/or certainty of the evidence remains low; however, the resulting recommendations can serve as a decision aid for practitioners and participants to make shared decisions.
[fig] Figure 1: Recommendations. [/fig]
[fig] ¼: no; NS no included studies; PN probably no; PUFA polyunsaturated fatty acids; PY probably yes; RX prescription; VL very low; Y yes. [/fig]
[table] Table 2: Summary of findings [/table]
[table] Table 3: Judgments across factors for decision-making [/table]
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https://academic.oup.com/painmedicine/article-pdf/20/7/1430/28908566/pnz051.pdf
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A series of systematic reviews and meta-analyses were conducted to evaluate whether current research on dietary ingredients for chronic musculoskeletal pain provides sufficient evidence for practice and self-care, specifically for Special Operations Forces personnel. Nineteen dietary ingredients were critically evaluated for their overall quality, efficacy, and safety. Evidence-based recommendations were made for practice and self-care use. This article details the evidence and factors leading to the resulting recommendations for practice.
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pubmed
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Guidelines for evaluation and management of cerebral collateral circulation in ischaemic stroke 2017
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Guidelines for evaluation and management of cerebral collateral circulation in ischaemic stroke 2017
Collateral circulation plays a vital role in sustaining blood flow to the ischaemic areas in acute, subacute or chronic phases after an ischaemic stroke or transient ischaemic attack. Good collateral circulation has shown protective effects towards a favourable functional outcome and a lower risk of recurrence in stroke attributed to different aetiologies or undergoing medical or endovascular treatment. Over the past decade, the importance of collateral circulation has attracted more attention and is becoming a hot spot for research. However, the diversity in imaging methods and criteria to evaluate collateral circulation has hindered comparisons of findings from different cohorts and further studies in exploring the clinical relevance of collateral circulation and possible methods to enhance collateral flow. The statement is aimed to update currently available evidence and provide evidence-based recommendations regarding grading methods for collateral circulation, its significance in patients with stroke and methods under investigation to improve collateral flow.
## Guidelines
AbsTrACT Collateral circulation plays a vital role in sustaining blood flow to the ischaemic areas in acute, subacute or chronic phases after an ischaemic stroke or transient ischaemic attack. Good collateral circulation has shown protective effects towards a favourable functional outcome and a lower risk of recurrence in stroke attributed to different aetiologies or undergoing medical or endovascular treatment. Over the past decade, the importance of collateral circulation has attracted more attention and is becoming a hot spot for research. However, the diversity in imaging methods and criteria to evaluate collateral circulation has hindered comparisons of findings from different cohorts and further studies in exploring the clinical relevance of collateral circulation and possible methods to enhance collateral flow. The statement is aimed to update currently available evidence and provide evidence-based recommendations regarding grading methods for collateral circulation, its significance in patients with stroke and methods under investigation to improve collateral flow.
## Context
Good collateral circulation could enhance the benefit of endovascular treatment in acute ischaemic stroke and reduce the risk of relevant haemorrhagic transformation 1-3 ; significantly reduce the risk of recurrent stroke in patients with symptomatic intracranial atherosclerotic stenosis (ICAS) [bib_ref] Collaterals dramatically alter stroke risk in intracranial atherosclerosis, Liebeskind [/bib_ref] ; and reduce the quantities and volume of infarction in ischaemic stroke. [bib_ref] Effect of Collaterals on Clinical Presentation, Baseline Imaging, Complications, and Outcome in..., Fanou [/bib_ref] Accurate assessment of the structure and function of cerebral collateral circulation is an important prerequisite for individualised management of patients with stroke. Currently, assessment and intervention of collateral circulation in ischaemic stroke have been under active investigation. Various imaging criteria have been developed to gauge the collateral status and correlate with prognosis in patients with stroke. There are also emerging interventions to enhance collateral circulation in patients with stroke. Therefore, a writing group has been established under the Society of Cerebral Blood Flow and Metabolism, the Chinese Stroke Association, for the current guideline on the evaluation and management of cerebral collateral circulation in ischaemic stroke. It is aimed to enhance general understanding of the cerebral collateral circulation among neurologists, neuroradiologists, neurointerventionalists and other relevant healthcare professionals, to provide evidence-based recommendations regarding collateral circulation in ischaemic stroke, and to promote future research in relevant areas. The current guideline is an update based on a previously published 'Chinese Consensus Statement on the Evaluation and Intervention of Collateral Circulation for Ischemic Stroke'. [bib_ref] Chinese consensus statement on the evaluation and intervention of collateral circulation for..., Liu [/bib_ref] overview Cerebral collateral circulation refers to the auxiliary vascular structures that compensate cerebral blood flow when 'normal' blood flow is impaired or restricted due to severe stenosis or occlusion of the principal supplying arteries or other focal or systemic situations. [bib_ref] Collateral circulation, Liebeskind [/bib_ref] The status of collateral circulation is critical in determining the presence and volumes of penumbra and ischaemic core, which are important factors leading to heterogeneity in the time course and severity of individual ischaemic strokes. Recognition of the importance of collateral circulation and accurate assessment of the collateral status may facilitate better prognostication of patients with stroke and provide therapeutic implications.
Cerebral collateral circulation is usually divided into primary, secondary and tertiary collaterals. Primary collaterals refer to the arterial segments of the circle of Willis; secondary collaterals include the ophthalmic artery and leptomeningeal arteries, as well as other anastomoses between the distal, small-calibre arteries; and tertiary collaterals refer to newly developed microvessels through angiogenesis at the periphery of ischaemic regions. Open access
The concept of 'collaterome' has recently been proposed to represent 'the elaborate neurovascular architecture within the brain that regulates and determines the compensatory ability, response and outcome of cerebrovascular pathophysiology'. [bib_ref] Imaging the collaterome: a stroke renaissance, Liebeskind [/bib_ref] The concept involves the entire cerebral circulation system, including the arteries, veins and microvessels, and incorporates interactions between the cerebral vascular architecture, cerebral blood flow dynamics and tissue metabolism, and neuronal functions. [bib_ref] Imaging the collaterome: a stroke renaissance, Liebeskind [/bib_ref] It is a rising scientific field that urges cross-disciplinary efforts in relevant basic, translational and clinical research.
imAging meThods And grAding CriTeriA for CerebrAl CollATerAl CirCulATion We herein summarise the imaging methods to assess the structure and function of cerebral collateral circulation.
imaging methods to assess the structure of cerebral collateral circulation Transcranial Doppler (TCD), transcranial colour-coded duplex sonography (TCCD), traditional single-phase CT angiography (CTA) or CTA-relevant methods such as CTA source image, CTA multiplanar reconstruction, CTA maximum intensity projection, timing-invariant CTA and multiphase CTA (or dynamic CTA), triphase CT perfusion (CTP), MR angiography (MRA) such as time-offlight MRA (TOF-MRA), phase-contrast MRA and quantitative MRA (QMRA), and digital subtraction angiography (DSA) have all been used in clinical practice and relevant research areas to assess the structure of cerebral collateral circulation. [bib_ref] Systematic review of methods for assessing leptomeningeal collateral flow, Mcverry [/bib_ref] 10 Among all these methods, DSA has been recognised as a gold standard to evaluate the collateral structure. However, due to the invasive nature and high cost of DSA, non-invasive imaging methods are more commonly used. Moreover, contrast injection during DSA exam may affect the blood flow rate and visibility of distal vessels, or even reverse the direction of blood flow within the circle of Willis, for example, the anterior or posterior communicating arteries.
TCD could non-invasively reflect real-time cerebral blood flow velocity, collateral status and cerebrovascular reactivity with a low cost, but the accuracy of TCD in diagnosing cerebrovascular abnormalities highly relies on the experience of the operators. Collateral flow through anterior communicating artery, posterior communicating artery, ophthalmic artery and leptomeningeal arteries could be directly or indirectly detected by TCD. The sensitivities of TCD in detecting a patent anterior communicating artery and collateral flow through basilar artery were reported to be 95% and 87%, and the specificities were 100% and 95%, respectively, with DSA as a reference standard. [bib_ref] Transcranial Doppler ultrasound in the evaluation of collateral blood flow in patients..., Müller [/bib_ref] In addition, the flow diversion phenomenon in TCD, that is, high-velocity and low-resistance flow in the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) in the presence of the middle cerebral artery (MCA) occlusion or severe stenosis, implies leptomeningeal collateral anastomoses between the ACA/PCA and the distal MCA branches. [bib_ref] Relationship between flow diversion on transcranial Doppler sonography and leptomeningeal collateral circulation..., Kim [/bib_ref] The sensitivity and specificity of flow diversion by TCD for predicting the presence of leptomeningeal collateral flow in DSA were, respectively, 81.1% and 76.7%, and the positive and negative predictive values were, respectively, 70.8% and 85.2% in a previous report. [bib_ref] Relationship between flow diversion on transcranial Doppler sonography and leptomeningeal collateral circulation..., Kim [/bib_ref] TOF-MRA is another non-invasive method commonly used to assess the structure of cerebral collateral circulation. The reliability of TOF-MRA to assess leptomeningeal collaterals is limited by its relatively low spatial resolution. TOF-MRA is usually used to assess primary collaterals via the circle of Willis. In reference to DSA, the sensitivity and specificity of TOF-MRA in detecting collateral flow via the anterior part of the circle of Willis were 83% and 77%, and 33% and 88% for the posterior part of the circle of Willis. [bib_ref] Diagnosing cerebral collateral flow patterns: accuracy of non-invasive testing, Hendrikse [/bib_ref] A combination of TOF-MRA and TCD yielded a sensitivity of 92% and a specificity of 65% for detecting collateral flow via the anterior circle of Willis, and a sensitivity of 88% and a specificity of 41% for collateral flow via the posterior circle of Willis. [bib_ref] Diagnosing cerebral collateral flow patterns: accuracy of non-invasive testing, Hendrikse [/bib_ref] CTA is also a non-invasive method that bears a high accuracy in assessing patency of the arterial segments in the circle of Willis, with >90% agreement with DSA, but its sensitivity (53%) is limited in depicting hypoplastic arterial segments. [bib_ref] Accuracy of CT angiography in the assessment of the circle of Willis:..., Han [/bib_ref] Blood flow via collaterals may delay as compared with normal antegrade flow. Thus, traditional single-phase CTA may underestimate compensating flow via collaterals. At present, timing-invariant CTA and multiphase CTA (or dynamic CTA or four-dimensional CTA) [bib_ref] Clot Burden and Collaterals in Anterior Circulation Stroke: Differences Between Single-Phase CTA..., Kaschka [/bib_ref] [bib_ref] Strategies of collateral blood flow assessment in ischemic stroke: prediction of the..., Beyer [/bib_ref] [bib_ref] Assessment of Collateral Status by Dynamic CT Angiography in Acute MCA Stroke:..., Van Den Wijngaard [/bib_ref] [bib_ref] Multiphase CT Angiography: A New Tool for the Imaging Triage of Patients..., Menon [/bib_ref] are increasingly used in clinical research to assess cerebral collateral status. Although such novel CTA methods could more accurately depict the collateral status and provide additional information such as the direction of the collateral flow, further investigation is needed before an extensive application in clinical practice.
imaging methods to assess the function of cerebral collateral circulation There are various imaging methods to evaluate the 'function' of cerebral collateral circulation, for instance, cerebrovascular reserve by TCD, xenon CT, single-photon emission CT (SPECT), positron emission tomography (PET), CTP, QMRA, traditional dynamic susceptibility contrast MR perfusion, arterial spin labelling (ASL), MR perfusion and others. These imaging methods usually gauge the cerebral blood flow direction/velocity/volume or perfusion status to reflect the blood flow compensating function of collaterals. Some novel imaging techniques could simultaneously reveal the structure and function of collateral circulation; for instance, QMRA could reveal directions of blood flow via collateral channels and quantify total/regional cerebral blood flow.
Rusanen et al [bib_ref] Collateral Circulation Predicts the Size of the Infarct Core and the Proportion..., Rusanen [/bib_ref] used collateral circulation to predict infarct size and penumbra following thrombolytic therapy of acute ischaemic stroke. They used the Alberta Stroke Program Early CT Score (ASPECTS) of mean transit time (MTT) to evaluate the brain tissue at ischaemic Open access risk and cerebral blood volume (CBV) score to evaluate the infarct core. The results showed that better MTT and ASPECTS score based on CBV correlated with better collateral circulation. A better collateral circulation is associated with a smaller infarct core and a larger mismatch ratio. [bib_ref] Association Between CT Angiogram Collaterals and CT Perfusion in the Interventional Management..., Vagal [/bib_ref] CTP has been used to screen patients in the randomised controlled trial (RCT) for revascularisation. [bib_ref] Endovascular therapy for ischemic stroke with perfusion-imaging selection, Campbell [/bib_ref] [bib_ref] Computed tomographic perfusion to Predict Response to Recanalization in ischemic stroke, Lansberg [/bib_ref] [bib_ref] Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion..., Albers [/bib_ref] Some MR perfusion parameters have been used for the assessment of collateral status. The Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke (DEFUSE 3) trial further added evidence on the benefit of perfusion imaging-based (CTP or MR perfusion mismatch) endovascular treatment in ischaemic stroke. [bib_ref] Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion..., Albers [/bib_ref] Commonly used grading scales for cerebral collateral circulation DSA-based grading scales The most widely recognised grading system is the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/ SIR) collateral scale based on DSA, classifying the cerebral collateral status to grades 0-4 as follows: grade 0, no collaterals visible to the ischaemic site; grade 1, slow collaterals to the periphery of the ischaemic site with persistence of some of the defect; grade 2, rapid collaterals to the periphery of ischaemic site with persistence of some of the defect and to only a portion of the ischaemic territory; grade 3, collaterals with slow but complete angiographic blood flow of the ischaemic bed by the late venous phase; and grade 4, collaterals with slow but complete angiographic blood flow of the ischaemic bed by the late venous phase. [bib_ref] Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic..., Higashida [/bib_ref] Grades 0-1, 2 and 3-4 are usually regarded as poor, moderate and good collateral flow. The ASITN/SIR collateral grading system has been demonstrated to be reliable in assessing the collateral status in patients with stroke in a number of multicentre studies.
The Endovascular Stroke Treatment (ENDOSTROKE) registry was an international, multicentre study recruiting adult patients with acute ischaemic stroke and intracranial large artery occlusion for whom mechanical revascularisation procedure was attempted. [bib_ref] Collateral vessels in proximal middle cerebral artery occlusion: the ENDOSTROKE study, Singer [/bib_ref] Among the 160 patients with acute proximal MCA occlusion in the ENDOS-TROKE registry, the ASITN/SIR collateral scale was used to gauge the collateral status to correlate with the imaging and clinical outcomes after acute endovascular treatment. The investigators found a positive correlation between a better collateral status and a higher reperfusion rate, leading to a smaller infarct volume and a better clinical outcome. The rates of achieving successful reperfusion by the Thrombolysis in Cerebral Infarction Scale 2b or 3 among those with ASITN/SIR collateral grades of 0-1, 2 or 3-4 were, respectively, 21%, 48% and 77% (p<0.001). The proportion of the infarcts smaller than one-third of the MCA territory (32%, 48% and 69% for collateral grades 0-1, 2 or 3-4; p<0.001), and more importantly the proportion of patients with a good functional outcome at least 3 months after the intervention (11%, 35% and 49% for collateral grades 0-1, 2 or 3-4; p=0.007), were both significantly higher in those with better collaterals. Multivariate analysis reinforced the role of collateral status as an independent predictor for reperfusion, infarct size and long-term functional outcomes in patients receiving endovascular treatment for acute proximal MCA occlusion. [bib_ref] Collateral vessels in proximal middle cerebral artery occlusion: the ENDOSTROKE study, Singer [/bib_ref] Another subgroup analysis of the ENDOSTROKE registry of 148 patients with acute basilar artery occlusion also indicated the predictive value of collateral status by the ASITN/SIR collateral scale for reperfusion and clinical outcomes. [bib_ref] Mechanical recanalization in basilar artery occlusion: the ENDOSTROKE study, Singer [/bib_ref] In addition, post-hoc analysis of the Interventional Management of Stroke III (IMS III) [bib_ref] Collaterals at angiography and outcomes in the Interventional Management of Stroke (IMS)..., Liebeskind [/bib_ref] and Solitaire FR With the Intention for Thrombectomy 32 trials' data showed similar results.
Christoforidis et al [bib_ref] Angiographic assessment of pial collaterals as a prognostic indicator following intra-arterial thrombolysis..., Christoforidis [/bib_ref] proposed another collateral grading system based on DSA that is less frequently used, which classifies the collateral status to five grades: grade 1, collaterals reconstituted the entire distal portion of the occluded vessel segment; grade 2, collaterals reconstituted vessels in the proximal portion of the segment adjacent to the occluded vessel; grade 3, collaterals reconstituted vessels in the distal portion of the segment adjacent to the occluded vessel; grade 4, collaterals reconstituted vessels two segments distal to the occluded vessel; and grade 5, little or no significant reconstitution of the territory of the occluded vessel. Good collateral status by this grading system (grades 1 or 2) has been correlated with smaller infarct volume, lower risk of haemorrhagic transformation and lower modified Rankin Scale (mRS) at discharge, in patients with ischaemic stroke receiving intra-arterial thrombolysis in relatively small-scale studies. This collateral grading method is not commonly used in clinical practice.
## Cta-based grading scales
The Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) study 2 is an international multicentre RCT study evaluating thrombectomy, with a primary prognostic indicator of functional outcome at 90 days after onset. The results showed that for patients with acute ischaemic stroke with favourable collateral circulation, based on multiphase CTA ASPECTS collateral circulation score (5-4 points), prompt administration of endovascular treatment improved functional outcome (mRS score at 90 days) and reduced mortality. [fig_ref] Table 1: Examples of collateral grading methods based on CTA Collateral status is graded... [/fig_ref] shows examples of other collateral grading methods based on CTA, including the methods proposed by Miteff et al [bib_ref] The independent predictive utility of computed tomography angiographic collateral status in acute..., Miteff [/bib_ref] (grading collateral flow distal to MCA occlusion), Maas et al [bib_ref] Collateral vessels on CT angiography predict outcome in acute ischemic stroke, Maas [/bib_ref] (assessing collaterals at the Sylvian sulcus and cerebral convexity, as well as collateral pathways via the circle of Willis), Tan et al 37 (grading collaterals in the MCA territory), the regional leptomeningeal collateral (rLMC) score 38 (assessing collaterals in MCA cortical regions, parasagittal ACA territory, the basal ganglia and the Sylvian sulcus), and the ACA-MCA and PCA-MCA regional collateral score. There are also modified versions of originally DSA-based collateral Collateral vessels in the Sylvian fissure and the leptomeningeal convexity are graded in CTA source images by comparing the symptomatic hemisphere with the contralateral unaffected hemisphere as: 1=Absent. 2=Less than the contralateral normal side. 3=Equal to the contralateral normal side. 4=Greater than the contralateral normal side. 5=Exuberant.
The presence and status of the anterior and posterior communicating arteries are graded as: 1=Absent. 2=Probably present. 3=Hairline. 4=Definitely present. 5=Robust.
## Tan collateral grading system 37
Leptomeningeal collateral status is graded in source images and maximum intensity projection reconstructions of single-phase CTA as below, with scores of 0-1 as poor and 2-3 as good collateral status. 0=No collateral supply to the occluded MCA territory. 1=Collateral supply filling ≤50% of the occluded MCA territory. 2=Collateral supply filling >50% but <100% of the occluded MCA territory. 3=100% collateral supply of the occluded MCA territory.
Regional leptomeningeal collateral (rLMC) score [bib_ref] Regional leptomeningeal score on CT angiography predicts clinical and imaging outcomes in..., Menon [/bib_ref] The rLMC score (20 points) compares the extent of contrast opacification in arteries distal to an M1 MCA occlusion (±internal carotid artery occlusion) in the symptomatic hemisphere with the contralateral hemisphere in multiplanar reformatted CTA, with a higher score indicating a better collateral status. The extent of contrast opacification is scored as 0 (artery not seen), 1 (less prominent) or 2 (equal or more prominent than the opposite hemisphere) for the six ASPECTS cortical regions (M1-6), parasagittal ACA territory and the basal ganglia, while pials in the Sylvian sulcus are given a higher score, that is, 0, 2 or 4. ACA-MCA and PCA-MCA regional collateral score The scoring system assesses the extent and prominence of pial arteries in the ACA-MCA and PCA-MCA regions, in patients with stroke with M1 MCA occlusion±intracranial internal carotid artery occlusion, in twodimensional multiplanar reconstructions of dynamic CTA. Collaterals in the ipsilesional ACA-MCA and PCA-MCA regions are each scored as 0-5 as below by comparing with the contralateral hemisphere, while the total score ranges from 0 to 10. 0=Absent. 1=Minimal. 2=Significantly decreased prominence and extent of pial arteries. 3=Moderately decreased prominence and extent. 4=Mildly decreased prominence and extent. 5=Normal or increased prominence and extent.
ACA, anterior cerebral artery; ASPECTS, the Alberta Stroke Programme Early CT Score; CTA, CT angiography; MCA, middle cerebral artery; PCA, posterior cerebral artery.
grading methods for CTA, such as the ASITN/SIR collateral scale [bib_ref] Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic..., Higashida [/bib_ref] for CTA and the Christoforidis collateral grading system 33 for CTA, which are not listed in table 1. There have been studies comparing the clinical relevance of these grading methods, but the findings were heterogeneous and none of the collateral grading systems have been well validated in large-scale studies. Further investigation is needed to establish an optimal method to non-invasively assess collateral circulation in patients with stroke.
The predictive values of the ACA-MCA and PCA-MCA regional collateral score, and the Maas et al [bib_ref] Collateral vessels on CT angiography predict outcome in acute ischemic stroke, Maas [/bib_ref] and Tan et al 37 collateral grading methods for a favourable 3-month functional outcome after intravenous thrombolysis and/ or endovascular treatment, among patients with acute stroke with M1 MCA occlusion±intracranial internal carotid artery (ICA) occlusion, were tested in 185 patients from the IMS III cohort. In multivariate analyses, collateral status by each of the collateral scales was significantly, independently correlated with an mRS of 0-2 at 3 months after treatment. [bib_ref] Differential Effect of Baseline Computed Tomographic Angiography Collaterals on Clinical Outcome in..., Menon [/bib_ref] Another study compared the abilities of the Miteff et al, [bib_ref] The independent predictive utility of computed tomography angiographic collateral status in acute..., Miteff [/bib_ref] Maas et al [bib_ref] Collateral vessels on CT angiography predict outcome in acute ischemic stroke, Maas [/bib_ref] and Tan et al 37 collateral grading methods and the rLMC score to predict the 3-month functional outcomes in acute anterior circulation stroke treated with intravenous thrombolysis. Among 200 patients, only good collateral status by the Miteff collateral grading method was found to be an independent predictor for Open access a favourable functional outcome (mRS 0-1) at 3 months (OR, 3.34; 95% CI 1.24 to 9.00; p=0.01). In addition, poor collateral status by the Miteff method, the Maas method and the rLMC score were all independently related to an extremely poor functional outcome (mRS 5-6) at 3 months. [bib_ref] Assessment of intracranial collaterals on CT angiography in anterior circulation acute ischemic..., Yeo [/bib_ref] A more recent study has compared four different CTA-based collateral scales in predicting the volume of infarct core and the perfusion:diffusion mismatch ratio within the first few hours after an ischaemic stroke among 30 patients with acute M1 MCA or terminal carotid artery occlusion. The ACA-MCA and PCA-MCA regional collateral score [bib_ref] Assessment of leptomeningeal collaterals using dynamic CT angiography in patients with acute..., Menon [/bib_ref] [bib_ref] Differential Effect of Baseline Computed Tomographic Angiography Collaterals on Clinical Outcome in..., Menon [/bib_ref] and a modified version of the ASITN/SIR collateral scale 28 for dynamic CTA both showed good correlations with early infarct core volume (Spearman's correlation coefficients both around -0.7; p<0.001) and the mismatch ratio (Spearman's correlation coefficients both around 0.6; p<0.001). However, the Miteff collateral grades, or a modified version of the Christoforidis collateral grading system 33 for dynamic CTA, were not significantly linearly correlated with the infarct core volume and the mismatch ratio. 42 recommendations 1. Different imaging modalities could be used to evaluate the cerebral collateral status in patients with ischaemic stroke or transient ischaemic attack (TIA). By far, DSA is a gold standard in the assessment of the presence and extent of primary and secondary collaterals. In non-invasive imaging modalities to assess the presence and extent of secondary collateral circulation, CTA is more reliable than MRA (class II; level of evidence C). 2. For patients with acute ischaemic stroke eligible for endovascular treatment, evaluation of the cerebral collateral circulation status by the ASITN/SIR collateral scale in DSA is reasonable, which helps predict the risk and benefit of acute endovascular treatment (class I; level of evidence A); multiphase CTA or perfusion imaging could also be used to assess the cerebral collateral circulation prior to endovascular treatment in such patients (class I; level of evidence B). 3. There is no general agreement regarding an optimal collateral grading system in ischaemic stroke based on non-invasive imaging modalities. The reliability and the clinical significance, such as the predictive values for prognosis of ischaemic stroke, of the currently available grading systems need further investigation.
CollATerAl CirCulATion And prognosis of isChAemiC sTroke Collateral circulation and hyperacute reperfusion therapies in stroke Hyperacute reperfusion therapies for ischaemic stroke include intravenous thrombolysis and endovascular therapies, and intravenous intra-arterial bridging therapies, while endovascular therapies usually refer to intra-arterial thrombolysis and mechanical thrombectomy. As a mainstay of early treatment in acute ischaemic stroke, timely restoration of cerebral blood flow salvages the ischaemic penumbra, improves functional outcome and reduces mortality, and is recommended in the American and Chinese guidelines as the first-line treatment for eligible patients presenting within corresponding time windows. [bib_ref] Guidelines for the early management of patients with acute ischemic stroke: a..., Jauch [/bib_ref] [bib_ref] American Heart Association/ American Stroke Association focused update of the 2013 Guidelines..., Powers [/bib_ref] The status of cerebral collateral circulation has significant predictive values for the imaging and clinical outcomes of patients with stroke receiving such treatment.
## Collateral circulation and intravenous thrombolysis in stroke
Intravenous thrombolysis is the first-line treatment for patients with acute ischaemic stroke presenting within 4.5 hours without contraindications. By far, there have been few prospective studies investigating the role of collateral circulation in determining outcomes of patients receiving intravenous thrombolytic therapy. Yet post-hoc analysis of several RCTs indicated that a better collateral status prior to intravenous thrombolysis was associated with less severe clinical symptoms (the Combined Lysis of Thrombus in Brain Ischemia Using transcranial Ultrasound and Systemic TPA trial, CLOTBUST), 47 a smaller infarct core in diffusion-weighted MRI and a larger diffusion-perfusion mismatch (Echoplanar Imaging Thrombolytic Evaluation Trial). [bib_ref] Failure of collateral blood flow is associated with infarct growth in ischemic..., Campbell [/bib_ref] More importantly, better collaterals at baseline were associated with a higher incidence of achieving a favourable functional outcome at 3 months after the treatment (CLOTBUST and IMS III trials). A recent systematic review and meta-analysis synthesised evidence regarding the impact of pretreatment collateral circulation on the outcomes of patients with stroke treated with intravenous thrombolysis. [bib_ref] Good collateral circulation predicts favorable outcomes in intravenous thrombolysis: a systematic review..., Leng [/bib_ref] Overall, 28 primary studies of 3057 patients were included in the analysis, including 25 cohort studies (mostly retrospective) and 3 post-hoc analyses of RCTs. Meta-analysis based on these data has demonstrated a favourable role of better collateral circulation in this subset of patients, including a lower risk of symptomatic intracranial haemorrhage (risk ratio (RR) 0.38; 95% CI 0.16 to 0.90; p=0.03), a higher incidence of early neurological improvement (RR 4.21; 95% CI 1.57 to 11.28; p=0.004) and a higher frequency of a favourable functional outcome (mRS 0-2 or 0-1 as defined in different primary studies) at 3-6 months after the thrombolytic treatment (RR 2.45; 95% CI 1.94 to 3.09; p<0.001). [bib_ref] Good collateral circulation predicts favorable outcomes in intravenous thrombolysis: a systematic review..., Leng [/bib_ref] Such findings may be attributed to a lower National Institutes of Health Stroke Scale score (NIHSS; mean difference 6.6; 95% CI 4.4 to 8.7; p<0.001) and a smaller infarct volume in patients with better collateral circulation. However, no significant correlation was identified between the baseline collateral status and successful reperfusion or recanalisation after intravenous thrombolytic therapy (RR 1.34; 95% CI 0.87 to 2.07; p=0.19). Unfortunately, data are limited to allow quantitative synthesis of the correlations between baseline collateral status and the overall risk of haemorrhagic transformation (symptomatic or asymptomatic), the final infarct volume and death risk at 3 months after treatment. [bib_ref] Good collateral circulation predicts favorable outcomes in intravenous thrombolysis: a systematic review..., Leng [/bib_ref]
## Open access
In summary, previous studies show that pretreatment collateral status plays an important role in determining short-term and long-term outcomes of patients with stroke receiving intravenous thrombolytic therapy, while further prospective investigations are needed before more confirmative conclusions could be drawn.
Collateral circulation and endovascular treatment in stroke A number of previous trials failed to prove the superiority of endovascular treatment over routine medical treatment with or without intravenous thrombolysis in acute ischaemic stroke. In 2015, several pivotal RCTs demonstrated the safety and efficacy of endovascular treatment in ischaemic stroke with cervical or intracranial arterial occlusion, when the American and Chinese guidelines on early management of ischaemic stroke were updated, recommending endovascular treatment for eligible patients presenting within 6 hours of symptom onset with or without prior intravenous thrombolytic therapy. Except for the application of newer generation thrombectomy devices, adding imaging eligibility criteria for patient selection, for example, a moderate-to-good collateral circulation, a smaller infarct core or evidence of salvageable brain tissue, may have contributed to the positive findings in these more recent RCTs. In 2017, encouraging evidence has emerged that patients with ischaemic stroke with cervicocerebral artery occlusion may benefit from endovascular treatment up to 24 hours after stroke onset. For instance, the Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment with Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention (DAWN) trial enrolled patients with occlusion of the ICA and/or the first segment of the MCA in 6-24 hours, and had a mismatch between the severity of the clinical deficit and the infarct volume, which was assessed with the use of diffusion-weighted MRI or perfusion CT. The DAWN trial witnessed a significant increase (an absolute increase of 35%) in the incidence of a 90-day favourable functional outcome (mRS 0-2) in patients with intracranial ICA or M1 MCA occlusion, yet a small infarct core treated with mechanical thrombectomy 6-24 hours after the stroke onset as compared with routine medical treatment. Moreover, the CT Perfusion to Predict Response to Recanalization in Ischemic Stroke trial revealed that baseline CTP 'target mismatch', which had a small ischaemic core and a large penumbra, indicated a significant improvement in the NIHSS score even in those treated up to 18 hours after symptom onset. [bib_ref] Computed tomographic perfusion to Predict Response to Recanalization in ischemic stroke, Lansberg [/bib_ref] The DEFUSE 3 trial indicates that endovascular thrombectomy for patients with ischaemic stroke 6-16 hours with proximal MCA or internal carotid artery occlusion, an initial infarct size of less than 70 mL, and a ratio of the volume of ischaemic tissue on perfusion imaging to infarct volume of 1.8 or more had a significant favourable functional outcomes on the mRS at 90 days compared with the medical therapy-alone group (OR, 2.77; p<0.001). [bib_ref] Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion..., Albers [/bib_ref] To enlarge the benefit of endovascular treatment within or beyond the 6-hour time window as recommended by current guidelines, it is also essential to find the 'right' patients to treat, while good pretreatment collaterals may play an important role in preserving salvageable tissue. Two recent systematic reviews and meta-analyses investigated the effects of pretreatment collateral circulation in governing clinical and imaging outcomes of patients with stroke receiving endovascular treatment. Based on data from over 20 studies of >2000 patients with stroke treated with intra-arterial thrombolysis and/or mechanical thrombectomy, with or without prior intravenous thrombolysis, better pretreatment collateral circulation is associated with slightly higher rates of successful recanalisation (RR [bib_ref] Impact of collaterals on the efficacy and safety of endovascular treatment in..., Leng [/bib_ref] Although the mechanisms underlying the protective effects of collateral circulation in such patients have not been well illustrated, inferences are that collateral circulation via the circle of Willis or pial arteries compensates cerebral blood flow adjacent to the ischaemic area, which provides better access of the clot to intrinsic and extrinsic thrombolytic agents and possibly a back pressure that facilitates dislodgement of the clot. It may also mitigate the ischaemia-reperfusion injuries. Collateral circulation and symptomatic iCAs ICAS is of high prevalence in the Chinese population, which is a major cause of ischaemic stroke and TIA in China and other Asian countries. For instance, in the Chinese Intracranial Atherosclerosis (CICAS) study, 46.6% of the 2864 patients with ischaemic stroke or TIA had ICAS. [bib_ref] Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in..., Wang [/bib_ref] In the 1089 patients with MRA images in the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events trial, 608 (55.8%) had ICAS. According to post-hoc analysis of the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial, the collateral status significantly altered the risk of recurrent stroke in patients with symptomatic ICAS. [bib_ref] Collaterals dramatically alter stroke risk in intracranial atherosclerosis, Liebeskind [/bib_ref] To further verify the impact of collateral circulation on the recurrent risk and functional outcomes of patients with symptomatic ICAS, we systematically searched PubMed for full-text publications between 1 January 2000 and 9 September 2017, and retrieved 457 relevant records. Seven of these publications reported correlations between the collateral status and prognosis of patients with ICAS, including post-hoc analyses of the CICAS 60 and WASID data. [bib_ref] Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Investigators. Collaterals dramatically alter stroke risk in..., Liebeskind [/bib_ref]
## Open access
Collaterals via the circle of Willis and outcomes of patients with symptomatic ICAS There is no confirmative conclusion regarding the effect of collaterals via the circle of Willis on the risk of recurrence and the functional outcomes of patients with symptomatic ICAS. The largest study by far reporting the correlation between the completeness of the circle of Willis and the recurrence risk in patients with ischaemic stroke or TIA was CICAS. [bib_ref] Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in..., Wang [/bib_ref] Patients with stroke or TIA with a complete circle of Willis had a higher risk of recurrence within 1 year, as compared with those without (adjusted HR 2.36; 95% CI 1.19 to 4.69; p=0.015). However, such findings were generated from an overall analysis of CICAS, including 1335 patients with and 1529 patients without ICAS. Thus, no conclusion could be drawn from such analysis concerning the protective or harmful effect of collateral flow through the circle of Willis in patients with ICAS. [bib_ref] Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in..., Wang [/bib_ref] There has been another small-scale study reporting that a complete circle of Willis reduced the risk of recurrence within 3 years among patients with 70%-99% symptomatic ICAS who received medical treatment, which did not affect the recurrent risk among 43 patients who received angioplasty with/without stenting therapy. [bib_ref] Clinical significance of the circle of Willis in intracranial atherosclerotic stenosis, Kim [/bib_ref] Leptomeningeal and other collateral pathways and outcomes of patients with symptomatic ICAS Among 569 patients recruited to the WASID trial with 50%-99% symptomatic atherosclerotic stenosis of a major intracranial artery, who were treated with antiplatelet or anticoagulant therapies, adequate angiographic data to assess the leptomeningeal collaterals were available in 287 patients. The angiogram-based collateral extent independently predicted recurrent ischaemic stroke in the symptomatic arterial territory (HR for none vs good collaterals, 1.14; 95% CI 0.39 to 3.30; HR for poor vs good collaterals, 4.36; 95% CI 1.46 to 13.07; p<0.0001). Subgroup analyses by the severity of arterial stenosis indicated that more robust leptomeningeal collaterals were associated with a lower risk of recurrence among patients with 70%-99% symptomatic ICAS (HR none vs good, 4.60; 95% CI 1.03 to 20.56; HR poor vs good, 5.90; 95% CI 1.25 to 27.81; p=0.0427), which, however, were associated with an increased risk of recurrence in those with 50%-69% symptomatic ICAS (HR none vs good, 0.18; 95% CI 0.04 to 0.82; HR poor vs good, 1.78; 95% CI 0.37 to 8.57; p<0.0001). [bib_ref] Collaterals dramatically alter stroke risk in intracranial atherosclerosis, Liebeskind [/bib_ref] A small-scale, single-centre study of 69 patients with 50%-100% symptomatic ICAS found that those with better leptomeningeal collateral compensations (ASITN/ SIR collateral flow grades 2-4 vs 0-1) had a better chance to achieve a favourable functional outcome at 3 months (adjusted OR 7.50; 95% CI 1.11 to 50.7; p=0.04) and a lower risk of recurrent ischaemic stroke or TIA within 1 year (OR 0.18; 95% CI 0.04 to 0.96; p=0.04). [bib_ref] Significance of good collateral compensation in symptomatic intracranial atherosclerosis, Lau [/bib_ref] Another small study of 88 patients with symptomatic MCA occlusion implied that better collaterals as defined by the presence of hyperintensities in the Sylvian fissure on fluid-attenuated inversion recovery sequence were independently correlated with a lower risk of poor functional outcome (mRS 3-6) at 3 months (adjusted OR 0.272; 95% CI 0.101 to 0.733; p=0.010). However, MCA occlusions in this study were attributed to various aetiologies, among which only 40% were of atherosclerotic origin. [bib_ref] Distal hyperintense vessels alleviate insula infarction in proximal middle cerebral artery occlusion, Song [/bib_ref] Lee et al 68 modified the ASITN/SIR collateral flow grades to assess the extent of vessel filling in the superior cerebellar artery territory (scores 0-4) and the anterior/posterior inferior cerebellar artery territory (scores 0-4), with a total score of 0-8, among 98 patients with symptomatic, atherosclerotic basilar artery stenosis (70%-99%). Better collateral status by such method was associated with a reduced incidence of poor functional outcome (mRS 3-6) at 3 months (OR of 1-score increment in the collateral score, 0.21; 95% CI 0.08 to 0.58; p=0.003). [bib_ref] Utility of digital subtraction angiography-based collateral evaluation in medically treated acute symptomatic..., Lee [/bib_ref] Except for the collateral pathways as mentioned above, the effect of the presence of the anterior temporal artery in patients with symptomatic MCA occlusion was investigated in 98 patients, which was significantly correlated with a favourable functional outcome (mRS 0-2) at 3 months (adjusted OR 4.45; 95% CI 1.52 to 13.03; p=0.007), independent of the baseline NIHSS score, the infarct size and pattern. [bib_ref] Presence of anterior temporal artery associates with good outcome in acute atherosclerotic..., Liu [/bib_ref] recommendations 1. For patients with acute ischaemic stroke with cervicocerebral arterial occlusion who receive intravenous, intra-arterial or intravenous intra-arterial bridging reperfusion therapies, the pretreatment cerebral collateral status possesses significant prognostic values for the outcomes (class I; level of evidence B). 2. Based on current evidence, assessment of the collateral status and infarct core helps identify patients who will benefit from such treatment, especially among those presenting beyond 6 hours after symptom onset (class I; level of evidence B). 3. For patients with symptomatic ICAS, the collateral status predicts the risk of recurrent stroke and the functional outcome (class I; level of evidence B). 4. The leptomeningeal collateral status could significantly alter the risk of recurrent stroke and the functional outcome of patients with symptomatic ICAS, but its possibly diverging effects in patients with different degrees of stenosis need to be validated in further studies (class IIb; level of evidence B). 5. There is no confirmative conclusion regarding the effect of collaterals via the circle of Willis on the risk of recurrence and the functional outcomes of patients with symptomatic ICAS, which warrants further investigation (class IIb; level of evidence B). 6. Prospective, registry studies based on non-invasive imaging methods to assess the collateral circulation may further reveal the role of collateral circulation in patients with acute ischaemic stroke who opted for hyperacute reperfusion therapies, or those with symptomatic ICAS or ischaemic stroke of other subtypes (class I; level of evidence C).
## Open access
inTervenTions To enhAnCe CerebrAl CollATerAl CirCulATion in isChAemiC sTroke non-pharmacological interventions Extracranial-intracranial bypass surgery Extracranial-intracranial (EC-IC) bypass surgery may improve haemodynamic parameters in patients with symptomatic cervicocerebral artery stenosis or occlusion. [bib_ref] Improvement in cerebral hemodynamic parameters and outcomes after superficial temporal artery-middle cerebral..., Low [/bib_ref] A large RCT (1377 patients) conducted over 30 years ago, the EC/IC Bypass Study, indicated the inferiority of direct EC-IC bypass surgery over medical treatment among patients with steno-occlusive disease of the extracranial and/or intracranial arteries. [bib_ref] Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke...., Ec/Ic Bypass Study [/bib_ref] From 2002 to 2010, the Carotid Occlusion Surgery Study (COSS) trial compared direct EC-IC bypass surgery plus medical treatment versus medical treatment alone among patients with symptomatic atherosclerotic internal carotid artery occlusion, who had haemodynamic cerebral ischaemia as defined by an increased ipsilateral:contralateral oxygen extraction fraction ratio on PET. [bib_ref] Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid..., Powers [/bib_ref] The COSS trial was prematurely terminated due to futility-the rates of stroke or death within 30 days and ipsilateral ischaemic stroke within 2 years were not significantly different between the surgical and non-surgical groups (21.0% vs 22.7%; p=0.78). [bib_ref] Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid..., Powers [/bib_ref] The Japanese EC-IC Bypass Trial (JET), recruiting patients between 1998 and 2002, had a similar study design with that of COSS, but the JET trial defined the cerebral haemodynamic compromise by decreased cerebral blood flow and deceased cerebrovascular reactivity to vasodilation in PET or SPECT.The JET trial reported a lower rate of the primary endpoint in the surgical than in the non-surgical groups among 196 patients (p=0.046). However, there have been concerns over the results of JET, since there was zero primary endpoint in the surgical group within the first month after the EC-IC bypass surgery in JET, which was 15% in the surgical group of the COSS trial. Overall, based on currently available evidence, direct EC-IC bypass surgery is not recommended for patients with ischaemic stroke or TIA and ipsilateral, atherosclerotic ICA or MCA stenosis or occlusion in the 2014 American Heart Association/American Stroke Association guidelines for secondary stroke prevention. [bib_ref] Guidelines for the prevention of stroke in patients with stroke and transient..., Kernan [/bib_ref] Encephaloduroarteriosynangiosis (EDAS), an indirect EC-IC bypass surgical method, has recently been reported safe and possibly effective in improving collateral circulation and reducing risk of recurrence, among small groups of patients with symptomatic ICAS with refractory stroke despite the best medical treatment. A prospective, single-arm clinical trial, the EDAS (Surgical) Revascularization for Symptomatic Intracranial Arterial Stenosis trial ( ClinicalTrials. gov identifier: NCT01819597), is investigating the safety and efficacy of EDAS in these patients.
## Partial aortic occlusion by the neuroflo technology
The NeuroFlo Catheter has two balloons which when mounted and inflated in the aorta could partially occlude the aortic lumen above and below the renal arteries, to increase cerebral blood flow. The Safety and Efficacy of NeuroFlo in Acute Ischemic Stroke (SENTIS) trial is the largest trial comparing the NeuroFlo technique with standard medical treatment among patients with acute cortical ischaemic stroke. [bib_ref] Partial aortic occlusion for cerebral perfusion augmentation: safety and efficacy of NeuroFlo..., Shuaib [/bib_ref] It demonstrated in 515 patients that partial aortic occlusion by NeuroFlo Catheter to increase cerebral blood flow is safe among patients with stroke (p value for comparison of serious adverse events between the two groups=0.923). There was no significant difference between the two groups in the primary efficacy outcome, a favourable function outcome (OR 1.17; 95% CI 0.81 to 1.67; p=0.407), but there was a trend of decreased all-cause mortality in the NeuroFlo-treated group (11.2% vs 16.3%; OR 1.60; 95% CI 0.91 to 2.83; p=0.086). [bib_ref] Partial aortic occlusion for cerebral perfusion augmentation: safety and efficacy of NeuroFlo..., Shuaib [/bib_ref] Subsequent subgroup analysis of the SENTIS data showed that patients aged over 70 years, patients who were treated with NeuroFlo within 5 hours of stroke onset and patients with moderate stroke severity (NIHSS scores of 8-14) may benefit more from the NeuroFlo treatment than medical treatment. Selecting appropriate patients is important for the NeuroFlo treatment to benefit, while relevant findings need further verification.
## External counterpulsation
External counterpulsation (ECP) is a non-invasive method that enhances cardiac output and blood flow to vital organs including the brain, by inflating pressure cuffs around the lower extremities and the buttocks during the diastole and deflating the cuffs during the systole. ECP treatment is safe and feasible in patients with ischaemic stroke. [bib_ref] Perfusion augmentation in acute stroke using mechanical counter-pulsation-phase IIa: effect of external..., Alexandrov [/bib_ref] [bib_ref] Preliminary findings of external counterpulsation for ischemic stroke patient with large artery..., Han [/bib_ref] [bib_ref] Feasibility and safety of using external counterpulsation (ECP) to augment cerebral blood..., Guluma [/bib_ref] It could augment cerebral blood flow in the ipsilateral and contralateral hemispheres among patients with stroke with large artery occlusive disease, which may imply enhanced collateral flow to the ischaemic territories. [bib_ref] External counterpulsation augments blood pressure and cerebral flow velocities in ischemic stroke..., Lin [/bib_ref] A single session of ECP (1 hour) may be associated with transient improvement in the neurological symptoms of patients with stroke, according to the Counterpulsation to Upgrade Forward Flow in Stroke trial (23 patients). [bib_ref] Feasibility and safety of using external counterpulsation (ECP) to augment cerebral blood..., Guluma [/bib_ref] Another pilot study of 50 patients with ischaemic stroke with large artery occlusive disease showed a slightly more significant decrease in the NIHSS score (2.1 vs 1.3; p=0.061) after 35 daily sessions of ECP treatment (1 hour per session) than no ECP treatment. [bib_ref] Preliminary findings of external counterpulsation for ischemic stroke patient with large artery..., Han [/bib_ref] Therefore, ECP is a safe and possibly effective method to enhance cerebral blood flow and improve outcomes of patients with stroke, which warrants further investigation.
## Lying-flat head positioning
Cerebral autoregulation may be impaired in patients with ischaemic stroke, especially in the affected cerebral hemisphere. Thus, a lying-flat head positioning may increase cerebral blood flow through collateral circulation or gravity, as compared with an upright head positioning. [bib_ref] Head-of-Bed Optimization of Elevation) Study: association of higher angle with reduced cerebral..., Hunter [/bib_ref] A systematic review and meta-analysis of four small studies (57 patients in total) indicated that ipsilesional but not contralesional MCA flow velocities were significantly higher when patients were in a lying-flat head position at 0° or 15° as compared with an upright head position of 30°. [bib_ref] Head position and cerebral blood flow velocity in acute ischemic stroke: a..., Olavarría [/bib_ref] The mean flow velocity of ipsilesional MCA increased by 8.3 cm/s on average with a head position Open access from 30° to 0° (95% CI 5.3 to 11.3 cm/s; p<0.001) and 4.6 cm/s from 30° to 15° (95% CI 2.9 to 6.2 cm/s; p<0.001). [bib_ref] Head position and cerebral blood flow velocity in acute ischemic stroke: a..., Olavarría [/bib_ref] The Head Position in Acute Stroke Trial (HeadPoST) investigated the effects of different head positions in altering outcomes of over 11 000 patients with acute ischaemic or haemorrhagic stroke who were nursed to a lying-flat or sitting-up (≥30°) head positions and remaining in the position for 24 hours. [bib_ref] Statistical analysis plan for the Head Position in Stroke Trial (HeadPoST): An..., Billot [/bib_ref] Unfortunately, the HeadPoST study did not show any difference in the lying-flat and sitting-up head positions in affecting the 3-month function outcome, in the overall analysis or in subgroup analyses according to stroke subtypes, initial stroke severity, age and others. [bib_ref] Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke, Anderson [/bib_ref] Of note, HeadPoST did not assess arterial occlusion status in patients with stroke, which reduced power to detect a benefit of lying flat. Therefore, no conclusion could be drawn based on current evidence regarding the effects of different head positions on clinical outcomes of patients with ischaemic stroke.
Other non-pharmacological interventions Remote limb ischaemic preconditioning (RIPC) may condition remote vital organs including the brain for subsequent ischaemic events, by inducing transient episodes of mild ischaemia in the limbs. There have been preliminary studies indicating that long-term, repeated RIPC of bilateral arms is safe and feasible in patients with stroke aged under or above 80 years who had symptomatic ICAS. Compared with standard medical treatment alone, RIPC plus standard medical treatment may reduce the risk of recurrent stroke or TIA in such patients by improving cerebral perfusion and relieving the inflammation stress. Large prospective studies are needed to further explore the efficacy of RIPC in patients with stroke, for instance, the Remote Ischemic Conditioning for Avoiding Recurrence of Ischemic Stroke in Patients with Symptomatic Intracranial Atherosclerotic Stenosis trial ( ClinicalTrials. gov identifier: NCT02534545), which is currently under way.
In addition, there are novel methods that have shown promising effects in enhancing cerebral collateral circulation and cerebral blood flow in experimental stroke models, such as inhaling nitric oxide, [bib_ref] Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by..., Terpolilli [/bib_ref] stimulating the sphenopalatine ganglion [bib_ref] Stimulating circle of Willis nerve fibers preserves the diffusion-perfusion mismatch in experimental..., Henninger [/bib_ref] and others. But more evidence is needed before testing these methods in patients with stroke.
## Pharmacological interventions statins
Statin therapy has been demonstrated to have a protective effect in preventing stroke in patients with stroke, TIA or coronary artery disease. The relative risk reduction of statins versus placebo for a stroke event during follow-up in previous RCTs ranged from below 5% to over 30%. [bib_ref] Stroke prevention, blood cholesterol, and statins, Amarenco [/bib_ref] A recent systematic review and meta-analysis has demonstrated that prestroke statin use is associated with milder initial stroke severity (OR 1.24; 95% CI 1.05 to 1.48; p=0.013), better functional outcome (OR 1.50; 95% CI 1.29 to 1.75; p<0.001) and lower mortality (OR 0.42; 95% CI 0.21 to 0.82; p=0.011). In-hospital statin use is also associated with better functional outcome and lower mortality. Among patients with stroke treated with thrombolytic therapy, statin use also leads to a higher rate of a favourable functional outcome (OR 1.44; 95% CI 1.10 to 1.89; p=0.001), despite a higher risk of symptomatic haemorrhagic transformation with statin use (OR 1.63; 95% CI 1.04 to 2.56; p=0.035). [bib_ref] Statins in acute ischemic stroke: a systematic review, Hong [/bib_ref] The protective effect of statins towards a better functional outcome and against stroke recurrence may lie in their pleiotropic effects, for instance, reducing the concentration of low-density lipoprotein cholesterol, mild effect in lowering the blood pressure and anti-inflammatory effects. [bib_ref] Stroke prevention, blood cholesterol, and statins, Amarenco [/bib_ref] Moreover, it has been indicated in small studies that prestroke use of statins might be independently associated with better collateral circulation in cardioembolic, large artery atherosclerotic strokes or strokes of unknown aetiologies, possibly through increasing nitric oxide synthesis and promoting ischaemia-induced neovascularisation. The pleiotropic effects of statins in patients with stroke, including that in boosting collateral flow, warrant further investigation.
Urinary kallidinogenase and dl-3-n-butylphthalide Urinary kallidinogenase increases cerebral blood flow velocity and reduces the infarct size in an experimental stroke model by thread occlusion of MCA in rats. [bib_ref] Use of laser speckle imaging to study effects of urinary kallidinogenase on..., Li [/bib_ref] A small, open-label, controlled, prospective study implied that short-term application of human urinary kallidinogenase could upregulate vascular endothelial growth factor and apelin expression, shorten the MTT in MR perfusion, and improve the 3-month functional outcome, as compared with control, among patients with acute stroke. [bib_ref] Human urinary kallidinogenase improves outcome of stroke patients by shortening mean transit..., Li [/bib_ref] According to a systematic review and meta-analysis of 24 trials with 2433 patients published in 2012, human urinary kallidinogenase injection reduced death or dependency in two trials (RR 0.69; 95% CI 0.55 to 0.86) and increased the rate of neurological improvement after treatment based on data from 20 trials (2117 patients) (RR 1.56; 95% CI 1.44 to 1.70) as compared with control, while the risks of non-fatal intracranial haemorrhage or death were not significantly different between those treated with human urinary kallidinogenase or controls. [bib_ref] Efficacy and safety of human urinary kallidinogenase injection for acute ischemic stroke:..., Zhang [/bib_ref] Administration of dl-3n-butylphthalidehas has been indicated to increase the number of perfused microvessels, enhance cerebral blood flow, and reduce the incidence and infarct size in rat stroke models. A systematic review and meta-analysis published in 2010 reported more significant neurological improvement in patients treated with dl-3n-butylphthalide than controls (21 studies of 2123 patients), while there was no report on the rates of death of dependency in these studies. [bib_ref] Dl-3-butylphthalide for acute ischemic stroke: a systematic review, Wang [/bib_ref] A recent RCT of 170 patients reported that dl-3n-butylphthalide plus standard medical treatment had a mild effect in enhancing neurological recovery in patients with acute ischaemic stroke as compared with standard medical treatment alone, which Open access was correlated with a significantly higher level of circulating endothelial progenitor cells that may promote angiogenesis and neovascularisation in those treated with dl-3n-butylphthalide. [bib_ref] Mobilization of circulating endothelial progenitor cells by dl-3-n-butylphthalide in acute ischemic stroke..., Zhao [/bib_ref] Another RCT compared the efficacies of 14-day infusion of dl-3n-butylphthalide followed by a dl-3n-butylphthalide capsule, 14-day infusion of dl-3n-butylphthalide followed by aspirin, or a 14-day infusion of ozagrel followed by aspirin, among 573 patients with acute ischaemic stroke treated starting within 48 hours of onset. The study found a significant better functional outcome at 90 days in patients treated with dl-3n-butylphthalide for 90 days than those treated with ozagrel (p<0.001). [bib_ref] Ninety-day administration of dl-3-nbutylphthalide for acute ischemic stroke: a randomized, doubleblind trial, Cui [/bib_ref] However, there are doubts in the study findings, since none of the treatment assignments in this study were standard medical treatment in clinical practice.
Overall, although urinary kallidinogenase and dl-3n-butylphthalide have shown promising effects in promoting collateral circulation, increasing cerebral blood flow and improving the functional outcome after ischaemic stroke in animal models and in preliminary clinical studies, flawed study design of previous relevant studies urges further investigation on the effects and pharmaceutical mechanisms of the two novel medications in patients with stroke.
## Drug-induced hypertension
Results of animal studies hinted that drug-induced mild hypertension could increase cerebral blood flow and cerebral oxygen metabolism in the infarct core and penumbra, which might lead to a smaller infarct size. [bib_ref] Mild induced hypertension improves blood flow and oxygen metabolism in transient focal..., Shin [/bib_ref] By far, data are limited regarding the safety and efficacy of induced hypertension therapy in patients with ischaemic stroke. A couple of small studies showed a possible favourable effect of induced hypertension (using phenylephrine to increase the systolic blood pressure to a target of 160-200 mm Hg or increase the mean blood pressure by 10%-20%) over early neurological improvement in patients with acute ischaemic stroke with large artery occlusion or significant perfusion-diffusion mismatch. [bib_ref] Blood pressure in acute ischemic stroke, Mcmanus [/bib_ref] Findings of a currently ongoing multicentre, randomised, open-label trial, the Therapeutic INduced HYPERTEN-SION in acute non-cardioembolic ischaemic stroke (SETIN-HYPERTENSION; ClinicalTrials. gov identifier: NCT01600235) trial, may yield valuable data for this topic.
## Hypervolaemic treatment
Preclinical studies and pilot clinical studies showed possible neuroprotective effect of hypervolaemic treatment using albumin in acute ischaemic stroke, which improved cerebral perfusion in regions with critically reduced cerebral blood flow that might lead to a better functional outcome. [bib_ref] The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy..., Palesch [/bib_ref] However, early initiation of albumin treatment has been shown to have no additional clinical benefit versus isotonic saline in adult patients with ischaemic stroke with a baseline NIHSS score of 6 or higher who were treated within 5 hours of symptoms onset, in a multicentre, double-blinded RCT, the Albumin in Acute Ischemic Stroke Trial (ALIAS) trial. The ALIAS trial was stopped early at 841 patients since no difference was identified in the albumin and saline treatment groups in the primary outcome (mRS 0- perspeCTives With rapid progress in neuroimaging and computational techniques in recent years, various novel and non-invasive methods are emerging to evaluate cerebral collateral circulation, haemodynamics, metabolism and neuronal functions. Advances in the assessment and interventions for cerebral collateral circulation will facilitate more precise diagnosis and risk stratification, and more patient-specific management of patients with stroke, which will lead to better prognosis of affected patients. Cerebral collateral circulation is becoming a hot spot in stroke research. The following directions are promising in the near future. 1. Advancing multimodal imaging and postprocessing technologies and optimising methods and criteria, for more accurate transient and dynamic evaluation of cerebral collateral circulation and haemodynamics; verifying the role of collateral circulation in governing the functional outcomes and recurrent risks in patients with ischaemic stroke with and without large artery atherosclerotic disease. There are ongoing research projects targeting at these topics. For instance, the cerebral collateral circulation evaluation and prediction for acute cerebral ischaemia (COLLATERAL) study, a prospective, multicentre, nested case-control study, plans to assess the collateral status and its prognostic value in 3750 patients with acute ischaemic stroke , in which study multiphase CTA is used for collateral assessment. In addition, studies are under way to compare the values of novel imaging and computational methods versus conventional methods in gauging collateral circulation and cerebral haemodynamics in patients with stroke with symptomatic intracranial atherosclerotic disease, for instance, pseudocontinuous ASL MR perfusion imaging to assess cerebral perfusion and collateral circulation, and angiographic imaging-based computational fluid dynamics modelling to quantify cerebral haemodynamic metrics such as intraluminal pressure, flow velocities, wall shear and others. These studies will provide insights for simple, non-invasive but more accurate assessment of collateral circulation and may yield higher prognostic values. 2. Verifying the role of collateral circulation in governing response to acute endovascular therapy in patients with stroke towards more reasonable selection of patients for endovascular treatment in an extended time window.
Evidence is rapidly accumulating regarding the remarkable benefit of acute endovascular treatment for patients with stroke, which urges an extension in the time window for treatment. When the DAWN trial and further studies ultimately extend the time window to 24 hours or beyond, selecting suitable patients to treat will be essential in maximising the benefit of endovascular treatment, while the pretreatment collateral status could be a key factor to be taken into account. Currently, multicentre, prospective studies are under way to further verify the role of collateral circulation in altering the imaging and clinical outcomes after endovascular treatment, and/or to explore the role of baseline collateral status in influencing clinical decisions for endovascular treatment, such as the Stroke: An Evaluation of Thrombectomy in the Ageing Brain (STABILISE), MR-based Collateral Imaging to Predict Response to Endovascular Treatment of Stroke (FAST-COLL), Measuring Collaterals With Multiphase CT Angiography in Patients With Ischemic Stroke (PRove-IT), and Optimising Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT) trials. CT-based and/or MR-based methods for collateral assessment are tested in these trials. Findings of these trials will provide clues for a better strategy in clinical decisions to pursue endovascular treatment in ischaemic stroke, especially in an extended time window. 3. Testing currently existing and promising methods, and in the meantime exploring new methods, to improve collateral circulation. Although various pharmaceutical and non-pharmaceutical interventions have shown promising effects in augmenting cerebral collateral circulation and cerebral blood flow in patients with stroke, current evidence is limited to support the application of these interventions in clinical practice. Further investigation is in progress on the effects of EDAS, ECP, RIPC, and medications such as statins, urinary kallidinogenase and dl-3n-butylphthalide in improving collateral circulation and prognosis of certain subgroups of patients with stroke. Efforts are also needed to pursue novel methods in this area. 4. Establishing interdisciplinary imaging processing and assessment platforms and promoting telestroke systems, for timely and accurate patient assessment and triage in comprehensive stroke centres, as well as in lower level stroke centres. With prompt advances of imaging and artificial intelligence technologies in recent years and the years to come, bioengineers and computer scientists are increasingly involved in medical imaging processing and assessment. Therefore, establishment of interdisciplinary imaging platforms is ultimately inevitable for timely and accurate imaging processing and evaluation in acute ischaemic stroke. On the other hand, application of telestroke systems will facilitate accurate diagnosis and triage of patients with stroke presenting at lower level stroke centres, so that such patients could be treated properly on site or be transferred to a higher level stroke centre for more advanced treatments (such as acute endovascular treatment) that are not available on site. In addition, incorporating resources from multiple disciplines and centres will provide big Open access data for research into precise stratification and management of relevant patients in the near future.
Correction notice This article has been corrected since it published Online First. The author affiliations have been corrected.
[table] Table 1: Examples of collateral grading methods based on CTA Collateral status is graded in maximum intensity projection reconstructions of single-phase CTA in axial, coronal and sagittal planes in patients with MCA occlusion, and graded as: ► Good, if major MCA branches are reconstituted distal to the occlusion. ► Moderate, if some MCA branches are shown in the Sylvian fissure. [/table]
[table] 1: or NIHSS scores 0-1 at 90 days; 44% vs 44%; RR 0.96; 95% CI 0.84 to 1.10), while there were more events of pulmonary oedema or congestive heart failure within 48 hours (13% vs 1%; RR 10.8; 95% CI 4.37 to 26.72) and symptomatic intracranial haemorrhage within 24 hours (4% vs 2%; RR 2.42; 95% CI 1.02 to 5.78) in those treated with albumin than isotonic saline. 106 recommendations 1. Direct EC-IC bypass surgery is not recommended for patients with general ischaemic stroke or TIA with symptomatic intracranial atherosclerotic stenosis or occlusion (class III; level of evidence A). Further investigation is needed on the safety and efficacy of direct EC-IC bypass surgery in carefully selected patients with large artery atherosclerotic stroke with significantly compromised cerebral blood flow and/or cerebrovascular reactivity (class IIb; level of evidence C). The safety and efficacy of EDAS in patients with symptomatic intracranial atherosclerotic stenosis or occlusion warrant further verification (class IIb; level of evidence C). 2. Although the NeuroFlo treatment shows additionalbenefit over medical treatment in certain subgroups of patients with stroke, it is not recommended in patients with general stroke based on current evidence (class III; level of evidence A). 3. ECP is safe and possibly effective to augment cerebral blood flow in patients with acute ischaemic stroke, while the clinical benefit needs further investigation (class IIb; level of evidence C). 4. Lying-flat head positioning may increase cerebral blood flow as compared with upright head positioning, but no conclusion could be drawn based on current evidence regarding the effects of different head positions on clinical outcomes of patients with ischaemic stroke (class IIb; level of evidence C). 5. RIPC is safe and feasible, and may benefit patients with stroke with symptomatic ICAS. Further investigation is under way (class IIb; level of evidence C). 6. Statin treatment may enhance collateral flow and have other protective effects in patients with non-cardioembolic or cardioembolic stroke. It is reasonable to use statins in patients with non-cardioembolic stroke (class IIa; level of evidence B), and possibly reasonable to use in patients with cardioembolic stroke as well (class IIb; level of evidence C). 7. Urinary kallidinogenase and dl-3n-butylphthalide have shown promising effects in improving cerebral blood flow and the functional outcome after ischaemic stroke, but further investigation is needed (class IIa; level of evidence B). 8. The safety and efficacy of induced hypertensive therapy in patients with acute ischaemic stroke with large artery occlusion and hypoperfusion are not clear based on current evidence (class IIb; level of evidence C). Hypervolaemic treatment is not recommended for patients with general acute ischaemic stroke based on current evidence (class III; level of evidence A). [/table]
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https://svn.bmj.com/content/svnbmj/3/3/117.full.pdf
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Collateral circulation plays a vital role in sustaining blood flow to the ischaemic areas in acute, subacute or chronic phases after an ischaemic stroke or transient ischaemic attack. Good collateral circulation has shown protective effects towards a favourable functional outcome and a lower risk of recurrence in stroke attributed to different aetiologies or undergoing medical or endovascular treatment. Over the past decade, the importance of collateral circulation has attracted more attention and is becoming a hot spot for research. However, the diversity in imaging methods and criteria to evaluate collateral circulation has hindered comparisons of findings from different cohorts and further studies in exploring the clinical relevance of collateral circulation and possible methods to enhance collateral flow. The statement is aimed to update currently available evidence and provide evidence-based recommendations regarding grading methods for collateral circulation, its significance in patients with stroke and methods under investigation to improve collateral flow.
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2019 Clinical Practice Guidelines for Type 2 Diabetes Mellitus in Korea
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2019 Clinical Practice Guidelines for Type 2 Diabetes Mellitus in Korea
The Committee of Clinical Practice Guidelines of the Korean Diabetes Association revised and updated the 6th Clinical Practice Guidelines in 2019. Targets of glycemic, blood pressure, and lipid control in type 2 diabetes mellitus (T2DM) were updated. The obese and overweight population is increasing steadily in Korea, and half of the Koreans with diabetes are obese. Evidence-based recommendations for weight-loss therapy for obesity management as treatment for hyperglycemia in T2DM were provided. In addition, evidence from large clinical studies assessing cardiovascular outcomes following the use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with T2DM were incorporated into the recommendations.
# Introduction
The prevalence of type 2 diabetes mellitus (T2DM) in Korea is estimated to be 14.4% (in those over 30 years of age), according to a report by the Korean National Health and Nutrition Examination Survey 2011 to 2016. The prevalence of diabetes mellitus (DM) increased in both men and women as age increased and the prevalence of DM exceeded 10% for men in their 40s and 10% for women in their 50s. The obese and overweight population is also increasing steadily in Korea. Half of the people with DM are obese; class II obesity (body mass index 30.0 to 34.9) is 8.4% and class III obesity (BMI ≥35.0) is 1.8% in people with DM. Thus the early detection and prevention of T2DM are major health concerns for Koreans and the government. The diagnosis and appropriate treatment for T2DM are very important issues in establishing and implementing high-priority health policies in Korea.
## Diagnosis of type 2 diabetes mellitus
The diagnostic criteria for T2DM are based on the plasma glucose, either the fasting plasma glucose (FPG) or the 2-hour plasma glucose during a 75-g oral glucose tolerance test (OGTT), or glycated hemoglobin (HbA1c) value . The HbA1c test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay. In Korea, HbA1c standardization has been widely performed since 2007, and since 2011, HbA1c has been included as a diagnostic criterion for the Korean Diabetes Association clinical practice guidelines. Unless there is a clear diagnosis (classic symptoms of DM with a random plasma glucose 200 mg/dL), diagnosis requires two abnormal test results from the same sample or in two separate samples. If two different tests (HbA1c and FPG) are both above the diagnostic criteria when analyzed from the same sample or same day, this confirms the diagnosis of DM. According to the study of 4,481 Korean people with HbA1c and FPG, but with no diabetic medications in the Korean National and Nutritional Examination Survey, the HbA1c levels corresponding to the FPG of 100 and 126 mg/dL were 5.75% and 6.42%, respectively. Therefore, the suitable cutoff value of HbA1c for the diagnosis of DM in the Korean population is 6.5%, as suggested by the American Diabetes Association (ADA). When 4,610 individuals with data from a 75-g OGTT and no previous history of DM were analyzed, individuals with impaired fasting glucose were classified into FPG 100 to 109 mg/dL and 110 to 125 mg/dL levels. More individuals with FPG 110 to 125 mg/dL were diagnosed with DM as determined by a 2-hour plasma glucose result ≥200 mg/dL. Therefore, to detect more cases of DM, the 75-g OGTT is recommended for all individuals with FPG 110 to 125 mg/dL.
## Targets of glycemic, blood pressure, and lipid control
In the Kumamoto studyand the UK Prospective Diabetes Study (UKPDS) study, intensive glycemic control proved to be effective in preventing microvascular complications, and long-term follow-up of UKPDS cohortsshowed enduring effects of early glycemic control on microvascular complications. In the Kumamoto study, the goal of the intensive glucose control group was to maintain the blood glucose control as close as possible to FPG <140 mg/dL, 2-hour post-prandial blood glucose <200 mg/dL, and HbA1c <7%. The actual HbA1c level achieved was 7.1%. During the 6-year study period, retinopathy decreased by 69%, nephropathy decreased by 70%, and nerve conduction velocity improved in the intensive glycemic control group. The researchers suggested that the glycemic threshold to prevent the onset and progression of microvascular complications was indicated as follows: HbA1c <6.5%, FPG <110 mg/dL, and 2-hour post-prandial blood glucose <180 mg/dL. Many . Diagnostic criteria for type 2 diabetes mellitus in Korea 1. Glycated hemoglobin (HbA1c) level ≥6.5% (HbA1c concentration must be measured through a standardized method) a or 2. Eight-hour fasting plasma glucose of ≥126 mg/dL a or 3. Plasma glucose concentration of ≥200 mg/dL at 2 hours after a 75-g oral glucose tolerance test a or 4. Classic symptoms of diabetes (polyuria, polydipsia, unexplained weight loss) with a random plasma glucose concentration of ≥200 mg/dL a Diagnosis must be confirmed through a repeat test on a different day. However, if more than two criteria are met on the same day, a definite diagnosis can be made. meta-analyses consistently provided evidence for the clinical benefits of achieving and maintaining intensive glycemic control to prevent diabetic complications. Therefore, optimal HbA1c target for patients with T2DM is recommended to be <6.5%, especially in the recently diagnosed, young patients with T2DM without severe complications or hypoglycemia, through lifestyle modification (LSM) and glucose-lowering agents, including insulin. However, the glycemic target should be individualized based on patient characteristics and preference. In patients with a history of severe hypoglycemia or advanced diabetic complications, short life expectancy, or advanced age, the glycemic target must be individualized with consideration of risks of complications such as hypoglycemia. The recommended glycemic target for type 1 DM is an HbA1c concentration of <7.0%.
The ADA recommends that the intensity of statin should be determined by the risk of cardiovascular disease (CVD) or the presence of CVD without setting a low density lipoprotein cholesterol (LDL-C) target. However, the LDL-C-lowering effect of statins in the Asian population can be more prominent than in Western populations. Clinical trials did not include enough Asian populations, so it is unreasonable to apply the ADA guidelines in Korea. However, multiple clinical trials have demonstrated the beneficial effects of statin therapy on atherosclerotic cardiovascular disease (ASCVD) outcomes in subjects with and without CVD. In a study of patients with acute coronary syndrome or previous CVD, the use of highdose statins to reduce LDL-C to less than 70 mg/dL significantly reduced the risk of subsequent CVD. Meta-analyses of randomized controlled trials demonstrated the benefits of statins in people without established CVD but with cardiovascular (CV) risk factors. The goal of LDL-C concentration is graded according to the risk level, and diabetic patients with CVD are classified as very high risk and should target LDL-C <70 mg/dL. In diabetic patients with target organ damages (albuminuria or glomerular filtration rate [GFR] <60 mL/min/ 1.73 m 2 ) or CVD risk factors (hypertension, smoking, family history of premature ASCVD), LDL-C target of <70 mg/dL should be considered. In diabetic patients without CVD, the recommended target for LDL-C is <100 mg/dL.
In the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) study, an intensive blood pressure (BP) control strategy to achieve a systolic BP (SBP) <120 mm Hg did not significantly reduce the composite of CVD death, nonfatal myocardial infarction, and nonfatal stroke compared with a standard SBP control goal of <140 mm Hg. In contrast, the Systolic Blood Pressure Intervention Trial (SPRINT) found a significant reduction in the number of CVD events with intensive BP control to a goal SBP of <120 mm Hg but excluded those patients with T2DM. It was reported that intensive BP control to a goal SBP of <120 mm Hg significantly reduced the risk of CVD outcomes in SPRINT-eligible AC-CORD-BP participants. Participants with DM in that study were eligible for the analysis if they were in the standard glucose control arm of ACCORD-BP and had the additional CVD risk factors required for SPRINT. According to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the management of high BP in adults, in adults with DM and hypertension, antihypertensive drug treatment should be initiated at a BP of 130/80 mm Hg or higher with a treatment goal of less than 130/80 mm Hg.
The risk and incidence of CVD in the Asian population are different from those in Western populations. For Asian populations, the risk of stroke compared with coronary artery disease is higher. In addition, the relationship between BP levels and stoke incidence is stronger in Asian populations, and the slope of association between BP levels and stroke events has also been shown to be steeper in Asians than in Western populations. The recent study of Korean cohort data among patients with T2DM without underlying CVD at baseline showed that a BP <130/80 mm Hg was associated with further lowering of the risk of CV events, but an SBP <110 mm Hg or diastolic BP (DBP) <75 mm Hg was associated with a higher risk of all-cause mortality. However, there is no definitive study comparing the effect of lowering SBP to below 130 mm Hg as op-
## Obesity management for the treatment of type 2 diabetes mellitus
According to the 2018 Korean Society for the Study of Obesity guidelines, the classification of obesity into classes I, II, and III relies on adult BMI, in accordance with WHO guidelines for the Asia-Pacific region. Class I obesity is defined as BMI 25 kg/m 2 to less than 30 kg/m 2 , class II obesity is defined as BMI 30 kg/m 2 to less than 35 kg/m 2 , and class III obesity was newly defined in 2018 as greater than 35 kg/m 2 . If a patient with T2DM and BMI >25 kg/m 2 (class I) fails to lose weight with diet, physical activity, and behavior counseling, weightloss medications may be considered. Bariatric surgery should be considered in patients with T2DM if BMI ≥35 kg/m 2 (class III obesity). Bariatric surgery may be considered in patients with T2DM ≥BMI 30 kg/m 2 (class II obesity) if nonsurgical treatment fails to result in weight loss or glycemic control. A substantial body of evidence has now been accumulated, including data from randomized controlled clinical trials, demonstrating that bariatric surgery achieves superior glycemic control and reduction of CV risk factors in patients with T2DM and obesity compared with various medical interventions. However, it is also reported that 35% to 50% of patients who initially achieve remission of DM after bariatric surgery eventually experience recurrence. Regardless of remission of DM, nearly all patients with T2DM and obesity who undergo bariatric surgery maintain significant improvements of glycemic control and other CV risk factors. Thus, it is important to recognize bariatric surgery as one treatment for the management of obesity and DM rather than focusing on the remission of DM after bariatric surgery.
## Antihyperglycemic therapy for adult patients with type 2 diabetes mellitus
LSM is an essential component of treatment for all patients with T2DM and should be initiated promptly and simultaneously with antihyperglycemic agents. Patients' education within a structured program should be provided from a health care professional at the time of diagnosis and then followed up with regular reinforcement checks. For patients with newly diagnosed T2DM, LSM that includes medical nutrition therapy, weight control, physical activity, smoking cessation, and avoidance of alcohol abuse should be initiated.
As an initial therapy for newly diagnosed patients with an HbA1c <7.5%, metformin must first be considered as first-line oral therapy but other drugs can be considered based on patient status. If metformin is not tolerable or is contraindicated, the alternative choices for monotherapy include dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, thiazolidinediones (TZDs), glucagon-like peptide 1 receptor agonists (GLP-1 RAs), sulfonylureas (SUs), glinides, α-glucosidase inhibitors, and insulin according to patient circumstances. In the Practical Evidence of Antidiabetic Monotherapy (PEAM) study, the glucose-lowering efficacies of SUs, metformin, and TZDs as antidiabetic monotherapies administered for 48 weeks were similar in drug-naïve Korean patients diagnosed with T2DM.
If the initial HbA1c level of a patient is ≥7.5% or the HbA1c target is not achieved within three months of initiating monotherapy, dual combination therapy can be considered. If the HbA1c target is not achieved within 3 months of initiating dual therapy, a third agent with a complementary mechanism of action can be added for triple combination therapy. The early combination therapy is preferred over maximizing the dosage of a single agent when considering glucose-lowering efficacy and side effects. Although there is no particular order of preference, efficacy, risk of hypoglycemia, weight gain, CV benefits, and presence of clinical data in the Korean population should be considered for this arrangement. Metformin is maintained as background therapy during dual or triple combination therapy.
In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial, empagliflozin added to the standard of care reduced the risk of three-point major adverse cardiovascular events (three-point MACE: composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) by 14%, CV death by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% in patients with T2DM and established CVD. When the effects of empagliflozin , sulfonylurea (SU), α-glucosidase inhibitor (α-Gi), or insulin as the initial therapy according to the patient's condition. If the initial HbA1c level is ≥7.5% or the HbA1c target is not achieved within 3 months of monotherapy, dual combination therapy can be considered. In this case, a second-line drug is added to metformin; however, any other combination of drugs with different mechanisms of action can be used depending on the patient's clinical characteristics. If the HbA1c target is not achieved within 3 months after commencing dual therapy, then proceed to triple combination therapy. In no particular order of preference, efficacy, cardiovascular benefit, risk of hypoglycemia, impact of body weight, and presence of clinical data in the Korean population should be considered for this arrangement. To aid the physician's choice, the characteristics of antihyperglycemic agent classes are shown as a bar scale. Efficacy (green), CV benefit (blue), hypoglycemia risk (red), and body weight changes (yellow) were assigned ratings of low, intermediate, or high (body weight changes; decrease, neutral, or increase) based on recently published studies identified in an extensive literature review; the scale bar is not constructed according to strict definitions but should be used as a guide for clinical decisions. This figure was illustrated based on the drugs' approval by the Korea Food and Drug Administration (http://www.mfds. go.kr/eng) in April 2019. GLN, glinide. a Body weight changes: decrease, neutral, or increase, b GLN can be used as dual combination therapy with metformin, TZD, α-Gi, or insulin or as a triple combination therapy with metformin and α-Gi, metformin and TZD, or metformin and insulin.
in Asian patients were investigated (n=1,517), empagliflozin reduced the risk of three-point MACE by 32% (hazard ratio, 0.68; 95% confidence interval, 0.48 to 0.95). The effects of empagliflozin on the components of MACE, all-cause mortality, and heart failure outcomes in Asian patients were consistent with the overall population. Therefore, for patients with established ASCVD, the SGLT2 inhibitors with proven CV benefits should first be considered. The GLP-1 RAs with proven CV benefits should be considered. The GLP-1 RAs can be used in monotherapy or in combination with oral hypoglycemic agents other than DPP-4 inhibitors or in combination with basal insulin. Especially, the GLP-1 RAs with proven CV benefits should be considered in T2DM patients with established CVD. Both liraglutide and semaglutide significantly reduced a composite three-point MACE outcome and mortality compared with placebo-treated group. For patients with T2DM who fail to achieve the glycemic target with adequate treatment with oral antihyperglycemic agents, proceed to insulin injection therapy. The addition of a GLP-1 RA or switching to a premixed insulin regimen could be another option depending on the patient's clinical situation . The initiation of insu- . Treatment algorithm for injectable therapy in type 2 diabetes mellitus (T2DM). (Left) Initiation of insulin treatment. If the initial glycated hemoglobin (HA1c) level is >9.0% and symptomatic hyperglycemia or metabolic decompensation is present, insulin therapy can be initiated with or without oral antihyperglycemic agents (OHAs) in patients with newly diagnosed T2DM. If the HA1c target range is not achieved after implementing a basal insulin regimen, then proceed to intensification treatment, for example, addition of a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a prandial insulin or switching to a premixed insulin regimen. (Right) For adult patients with T2DM who have not achieved their glycemic target following adequate treatment using OHAs. When OHAs fail, proceed to basal insulin either with or without OHAs. The addition of a GLP-1 RA or switching to a premixed insulin regimen could be another option depending on the patient's clinical situation. The width of each black line reflects the strength of the expert consensus recommendations. In patients above the HbA1c target on basal insulin or premixed insulin once or twice daily, further intensification outlined in this algorithm may be considered. lin should be considered in patients with newly-diagnosed T2DM if the initial HbA1c level is >9.0% and symptomatic hyperglycemia or metabolic decompensation is present. Insulin also should be considered when adequate glycemic control is not obtained in patients with decompensated hepatic or renal insufficiency and when patients have suffered from myocardial infarction, stoke, or a major operation.
## Diabetic nephropathy
It is recommended that urinary albumin excretion and estimated GFR should be assessed at least once a year. A urine albumin-creatinine ratio ≥30 mg/g is generally defined as albuminuria, and decreased GFR is defined as GFR <60 mL/min/ 1.73 m 2 . Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists are recommended as first-line medications for BP control in diabetic patients with albuminuria. Glycemic control has been shown to be effective to slow the progression of nephropathy in patients with early diabetic nephropathy. Recently, several hypoglycemic agents demonstrated beneficial effects on the progression of diabetic nephropathy. Empagliflozin showed a significantly lower risk of albuminuria progression or renal outcomes, such as a doubling of the serum creatinine level and initiation of renal-replacement therapy, than the placebo group. Some GLP-1 RAs also demonstrated a renal protective effect in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) and the Preapproval Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trials. However, their renal outcome was studied as a secondary outcome. Recently, in T2DM with renal disease, canagloflozin lowered the risk of kidney failure or renal death about 30% than in the placebo group.
Appropriate clinical practice guidelines customized for Korean people with T2DM have been developed and updated to provide better glycemic control and favorable clinical outcomes. More evidence and clinical trials should be undertaken, especially in Asia, including Korea.
## Conflicts of interest
No potential conflict of interest relevant to this article was reported.
## Orcid
## Mee kyoung kim https://orcid.org/0000-0003-3205-9114
Hyuk-Sang Kwon https://orcid.org/0000-0003-4026-4572
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https://www.e-dmj.org/upload/pdf/dmj-43-398.pdf
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The Committee of Clinical Practice Guidelines of the Korean Diabetes Association revised and updated the 6th Clinical Practice Guidelines in 2019. Targets of glycemic, blood pressure, and lipid control in type 2 diabetes mellitus (T2DM) were updated. The obese and overweight population is increasing steadily in Korea, and half of the Koreans with diabetes are obese. Evidence-based recommendations for weight-loss therapy for obesity management as treatment for hyperglycemia in T2DM were provided. In addition, evidence from large clinical studies assessing cardiovascular outcomes following the use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists in patients with T2DM were incorporated into the recommendations.
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d4f14c52a7651055a574f1a19309acad8a39fc27
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pubmed
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Application of New Cholesterol Guidelines to the Korean Adult Diabetic Patients
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Application of New Cholesterol Guidelines to the Korean Adult Diabetic Patients
Patients with diabetes over 30 yr of age were analyzed by the two guidelines. Of the total 1,975 diabetic patients, only 377 (19.1%) were receiving drugs for dyslipidemia. Among 1,598 patients who had not taken any medications for dyslipidemia, 65.6% would be indicated for statin therapy according to the ATP-III guidelines. When we apply the new guidelines, 94.3% would be eligible for statin therapy. Among the total diabetic patients, the new guidelines, compared with the ATP-III guidelines, increase the number eligible for statin therapy from 53.1% to 76.2%. The new guidelines would increase the indication for statin therapy for most diabetic patients. At present, many diabetic patients do not receive appropriate statin therapy. Therefore efforts should be made to develop the Korean guidelines and to ensure that more diabetic patients receive appropriate statin therapy.
# Introduction
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with diabetes. Dyslipidemia, a common condition coexisting with type 2 diabetes, is a major cause of atherosclerosis and a risk factor for CVD. Numerous studies have shown that lowering lipid levels is very important for preventing CVD in patients with diabetes [bib_ref] Effect of a multifactorial intervention on mortality in type 2 diabetes, Gaede [/bib_ref].
Since their release, the guidelines of the Third Adult Treatment Panel (ATP-III) of the National Cholesterol Education Program have been used globally in the treatment of hyperlipidemia. The ATP-III guidelines defined patients with diabetes as coronary heart disease equivalent condition and high risk of CVD group. Individuals at high risk with low-density lipoprotein cholesterol (LDL-C) levels ≥ 100 mg/dL are candidates for statin therapy. The ATP-III guidelines calculated the 10-yr risk of coronary heart disease (CHD) using the Framingham risk calculator [bib_ref] National Heart L, and Blood Institute, Grundy [/bib_ref].
The American College of Cardiology and the American Heart Association (ACC/AHA) guidelines for the management of cholesterol were released in November 2013. The new guidelines expand the recommendation for statin therapy to all patients with diabetes aged 40-75 yr with LDL-C levels ≥ 70 mg/dL who also have a 10-yr risk of CVD ≥ 7.5%, as estimated based on new pooled cohort equations.
In Korea, the prevalence rate of dyslipidemia increased from 1998 to 2010, but the treatment rate of diabetic patients in 2010 was only 23.6% [bib_ref] Prevalence and management of dyslipidemia in Korea: Korea National Health and Nutrition..., Roh [/bib_ref]. This study used data from the Korea National Health and Nutrition Examination Surveys (KNHANES) to estimate the number of patients with diabetes in Korea for whom statin therapy would be recommended based on the new guidelines compared with the ATP-III guidelines.
# Materials and methods
## Study population
This study was performed using data from the KNHANES V (2010-2012) conducted by the Division of Health and Nutritional Survey under the Korean Centers for Disease Control and Prevention (KCDCP). This is a nationwide, community-based crosssectional survey examining the general health and nutrition status of the civilians of Korea. Participants were selected from sampling units based on geographical area, sex, and age group using household registries and a stratified, multistage, clustered, probability sampling design. This sampling method is certified to produce representative statistics by the Korea National Sta-tistical Office.
The diagnostic criteria for diabetes were taken from the American Diabetes Association (ADA) guidelines. Patients over 30 yr of age were defined as having diabetes if they had already been diagnosed as diabetic by a physician or had a fasting plasma glucose level ≥ 126 mg/dL or HbA1c level ≥ 6.5%. We excluded participants who fasted less than 8 hr before blood sampling and who had missing LDL-C level data. After these exclusions, a total of 1,975 patients with diabetes for whom LDL-C levels that were directly measured or calculated by Friedewald's equation were available [bib_ref] Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use..., Friedewald [/bib_ref].
The diabetic patients were divided into dyslipidemia treatment versus non-treatment groups. The patients in the dyslipidemia treatment group were defined as those who reported taking medications for dyslipidemia. Treatment for dyslipidemia was not limited to statins but included any type of drug. We assessed the eligibility for statin therapy using the 2004 updated ATP-III criteria as well as the 2013 ACC/AHA guidelines. According to the ATP-III guidelines, patients with diabetes should be considered at high risk. Statin therapy is recommended in high-risk patients with a LDL-C level ≥ 100 mg/dL. The new ACC/AHA guidelines recommend moderate-intensity statin therapy in all diabetic patients between the ages of 40 and 75 yr and moderate-to-high-intensity statin therapy in those with a 10-yr risk of CVD ≥ 7.5%.
## Biochemical measurements
After fasting for 8 hr or more, blood samples were drawn from the antecubital vein of each participant in the morning. Samples were processed appropriately, refrigerated at 2-8°C, and transported to the Central Testing Institute, Seoul, Korea. After transport, plasma was separated by centrifugation and analyzed within 24 hr.
The fasting plasma concentrations of glucose and lipid were measured using a Hitachi Automatic Analyzer 7600 (Hitachi, Tokyo, Japan). High-performance liquid chromatography (HLC-723G7; Tosoh, Tokyo, Japan) was used to measure HbA1c.
The HDL-C level was calculated according to the Lipid Standardization Program of the US Centers for Disease Control and Prevention (CDC). The formula used in 2012 was different from that in 2010-2011. LDL-C levels have been measured directly using automated enzymatic techniques since 2009 in KNHANES IV. LDL-C levels were calculated using Friedewald's formula [bib_ref] The Centers for Disease Control-National Heart, Lung and Blood Institute Lipid Standardization..., Myers [/bib_ref] in subjects with no direct LDL data.
# Statistical analysis
All statistical analyses in this study were performed using weighted variables with stratification and clustering variables to incorporate sample weights and to adjust for the complex sample design of the survey. Nominal variables are presented as the numbers of cases and percentages, and continuous variables are presented as means ± standard deviations. We compared the baseline characteristics of men and women by Student's ttest and chi-square test. We determined the proportion of the patients with diabetes in KNHANES for whom statin therapy would be recommended on the basis of the two guidelines.
We calculated the new ACC/AHA pooled-cohort equations to determine the proportions of adults with a 10-yr risk of CVD ≥ 7.5%. All analyses were conducted using SPSS version 19.0 software (IBM, Chicago, IL, USA).
# Ethics statement
The survey was approved by the institutional review board of KCDCP (approval numbers 2010-02CON-21-C, 2011-02CON-06-C, and 2012-01EXP-01-2C). All participants provided informed consent.
# Results
A total of 25,534 individuals participated in the health interview and examination in KNHANES V in 2010-2012. Of these, 17,292 subjects were ≥ 30 yr of age, among whom 12.5% (2,165 patients) had diabetes. A total of 190 participants was excluded because of missing LDL-C data, leaving 1,975 patients (aged 62.64 ± 11.42 yr, 30-90 yr) with diabetes analyzed in this study. [fig_ref] Table 1: Comparison of baseline characteristics between men and women among Korean adult diabetic... [/fig_ref] shows a comparison of the baseline characteristics between men and women. There was no difference in HbA1c levels between men and women (7.3 vs. 7.3, respectively, P = 0.996). Women were older than men (64.11 vs. 61.24, respectively, P < 0.001) and had higher levels of total cholesterol and LDL-C (193.2 vs. 182.61, respectively, P < 0.001; 115.61 vs. 108.65, respectively, P < 0.001). A larger proportion of female patients (23.9%) than male patients (14.5%) had been taking medications for dyslipidemia. shows the flow of the process used to determine the final subjects selected for analysis according to the two sets of guidelines for the management of cholesterol. Among the 1,598 diabetic patients who had never taken medications for dyslipidemia, 1,048 patients (65.6%) were recommended for statin therapy according to the NCEP/ATP-III guidelines. According to the new ACC/AHA guidelines, 94.3% (72.8% required moderate-to-high-intensity therapy; 21.5% required moderate-intensity therapy) were recommended for statin therapy.
Among the 1,975 Korean adult diabetic patients, [bib_ref] Application of new guidelines for the primary prevention of atherosclerotic cardiovascular disease..., Kim [/bib_ref].1% (n = 377) had already been taking drugs for dyslipidemia. If patients with LDL levels > 130 mg/dL were recommended for statin therapy, an additional 25.3% (n = 500) would be classified as requiring statin therapy. After application of the NCEP/ATP-III guidelines, an additional 53.1% (n = 1,048) were classified as requiring statin therapy. Application of the new ACC/AHA guidelines resulted in an indication for statin therapy in an additional 76.2% of patients (n = 1,506) .
Among the 1,598 patients not taking any drugs for dyslipid- .
# Discussion
Over the past two decades, many randomized controlled trials have shown that lowering LDL-C levels with statin therapy reduces the incidence of atherosclerotic CVD under clinical conditions [bib_ref] Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis..., Baigent [/bib_ref] [bib_ref] The effects of lowering LDL cholesterol with statin therapy in people at..., Mihaylova [/bib_ref]. The new ACC/AHA cholesterol guidelines were developed based on this evidence and emphasize primary prevention of cardiovascular disease. In diabetic patients, the new guidelines suggest that most patients require statin therapy. The 2015 ADA guidelines accept this concept of statin therapy for primary prevention in diabetic patients. We estimated the percentage of Korean adult diabetic patients requiring statin therapy according to the two sets of guidelines using the KNHANES data.
In this study, female Korean diabetic patients had higher levels of total cholesterol and LDL-C despite the larger portion taking drugs for dyslipidemia. As the mean age of women was older than that of men, it is possible that the group of women included a larger number of those older than 50 yr. According to a previous study, in the Korean general population, men had more hypercholesterolemia and hyper-LDL-cholesterolemia among the younger aged population (< 50 yr), whereas among those of older age (≥ 50 yr), women had more hypercholesterolemia and hyper-LDL-cholesterolemia. Women had higher HDL-C levels in all age groups [bib_ref] Prevalence and management of dyslipidemia in Korea: Korea National Health and Nutrition..., Roh [/bib_ref]. The same difference in HDL-C level was also found in American national data [bib_ref] Total and high-density lipoprotein cholesterol in adults: National Health and Nutrition Examination..., Carroll [/bib_ref] [bib_ref] Hypertension, abnormal cholesterol, and high body mass index among non-Hispanic Asian adults:..., Aoki [/bib_ref]. In this study, Korean diabetic patients showed no differences in HDL levels between men and women. This may have been because diabetic patient have low levels of HDL-C.
We estimate that under the new guidelines, 94.3% of diabetic patients will be indicated for statin therapy, representing almost all patients with diabetes. This population would represent an increase of 28.7% over the number currently eligible according to the ATP-III guidelines (65.6%). These new treatment recommendations have a larger effect in older aged (≥ 60 yr) than younger aged individuals (< 60 yr) and in men than women . These trends are similar to those in the general population in the USA (17). The differences according to age may be partially explained by the new pooled-cohort equations. The new equation targeted prevention of stroke and coronary heart disease, as the prevalence of CVD rises markedly with age [bib_ref] Heart disease and stroke statistics--2013 update: a report from the, Go [/bib_ref]. In the Korean population, approximately 90% of old people require statins for primary prevention according to the new guidelines [bib_ref] Application of new guidelines for the primary prevention of atherosclerotic cardiovascular disease..., Kim [/bib_ref]. However, there are few data showing the benefit of statin treatment in older people without CVD [bib_ref] Is it time for a cardiovascular primary prevention trial in the elderly?, Robinson [/bib_ref]. Instead, younger individuals were shown to require more aggressive preventive treatment for CVD. The new guidelines would also result in more http://dx.doi.org/10.3346/jkms.2015.30.11.1612 men being newly indicated for statin therapy than women, although women had worse dyslipidemia. This may be explained by the new guidelines also expanding the indication for statin therapy among adults with other risk factors for CVD, even at lower levels of LDL-C. More male than female patients are smokers.
The purpose of treatment of dyslipidemia is not simply normalization of cholesterol level itself, but also the prevention of CVD and a decrease in mortality rate. Diabetes is a serious risk factor for CVD. Therefore, the ADA recommended statin therapy for all patients with diabetes aged > 40 yr without additional CVD risk factors, with consideration of moderate-intensity statins for primary prevention. However, it remains unclear whether Asian diabetic patients should follow these guidelines. The Japan Atherosclerosis Society (JAS) recommends a goal of LDL-C level < 120 mg/dL for the high-risk group as well as diabetes for primary prevention [bib_ref] Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention..., Teramoto [/bib_ref]. These recommendations are based on Japanese epidemiological studies [bib_ref] The relationship between serum total cholesterol and all-cause or causespecific mortality in..., Okamura [/bib_ref] [bib_ref] Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a..., Nakamura [/bib_ref] [bib_ref] Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS):..., Yokoyama [/bib_ref]. These studies indicated that low-dose statins are effective for prevention of atherosclerotic CVD (ASCVD) in Japanese patients. Several studies showed that relatively low-dose statins had a high lipid-lowering effect in Korean subjects [bib_ref] Comparison of efficacy and safety after administering high potency statin to high..., Yun [/bib_ref] [bib_ref] Comparing high-intensity versus low-to moderate-intensity statin therapy in Korean patients with acute..., Kim [/bib_ref] [bib_ref] Cholesterol lowering effects of low-dose statins in Korean patients, Kwon [/bib_ref]. According to the new guidelines, high-intensity statins are a taken at a daily dose that lowers LDL-C by an average of approximately ≥ 50%, e.g., atorvastatin 40-80 mg or rosuvastatin 20-40 mg. Moderate-intensity statins are taken at a daily dose that lowers LDL-C by 30%-50%, such as atorvastatin 10-20 mg or rosuvastatin 5-10 mg. A clinical study in Korea showed that atorvastatin at 10 mg decreased LDL-C levels by 41.8% from baseline, and a decrease of 48.8% was observed with only 5 mg rosuvastatin. In another Korean study, there were no differences in major adverse cardiac events between high-intensity and low-to-moderate-intensity statin therapy in patients with acute myocardial infarction [bib_ref] Comparing high-intensity versus low-to moderate-intensity statin therapy in Korean patients with acute..., Kim [/bib_ref]. Therefore, it may be possible for Korea to reach the same goal of CVD prevention as the new guidelines but with relatively lower doses of statin. However, it is still controversial as to which statins and doses are most effective, as the Korean absolute CVD risk is lower than those in Western countries, and there are insufficient long-term data. Even among Asian ethnic differences in cardiovascular mortality [bib_ref] Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in..., Anand [/bib_ref] , respective countries need their own guidelines for prevention of ASCVD.
Nevertheless, Korean diabetic patients have not received appropriate management for dyslipidemia. We showed that only 19.1% of diabetic patients were taking antidyslipidemic medications. As these medications include any drugs for dyslipidemia, the real proportion of patients taking statin may be smaller than 19%. If we assume the goal is to lower LDL-C levels to < 130 mg/dL, an additional 25.3% of patients need statin therapy. This level is higher than the JAS guidelines for diabetic patients. Even according to the ATP-III guidelines, an additional 53.1% of patients require statin treatment. At present, the Korean national health insurance system guarantees statin therapy in cases with LDL-C levels > 100 mg/dL. Therefore, more than half of all diabetic patients in Korea have not received statin therapy. It is necessary to at least ensure that diabetic patients are managed according to the proper guidelines. This is the first study regarding application of the new cholesterol guidelines to Korean diabetic patients. We used validated national data from KNHANES V (2010-2012). However, we did not consider peripheral vascular disease or previous cardiovascular events and did not predict real effects of the new and old guidelines on diabetic patients due to a lack of Korean cohort data.
In conclusion, the new ACC/AHA guidelines would increase the indication for statin therapy of most diabetic patients. The issues involved with application of the new guidelines to the Korean diabetic population should be discussed further in future studies. At present, many diabetic patients do not receive appropriate statin therapy. Efforts should be made to ensure that more diabetic patients receive appropriate statin therapy and to develop the Korean guidelines.
[table] Table 1: Comparison of baseline characteristics between men and women among Korean adult diabetic patients BP, blood pressure. http://dx.doi.org/10.3346/jkms.2015.30.11.1612 [/table]
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The American College of Cardiology and the American Heart Association (ACC/AHA) 2013 joint guidelines for the treatment of hypercholesterolemia expand the indications for statin therapy. This study was performed to estimate the numbers of diabetic patients indicated for statin therapy according to the Third Adult Treatment Panel (ATP-III) of the National Cholesterol Education Program guidelines and the new ACC/AHA guidelines in Korea. We analyzed the data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2012. Patients with diabetes over 30 yr of age were analyzed by the two guidelines. Of the total 1,975 diabetic patients, only 377 (19.1%) were receiving drugs for dyslipidemia. Among 1,598 patients who had not taken any medications for dyslipidemia, 65.6% would be indicated for statin therapy according to the ATP-III guidelines. When we apply the new guidelines, 94.3% would be eligible for statin therapy. Among the total diabetic patients, the new guidelines, compared with the ATP-III guidelines, increase the number eligible for statin therapy from 53.1% to 76.2%. The new guidelines would increase the indication for statin therapy for most diabetic patients. At present, many diabetic patients do not receive appropriate statin therapy. Therefore efforts should be made to develop the Korean guidelines and to ensure that more diabetic patients receive appropriate statin therapy.
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85a10791ca249f866cc01f05dc2a12b8096821ee
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pubmed
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Consensus statement of the Italian society of colorectal surgery (SICCR): management and treatment of hemorrhoidal disease
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Consensus statement of the Italian society of colorectal surgery (SICCR): management and treatment of hemorrhoidal disease
Hemorrhoidal disease (HD) is the most common proctological disease in the Western countries. However, its real prevalence is underestimated due to the frequent self-medication. The aim of this consensus statement is to provide evidence-based data to allow an individualized and appropriate management and treatment of HD. The strategy used to search for evidence was based on application of electronic sources such as MEDLINE, PubMed, Cochrane Review Library, CINAHL, and EMBASE. These guidelines are inclusive and not prescriptive. The recommendations were defined and graded based on the current levels of evidence and in accordance with the criteria adopted by American College of Chest Physicians. The recommendations were graded A, B, and C.
study methodology (sampling, blinding, and analytical methods), English language, and the evaluation of papers published only in indexed journals with impact factor. Prospective randomized-controlled trials and meta-analyses were given preference in developing these guidelines.
Directed searches of the embedded references from the candidate articles were also performed.
The recommendations were defined and graded based on the current levels of evidence and in accordance with the criteria adopted by the American College of Chest Physicians.
Three evidence levels were defined. The recommendations were graded A, B, and C.
Members of the SICCR were invited to contribute to the production of these guidelines and final recommendations were reviewed by the entire Clinical Practice Guidelines Committee. SICCR Clinical Practice Guidelines are updated every 4 years.
## Target users
The target users of guidelines are coloproctological surgeons, gastroenterologists, general practitioners, nurses, and other medical specialists who treat anoperineal diseases.
The guidelines may be used to inform clinical decisions and standards of care. The guidelines are also intended to inform patients about the possible alternatives for the management of their condition.
## Introduction: symptoms, classification, scoring system and diagnosis of hd
HD is the most common proctological disease with an estimated prevalence rate of 4.4%, with a peak in individuals between 45 and 65 years of age. Furthermore, 50% of the population over 50 years old have experienced problems related to HD.
Symptoms of HD may overlap with those of other anorectal conditions such as skin tags, abscesses, fissures, polyps, inflammatory bowel disease (IBD), and anorectal neoplasms. The most common presentation of HD is painless rectal bleeding that occurs during or immediately after defecation. Usually, it is mild-moderate bright red bleeding which the patient observes on the feces or staining the toilet paper. Recurrent bleeding may result in secondary iron deficiency anemia. Sometimes, HD may cause massive hemorrhage requiring urgent hospitalization and blood transfusions. Other symptoms to consider are swelling, prolapse, soiling, perianal skin irritation, itching, and discomfort. Furthermore, large hemorrhoidal prolapse may cause sense of rectal filling and, rarely, difficult defecation.
Pain is rare in case of uncomplicated HD. In fact, its presence may indicate other simultaneous painful conditions (fissure, abscess, pudendal neuropathy, proctalgia fugax, and anorectal neoplasm). Acute edema and thrombosis of external hemorrhoids (TEH) are responsible for acute anal pain irrespective of bowel movements. Although several HD symptom scores have been proposed so far, to date, none are widely used or considered the gold standard evaluation tool, even though after the publication of the HubBLe Trial, the use of these scoring systems has increased to more easily compare data from the scientific literature.
## Classification and scoring system for hd
HD classifications should meet the need to choose the most suitable therapeutic approach as well as to have shared parameters for trials and guidelines.
Internal hemorrhoids are classified according to the presence and severity of prolapse as in the Goligher Classification.
Unfortunately, the Goligher classification has several limitations, because it does not consider the associated symptoms and their impact on quality of life, the etiopathogenesis of the disease, and specific clinical conditions such as circumferential prolapse or single prolapsed pile.
Therefore, it may not reflect the true severity of the disease and the effect of HD on the patient.
To overcome these limitations, different grading systems have been developed. All the grading systems are patient self-reported assessments focusing on the presence and frequency of different symptoms. Nystrom in 2009 used a five-point-based questionnaire assessing the frequency of pain, discomfort, itching, soiling, and need for manual reduction of hemorrhoids. The system is easy to use and reproduce and has been successfully validated, but it fails to consider the presence and frequency of prolapse that does not need manual reduction. However, hemorrhoidal prolapse is a very important manifestation of HD and can impact on quality of life. Furthermore, the frequency of the symptoms was divided in four grades including "never", "less than once a week", "1-6 times per week", and "every day". Other grading systems assessing frequency of symptoms of hemorrhoids, similarly to those assessing severity of other conditions such as fecal incontinence, are based on five grades of frequency including" between never and less than once a week". Yet, probably, the most important flaw of the Nystrom system is the lack of a score for the quality of life. HD is a benign condition and its severity is not only related to the frequency of its symptoms but rather to how they are perceived by the patient. Indeed, similar symptoms may affect patients' life style and quality of life in very different ways with a significant variation from patient to patient. For this reason, quality of life should be considered when. The severity of hemorrhoidal symptoms was scored using a specifically designed questionnaire assessing five different parameters each one scoring from 0 to 4 points, with zero indicating no symptoms and four daily symptoms or symptoms with every defecation. A score of zero corresponds to the complete absence of hemorrhoidal symptoms, while 20 corresponds to the worst possible symptoms. The five parameters assessed are bleeding, prolapse, need for manual reduction, pain, discomfort, and discharge as one parameter and impact on quality of life. This very simple and intuitive system has been proved useful and effective within clinical trials. Sodergren et al.elaborated a more complex dedicated scoring system based on symptoms as reported by patients, taking into account how individual symptoms impact on patients' quality of life. Based on their findings, the most relevant symptoms were selected and scored according to their frequency not in a linear way but according to what their expected impact on patients' quality of life would be. Very surprisingly, the authors focused strictly on symptoms and the need for manual reduction was not considered. Yet, although strictly speaking this may not be a symptom, it is certainly an important sign of severity of HD and its frequency can impact on quality of life. While the work done by Sodergren and colleagues is very interesting and provides useful information about how this condition affects patients quality of life, it was validated on a small sample size (n = 45) and it is not tailored to individual patients. It takes for granted that all patients suffering with HD are affected in the same way by each individual symptom, but this may not be necessarily always the case. Furthermore, because the score for each symptom is not linear, the system is not very easy to memorise and could be difficult to use in everyday practice.
Recently, Havard et al.modified the Nystrom score considering how often the patient experiences prolapse instead of the need of manual reduction. Furthermore, they adapted the Short Health Scale (SHS), previously used in patients with inflammatory bowel disease (IBD), to HD. This system remains very faithful to the Goligher classification while considering the quality of life using the SHS.
Apart from the previously mentioned system, some authors have proposed other classificationthat are not widely used, due to their complexity.
## Diagnosis
Diagnosis should focus on a related medical history for specific symptoms and risk factors corroborated by physical examination suggestive of HD (Level of evidence: 1;
## Grade of recommendation: c).
Diagnosis of HD should start with the collection of medical history identifying symptoms suggestive of the disease and risk factors such as constipation, a low fiber diet, sedentary lifestyle, and pregnancy. History of longstanding or uncontrolled portal hypertension should be considered for differentiate HD from anorectal varices. Moreover, history of IBD and symptoms related to impaired anal continence should be investigated to plan the most appropriate treatment.
Physical examination should confirm the presence of HD ruling out other anorectal diseases. It should include inspection of the perianal tissues, anorectal digital examination, and the evaluation of hemorrhoidal prolapse degree during straining. The anorectal mucosa should be examined with an anoscope. The Sims position should be preferred because less embarrassing for the patient than prone position.
Patients with HD and rectal bleeding should undergo colonoscopy to rule out other colorectal diseases (Level of evidence: 1; Grade of recommendation: B)
In Western countries, HD is one of the most frequent causes of severe acute lower gastrointestinal bleeding. Nevertheless, rectal bleeding is a common early symptom of colorectal cancer, as well as of other colorectal diseases such as IBD, diverticular disease, and angiodysplasia. For this reason, patients with rectal bleeding should undergo colonoscopy to rule out these diseases.
Colonoscopy should be mandatory in older patients and when there is a personal and/or a family history of colorectal neoplasms or documented advanced adenoma, IBD, history of altered bowel habits, recent significant weight loss, and a laboratory findings of iron deficiency anemia or a positive fecal immunochemical test (FIT) and guaiac-based fecal occult blood test (gFOBT).
Flexible sigmoidoscopy may be associated with other screening modalities, such as gFOBT or FIT, in patients that are not willing or able to undergo colonoscopy.
Sigmoidoscopy and colonoscopy should be integrated with anoscopy that has proven to have a higher detection rate of perianal pathology.
Although an increased maximum resting anal pressure is a common finding in non-prolapsing hemorrhoids, manometry is not routinely performed for diagnosis. Furthermore, anorectal endosonography is not usually indicated for the diagnosis of HD, but may disclose a thickening of submucosal tissue as well as of the internal or external anal sphincter.
## Conservative treatments
The goal of these treatments is the control of symptoms and not the correction of pathophysiological changes.
A balanced diet with adequate fiber and oral fluid intake may improve stool consistency and is one of the main purposes of lifestyle changes of the conservative treatment for 1 3 HD. Constipation and in particular hard stool usually worsen symptoms related to the hemorrhoidal prolapse. A regular defecation with type 3 or 4 stool, according to the Bristol Stool Form Scale, without prolonged time on the toilet, to avoid straining during attempted defecation, may improve symptoms. Furthermore, the addition of anti-inflammatory agents or local steroids may be an effective first-line treatment and it should also be suggested as bridge to surgery. Local therapies such as anesthetics, antiseptics, and steroids show a temporarily relief of HD-related symptoms, but the efficacy of their prolonged application is not demonstrated and could induce local reactions or sensitization.
## Fiber and/or laxatives
Daily oral intake of fiber, either food or supplements, shows a consistent beneficial effect for HD symptoms reducing the risk of bleeding, in case of an acute event, and as the risk of not improving symptoms in about 50% and 47% of patients, respectively. Several trials show a lack of evidence regarding a direct effect on prolapse, pain and itching (Level of evidence: 1; Grade of recommendation: B).
Dietary fiber intake is generally used in patients with I-II-degree HD even if it can be effective in more advanced stages. Fiber restores the normal frequency of bowel movement thanks to the increase in fecal mass, volume, and softness. Fiber should be associated with an adequate oral fluid intake, although its efficacy in treating constipation remains controversialStimulant laxatives or osmotic agents have been shown to be effective for the treatment of HD symptoms in several randomized trials with consistent results over time in reducing the risk of bleeding as well as the risk of persisting symptoms if compared with the placebo group. However, the methodology was often too weak to draw the final conclusions and more attention needs to be given to the costeffectiveness ratio.
## Sitz bath
A sitz bath with warm water (not exceeding 40-42 °C for 3 min) is a traditional and frequently recommended remedy for a variety of anal disorders including HD. Unfortunately, the proper instructions to execute it are rarely given to patients.
There is a lack of RCTs defining the role of sitz bath with warm water in the treatment of HD-related pain (Level of evidence 2; Grade of recommendation C).
Pain relief may be related to internal sphincter relaxation with a decrease of anal resting pressureaccording to the thermosphincteric reflex described by Shafik in 1993.
Another option is to sit upon a warm water bag to avoid the vacuum below the buttocks.
Despite its benefit, it can be difficult for the patients to perform in the hospital or at home.
For this reason, another option is to sit upon a warm water bag. Furthermore, Hsu et al. demonstrated that the warm water spray method can be a safe and easily performed alternative to size bathPhlebotonics Phlebotonics has a statistically significant effect on HDrelated symptoms (bleeding, pain, itching, and symptoms recurrence) if compared with a control group(Level of evidence: 1; Grade of recommendation: B).
Phlebotonics are a heterogeneous class of drugs composed by products extracted directly from plants such as flavonoids or synthetic compounds as calcium dobesilate. They simultaneously increase the vascular tone and the lymphatic drainage, decreasing vascular capacity, and stabilizing capillary permeability. However, their precise mechanism of action is not completely understood.
They are usually well tolerated with a few adverse effects. Their main side effects are mild symptoms as headache, gastrointestinal symptoms, or tingling sensations.
Furthermore, a prolonged exposition to high levels of flavonoids (many times more than their common dietary sources), through an unbalanced diet or by supplementation, may lead to an excess of reactive oxygen species formation and subsequent deoxyribonucleic acid (DNA) damage. These effects may be relevant during pregnancy, because flavonoids can cross the placenta.
A meta-analysisincluding 14 trials and 1514 patients found that the use of flavonoids decreases the risk of worsening or persisting symptoms by 58% [relative risk (RR) 0.42 (95% confidence interval (CI) 0.
## Traditional chinese medicine
Traditional Chinese medicine is based on the use of medicinal herbs.
In the nine published trials included in a Cochrane review, the herbs are divided into two types: patent herbal medicine or the self-produced compound. The most frequent herbs used are: Radix Sanguisorbae, Radix Rehmanniae, Fructus Sophorae, Radix Angelicae Sinensis, Radix Scutellariae, and Cacumen Biotae. Their dosage is rarely reported resulting in a huge bias which limits the study reproducibility.
Traditional Chinese herbs were not proved as useful for stopping bleeding from hemorrhoids in a Cochrane Review
## (level of evidence: i; grade of recommendation: b).
## Outpatient treatments
## Rubber band ligation (rbl)
RBL is the most popular non-invasive procedureand should be used for the treatment of I, II, and III-degree HD that fails conservative treatment(Level of evidence:
## 1; grade of recommendation: b).
A rubber band is applied to the base of the internal hemorrhoid, above the dentate line to avoid severe pain, causing ischemic necrosis, fibrosis, and fixation of the remaining mucosa. Usually, the necrotic hemorrhoidal tissue drops out within the following 7-10 days.
According to a recent Italian survey of over 32,000 patients, II-degree HD is treated with RBL in over 90% of the patients. RBL is contraindicated in patients on anticoagulants or with a bleeding disorder, thrombosed hemorrhoids, concomitant anorectal sepsis, anal fissures, abscess and fistula, colitis, colorectal tumors, pregnancy, immunodeficiency, and diabetes mellitus.
Although the procedure is often avoided in patients with anticoagulants, according to one of the largest retrospective studies regarding RBL, only 2.9% of the patients taking warfarin or anti-inflammatory drugs bled post-procedure. These results were confirmed by Hite al, who demonstrated that Clopidogrel does not increase bleeding complications in the postoperative period.
A recent cost-effectiveness analysisof 2026 patients undergoing RBL for symptomatic HD with six board-certified colorectal surgeons between March 2012 and March 2017 stated that RBL had a lower average estimated cost and a lower average quality-of-life deficit per patient if compared with hemorrhoidal artery ligation (HAL), stapled hemorrhoidopexy (SH), or surgical hemorrhoidectomy. In this review, only 6% of the entire cohort required surgical treatment; meanwhile, most of the patients solved the problem with further banding procedures. In fact, repeated RBL treatment were reported in 8-10% of patients, with a recommended 4-week interval between the sessionsIn the HubBLe trial, 185 patients were assigned to the HAL group and 187 to the RBL group. Patients treated with RBL had a lower rate of pain (1 versus 5) and bleeding requiring transfusion (1 versus 2) but a higher rate of recurrence. However, patients may prefer RBL as the first-line treatment.
A Dutch national survey demonstrated the superiority of RBL for II-degree HD and of excisional procedures for IIIdegree HD.
In RBL, bleeding stops in up to 90% and improvement in II-degree HD has been shown in 93-100% of patients. Furthermore, III-degree HD improves in 78-83.8%, but IV-degree prolapse should have a more invasive treatment.
The possible minor complications of the technique include pain, bleeding, thrombosis, and skin tags.
Unfortunately, rare but severe complications such as massive gastrointestinal hemorrhage, liver abscesses, endocarditis, perineal sepsis, and also deathwere described after RBL.
## Sclerotherapy
## Injection sclerotherapy (is) should be used for the treatment of i-ii and iii-degree hd that fail conservative treatment (level of evidence: 1; grade of recommendation: b)
IS, initially described by Morgan in England in 1869, is the injection of sclerosing agents at the apex of the internal hemorrhoidal complex, above the dentate line, leading to moderate tissue destruction with scarring, fibrosis, and fixation of the hemorrhoidal tissue. Several sclerosing agents have been described and used [5% phenol in almond oil, aluminum potassium sulfate and tannic acid (ALTA), and 50% dextrose water].
Among these agents, ALTA seems to be the most effective one, even if in low resource countries, 50% dextrose water could be a safe and effective alternative.
Moser et al.in 2007 introduced foam sclerotherapy with polidocanol 3%. Subsequently, the authors compared, in a randomized, controlled, single-blind, multicenter trial, polidocanol foam with liquid polidocanol in the treatment of I-degree symptomatic HD demonstrating the superiority of the foam, after 12-week-follow-up, regarding success rate after one IS session (58/66 pts 88% vs 44/64 pts 69%; p = 0.01), number of session required for success [1.08 (± 0.32) vs 1.42 (± 0.64); p < 0.001), and total amount of injected polidocanol (35 mg (± 10) vs 85 mg (± 38); p < 0.001). Only one adverse drug reaction (acute prostatitis) was observed in the foam group. After that complication, the authors modified the injection technique placing the first injection at 11 o'clock.
Probably, the low dose of drugs used for the foam injection will lead to a decrease of the complication rate.
Several studies reported a 92-100% improvement in bleeding of patients with II-and III-degree HD with the use of IS. Resolution of prolapse was reported in 85-94% of patients with II-III-degree hemorrhoids with 5 year follow-up.
Subjective moderate/excellent improvement was reported in 70-92% of patients suffering from III-and IV-degree HD. Recurrence of prolapse is currently 15% at 1 year in unselected II degree; meanwhile, the failure rate at 1 year was reported to be, respectively, 25% and 80% in III-degree HD patients treated with ALTA and 5% phenol in almond oil.
Patients reported a relatively low rate of postoperative pain (24-49%): the intra-procedural injection was painful in up to 90%. Bleeding is rare.
Mucosal ulceration is one of the most frequent complications, reported in 3.6% of patients. Major complications including impotence, severe acute liver injury, fistula formation, fatal necrotizing fascitis, and abdominal compartment syndrome following sclerotherapy have been reported.
## Infrared coagulation
Infrared Coagulation (IRC) should be used for the treatment of I-II and III-degree HD that fail conservative treatment (Level of evidence: 1; Grade of recommendation: B).
It consists of the exposure of the internal hemorrhoids to infrared waves, resulting in a protein coagulation and necrosis, immediately visible as a white spot.
Dimitrolopoulus et al.reported a success rate of 78%, 51%, and 22%, respectively, for I-, II-, and III-degree HD with a cumulative subjective improvement of 81-93% for I-II-degree HD.
The most frequent complication of IRC is a post-procedural pain which occurs in 16-100% of patients. The incidence of postoperative bleeding is 15-44%.
Recurrence of bleeding is reported in 13% of patients at 3-month follow-up. Data are insufficient for the assessment of the long-term efficacy of the technique.
## Non-excisional procedures
## Stapled hemorrhoidopexy
SH is an effective technique for the treatment of HD. When compared with conventional hemorrhoidectomy, SH is associated with less operating time, earlier return of bowel function, shorter hospital stay, less pain, a faster functional recovery with shorter time off work, an earlier return to normal activities, and better wound healing (Level of evidence 1; Grade of recommendation: A).
However, the incidence of recurrence and the need for additional operations are also significantly higher when compared to conventional hemorrhoidectomy (Level of evidence 1; Grade of recommendation: A).
Numerous studies on short-term outcomes have demonstrated that when compared to conventional hemorrhoidectomy, SH is quicker to perform and patients experience less postoperative pain, postoperative bleeding, wound complications, and constipation. Hospital stay and time to return to normal activities were also shorter. Furthermore, the requirements for non-surgical and surgical reinterventions and the readmission rate are similar following SH and conventional hemorrhoidectomy. However, meta-analyses looking at long-term outcomes after SH and conventional hemorrhoidectomy found significantly higher recurrence rates following SH.
The higher recurrence rate was confirmed by a recently published retrospective study that analyzed the long-term outcome (15-year follow-up), of 257 patients who underwent SH. Follow-up data were available in 140 cases even if only 116 answered the questionnaire regarding recurrence. 55 patients reported the recurrence of at least one hemorrhoidal symptom and 17 patients required a further surgical treatment. Large capacity stapling devices may lead to better results, but this remains unclear.
SH is more expensive than traditional excisional surgery. The cost-utility analysis indicates that SH has < 0.1% probability of being cost-effective at £20,000 and 0.1% probability of being cost-effective at a £30,000 willingness to pay threshold
## (level of evidence: 1; grade of recommendation: a).
Although all major prospective randomised trials have failed to demonstrate any significant adverse event related to the use of SH, in up to 10% of these patients, several complications were observed. Numerous minor and major complications have been widely reported outside the major trials(Level of evidence: 2; Grade of recommendation: C).
## Transanal hemorrhoidal dearterialization (thd) or doppler-guided hemorrhoidal artery ligation (dghal)
THD or DGHAL is a treatment option for II-and IIIdegree haemorrhoids and in experienced hands possibly also for IV degree(Level of evidence: 1;
## Grade of recommendation: a).
THD/DGHAL is associated with decreased postoperative pain, reduced postoperative events, and faster recovery than excisional hemorrhoidectomy, but carries higher recurrence rates (Level of evidence: 1; Grade of recommendation: A).
Following THD, fewer patients had postoperative bleeding compared with open hemorrhoidectomy or SH. THD is associated with fewer emergency reoperations than open, closed, stapled and LigaSure™ procedures, with a high probability of being the best treatment regarding this 1 3 outcome (p = 0.710). In addition, it has been shown that compared to more invasive surgical techniques THD is associated with shorter operating time, less postoperative complications, and notably decreased postoperative pain. This resulted in a shorter length of hospital stay and an earlier time to the first bowel movement. Work or normal daily activities were also resumed quicker following THD (p = 0.09). However, Other studies demonstrated that compared with hemorrhoidectomy, dearterialization with mucopexy resulted in similar postoperative pain and morbidity and a similar 24-month cure rate .
Three studies comparing the use of Doppler to a blinded transfixation suggested that operative time was significantly longer and the postoperative pain score higher with the use of Doppler, while there was no difference in recurrence rates. However, bias regarding technique and instrumentation used in these studies make their results difficult to interpret and as such the quality of the data is not good enough for a recommendation.
When compared to SH, THD was associated with significantly less postoperative pain. Both techniques were equally effective in the short term with similar rates of complications and recurrence
## ] (level of evidence: 1; grade of recommendation: b).
The recurrence rate following THD/HAL seems to be influenced by surgical experience. Overall recurrence rate ranges between 3 and 24% (HAL 3.3-24%; THD 3-20%) with reintervention, to treat recurrent symptoms, necessary in 2.7-22% of patients (HAL 2.7-22%; THD 4.1-17.8%).
The use of a mucopexy has become a routine part of the procedure though, in patients with bleeding as the only symptom, dearterialization alone may suffice. In the presence of any degree of hemorrhoidal or mucosal prolapse, mucopexy should be added to the dearterialization. A THD technique with targeted mucopexy has been described as the best way to tailor this procedure to each individual patient.
Pain following THD can occur in up to 38% of operated patients (HAL range 0-38% of patients; THD range 0-35% of patients). Yet, in the majority of series, the incidence of postoperative pain was less than 10%. Postoperative bleeding was reported in up to 18% of patients (HAL range 0.9-18%; THD range 0-13%) and, in rare instances, required hospital admission and reintervention. Other postoperative events include tenesmus, which is more frequent in patients who underwent mucopexy, hemorrhoidal thrombosis, observed in up to 8.6% of patients (HAL range 2.3-6.7%; THD range 0-8.6%), and anal fissure (2.1% of patients; HAL range 0.9-2.1%; THD range 0.6-1.5%). Transient fecal urgency has also been reported.
## Excisional procedures
## Excisional hemorrhoidectomy
The traditional excisional methods (Milligan-Morgan, Ferguson procedures) still remain the first choice and the most common indication for symptomatic III-and IV-degree HD .
Open hemorrhoidectomy (OH) and closed hemorrhoidectomy (CH) are both efficient surgical procedures for the treatment of HD, despite the presence of some disadvantages due to the extent of dissection as well as to the presence of wounds below the dentate line with postoperative pain that can be severe delaying the return to normal daily activities. According to a recent meta-analysisof 11 RCTs and 1326 patients comparing OH and CH, the Ferguson procedure was associated with reduced postoperative pain, faster wound healing, lesser risk of postoperative bleeding, and longer procedure time (Level of evidence:
## ; grade of recommendation: a).
Radiofrequency hemorrhoidectomy is a sutureless technique dependent on a modified electrosurgical unit to achieve tissue and vessel sealing. It results in less blood loss, postoperative pain, and complications. It is technically simple, because suturing is not required and hemostasis is easy to achieve. It has the potential of making hemorrhoidectomy into a day-care regimen (Level of evidence: 1;
## Grade of recommendation: b).
Pain following hemorrhoidectomy is well described in the literature and seems to be less after radiofrequency hemorrhoidectomy. Postoperative bleeding is reported in up to 3% of patients (OH range 0.2-5%; CH range 0-4%). The overall recurrence rate is between 2 and 8% (OH 2.8-7.8%; CH 2-8%). Fecal incontinence following hemorrhoidectomy is reported as 6% with no significant difference between OH and CH. There is no difference between OH and CH regarding the rate of fecal impaction, anal stenosis, anal fissure, and some loss of the sensitive anal mucosa.
## Management of hd in special conditions
## Pregnancy
The prevalence of symptomatic hemorrhoids is higher in pregnant than in non-pregnant women.
Pregnancy and spontaneous vaginal delivery are wellestablished predisposing factors for the development of HD in females due to the increased intra-abdominal pressure from uterine growth, the hormonal changes, and constipation (38% of the pregnant females). Clinical reports demonstrated that HD is mostly prevalent in the last trimester of pregnancy and in the first month after delivery, with about 25-35% of the pregnant females suffering from this disease. In particular, thrombosed external hemorrhoids (TEH) are more frequent during the last trimester of pregnancy and immediately after delivery (7.8% and 20%, respectively). The prevalence of symptomatic hemorrhoids in pregnant females is higher with the increase in age and parity. Insufficient data exist on the safety of anti-hemorrhoidal treatment in pregnancy.
Patients with I-and II-degree HD may benefit from oral rutosides for symptom relief. However, their use cannot be recommended until new evidence about their safety is available
## (level of evidence: 1; grade of recommendation: b).
Sitz baths have been shown to be a statistically significant choice in achieving a complete healing of HD in pregnant females compared to conservative treatment with an anorectal cream (p < 0.005)
## (level of evidence: 2; grade of recommendation: c).
Although there is a tendency toward conservative treatment, hemorrhoidectomy (CH) has been successfully performed without risk to the fetus. In fact, excisional surgery should be considered, especially in case of hypotensive risk due to postoperative bleeding. In this case, excision of the symptomatic pile is required (Level of evidence: 2;
## Grade of recommendation: c).
According to Mirhaidari et al., an excision under local anesthesia in an outpatient regimen of the thrombosed pile/s can be easily performed without any special monitoring as well as any risk of preterm labor or miscarriage (Level of evidence: 2; Grade of recommendation: C).
There are no safety data available for any of the compounds commonly used for HD during pregnancy. Thus, it should be treated by increasing fiber and oral fluid intake, administering stool softeners, improving toilet habits, and sometimes by adding topical treatment.
The course of HD tends to be longer during pregnancy and most symptoms will resolve spontaneously after delivery, with a few cases requiring a surgical evaluation during pregnancy or after delivery.
## Thrombosed hemorrhoids
TEH can be easily recognized on physical examination as usually tender visible blue perianal/anal lumps. TEH most frequently causes acute and severe pain, but the severity of the symptoms depends on the size of the thrombus. Without intervention, the pain typically gets better over 2-3 days, with a continuous improvement as the thrombus gradually absorbs over several weeks. Analgesics and stool softeners may be beneficial.
Heparin treatment, a highly standardized and bioavailable mixture of flavonoids and triterpenes, topical nifedipine, and botulinum toxin injectionare reliable options especially in delaying or avoiding a surgical procedure.
Conservative treatment for prolapsed thrombosed internal haemorrhoids, if compared with urgent hemorrhoidectomy, is associated with a shorter inpatient stay and less anal sphincter damage than operative treatment .
Excision has been shown to have better results in terms of reduction of pain, recurrences, and number of skin tags in comparison to simple incision and conservative treatment with glyceryl trinitrate (GTN) (p < 0.001)
## (level of evidence: 1; grade of recommendation: b).
A literature searchconsidering 800 articles on hemorrhoids stated that excision allows better results than incision or topical GTN meanwhile symptoms last over 3 weeks with conservative treatment (Level of evidence: 1; Grade of recommendation: B). This latter can be avoided by combining topical nifedipine and lignocaine rather than using lignocaine alone (Level of evidence: 1; Grade of recommendation: B).
Thus, most patients with TEH benefit from surgical excision within 72 h of the onset of symptoms
## (level of evidence: 1; grade of recommendation: b).
These data were confirmed by Jongen and Collwho conducted a retrospective analysis of complication rates, symptom recurrences, long-term results, and patient satisfaction after outpatient excision (local anesthesia) of TEH in 340 patients. They concluded that outpatient excision of TEH under local anesthesia can be safely performed with a low recurrence and complication rate and with a high level of patient acceptance and satisfaction (Level of evidence: 2; Grade of recommendation: C).
Zuberproposed hemorrhoidectomy for TEH. He suggested that hemorrhoidectomy be performed through an elliptic incision over the site of thrombosis with removal of the entire diseased hemorrhoidal plexus in one piece. He underlined that caution must be exercised to avoid cutting into the muscle sphincter below the hemorrhoidal vessels. Infection after suture closure is rare secondary to the rich vascular network in the anal area. Stool softeners must be prescribed postoperatively to help prevent tearing at the suture line. Moreover, training and experience in general and skin surgery are necessary before the physician attempts this procedure unsupervised.
SH is a feasible treatment for selected patients with an acute hemorrhoidal crisis and has a similar complication rate if compared with a conventional excisional hemorrhoidectomy. SH is associated with less postoperative pain, shorter operation time, a shorter hospital stay, and an earlier return to normal activities(Level of evidence: II; Grade of recommendation: B). However, older patients with anemia or a prolonged hemorrhoidal crisis are unsuitable for stapled hemorrhoidectomy
## (level of evidence: ii; grade of recommendation: c).
## Immunosuppressed patients
HD is common in patients with acquired immunodeficiency syndrome [AIDS], often resulting from chronic diarrhea brought on by medications.
As suggested by Gupta, selective management will result in high rates of symptomatic relief and complete wound healing after HD surgery without excessive morbidity and mortality.
Even if the indications for hemorrhoidectomy in patients with AIDS need to be considered extremely carefully because of the high incidence of delayed wound healing, nowadays, there is no significant increase in complication rate for patients with a low CD4 + T-cell count (< 200/ μL) compared to those with a higher count
## (level of evidence: i; grade of recommendation: c).
Recently, Fan and Collreported that tissue-selecting therapy stapler (TST) for prolapsing hemorrhoids in human immunodeficiency virus (HIV)-infected patients is a safe technique with a low complication rate and minor technical difficulties, especially for HIV-infected patients who have a high satisfaction index (Level of evidence: 2; Grade of recommendation: C).
In conclusion, there is no evidence for the best treatment regarding HIV + patients with hemorrhoids. Further studies are requested to provide some scientific evidence. Moreover, no data of transplanted patients have been reported in the international literature.
## Inflammatory bowel disease
There is no consensus in the scientific literature regarding the exact indications for surgery in patients with IBD who have HD.
D'Ugo et al.suggested that first-line management should be medical therapy, considering that a spontaneous healing is possible. Despite the higher risk of complications in patients with IBD, in non-responding patients, the surgical options on a highly selective basis can be considered with acceptable results(Level of evidence: 2; Grade of recommendation: C).
## Radiation proctitis
There is no consensus in the scientific literature regarding the exact indications for surgery in patients who have had pelvic radiotherapy for malignancy. reported severe complications in the treatment of HD in patients with radiation proctitis (Level of evidence: 2; Grade of recommendation: C).
After radiation in the pelvic region, most symptoms are linked to the radiotherapy and not to the HD. For this reason, any invasive procedure for benign disease, especially for hemorrhoidal-like symptoms, must be strongly discouraged.
## Coagulopathies
The frequent use of anticoagulants has likely led to an increased incidence of bleeding in patients with a clinically significant internal hemorrhoids. Society guidelines recommend that anticoagulation be suspended prior to hemorrhoidal surgery and procedures.
However, there is no consensus regarding the exact indications for surgery in patients with HD affected by coagulopathy.
As already described, Hite et al.reported that the risk of a bleeding complication after RBL for HD does not appear to be increased in patients taking clopidogrel (Level of evidence: 1; Grade of recommendation: C). These results were confirmed by Atallah et al.who reveal that THD can be performed on anticoagulated patients without cessation of oral agents without an increased risk of postoperative bleeding. Nevertheless, Albuquerquesuggested that secondary bleeding normally occurs 10-14 days after RBL and patients taking anti-platelet and/or anti-coagulant medication have a higher risk, with some reports of massive life-threatening hemorrhage (Level of evidence: 2; Grade of recommendation: C).
## Emerging technologies
## Embolization of the hemorrhoidal arteries
Embolization of the hemorrhoidal arteries, the so-called "Embhorroid technique", was first described for the treatment of HD in 2014 by Vidal et al..
It consists in the embolization of the hemorrhoidal arteries, in which arterial occlusion is achieved through an endovascular approach (usually transfemoral) using coils placed in the terminal branches of the superior rectal arteries. The use of polyvinyl alcohol (PVA) particles of 0.3 mm and metallic coils seems to be more effective in symptom relief than the use of metallic coils alone. In fact, the use of 0.3 mm particles determines a more distal hemorrhoidal plexus embolization reducing the reloads by the middle rectal arteries and avoiding rectal ischemia, because the particles do not pass the inferior rectal artery anastomoses.
It could be performed in an outpatient setting and has been shown to be a safe and effective technique for the 1 3 treatment of II-III-degree HD(Level of evidence:
## 2; grade of recommendation: c).
It should be reserved for a selected group of patients with disabling and refractory hemorrhoidal symptoms and without irreducible prolapse(Level of evidence: 2;
## Grade of recommendation: c).
Emborrhoid showed good bleeding control in patients with contraindications for conventional surgery with a clinical score improvement in 72% of cases after the first embolization session(Level of evidence: 1; Grade of recommendation: C).
## Help
HeLP is the acronym for Hemorrhoidal Laser Procedure and is based on the application of a 980-nm diode causing shrinkage of the terminal branches of the superior hemorrhoidal artery.
To carefully detect the superficial arteries at approximately 2.5 cm above the dentate line, a 20 MHz Doppler transducer is used. The laser energy delivered at 980 nm wavelength at that level induces a shrinkage up to a depth of 4 mm, thus reducing the blood flow.
HeLP has been shown to be safe, effective, and easy to perform. It is an effective alternative for the treatment of symptomatic hemorrhoids, especially with bleeding and pain as prominent symptoms, in the absence of severe mucosal prolapse even if an improvement of the latter has been described. This procedure can be also associate with rectoanal repair or with mucopexy (Level of evidence: 1;
## Grade of recommendation: c).
This novel technique shares the rationale of the HAL and THD procedures but with the potential advantage of being less invasive and not requiring general anesthesia(Level of evidence: 1; Grade of recommendation: C).
The most common intraoperative procedure-related complication reported is postoperative bleeding, ranging from 5.9% to 8.8% of cases with more than a half of them needing an hemostatic procedure
## (level of evidence: 2; grade of recommendation: c).
Short-and long-term postoperative complications rate is very low with pain as the most significant postoperative symptom. It required medications for an average of 3 days after surgery in around 9.5% of patients. Anyway, it has also been reported a case of life-threatening condition in which it was necessary to fashion a diverting stoma due to bowel obstruction after a postoperative rectal hematoma.
Symptoms recurrence ranges from 10 to 20% for II-IIIdegree HD(Level of evidence: 2; Grade of recommendation: C).
## Laser hemorrhoidoplasty
Laser hemorrhoidoplasty (LHP) is based on the application of the laser beam inside the hemorrhoidal tissue. After making a 1-mm opening at the cutaneous anal edge of the hemorrhoidal pile, the fiber is introduced inside the tissue parallel to the anal sphincter as well as to the rectal axis. The fiber is then pushed up to the upper part of the piles and three pulses at a power of 15 W are delivered. This maneuver is repeated thorough the same hole but in different directions. The laser beam induced a shrinkage of underlying tissues up to approximately 5 mm of depth.
LHP seems to reduce postoperative pain, intraoperative bleeding, and the need of postoperative analgesics if compared with Milligan-Morgan procedure, with a complete resolution of symptoms in about 70% of cases(Level of evidence: 2; Grade of recommendation: B).
It is associated with shorter operative time and less postoperative pain compared to excisional surgery. Furthermore, in a recent observational study concerning 50 patients with II-and III-degree HD, Brusciano et al.reported a quick return to daily activity 1 day (40%) and 2 days (100%) after the procedures. (Level of evidence: 2;
## Grade of recommendation: c).
After a mean follow-up of 5.4 years, recurrences was reported in 39% and 33% of patients with II-and III-degree HD, respectively, without any statistically significant differences related to the degree of HD (p = 0.761) (Level of evidence: 1; Grade of recommendation: C).
## Complications of surgical treatments for hd
1. Open and closed hemorrhoidectomies have a significantly more severe negative impact in the early postoperative period than stapled, THD, LigaSure™, and Harmonic™ hemorrhoidectomies (Level of evidence:
## 1; grade of recommendation: b)
Various studies have shown that the closed and radiofrequency hemorrhoidectomies had significantly more postoperative complications (mainly pain) than the open, stapled, LigaSure™, Harmonic™, and THD procedures. Furthermore, OH and CH were associated with greater operative blood loss and a longer operating time compared with the other surgical techniques. Nevertheless, a low recurrence rate is perceived to be the most important advantage of OH and CH which were found to have a lower recurrence rate than THD and SH. Moreover, the use of energy devices such as LigaSure or Harmonic may reduce complication rate, even if with increased costs. Overall procedural complication rates of SH ranged from 2 to 68%. However, these complications may typically occur in about 16% of procedures.
The overall complication rates after SH and THD were comparable with no significant differences. Despite a more favourable postoperative period for SH or THD/DGHAL techniques, some procedure-specific complications have been described, and should be considered during preoperative discussion with the patients regarding indications for surgery.
Early fecal urgency after SH has been reported, with incidence rates of 0-25%, and a median of 8%.
On the other side, postoperative tenesmus was reported in up to 24% of patients and pruritus in up to 15% after DGHAL, especially if mucopexy was contemporary performed.
Several studies described different complication rates following office procedures (such as RBL, sclerotherapy, and infrared coagulation), ranging from 3% to 18.8%. A review of 39 studies including 8060 patients who had RBL revealed post-banding complications in 14% of the patients, although severe complications are rarely reported.
Urinary retention is one of the most common complications after surgery for HD, with incidence rates of 3-50% with most studies reporting a rate around 15%.
## Emergency reoperation may be required in about 2% of patients after a surgical treatment for hd (level of evidence: 1; grade of recommendation: b)
Up to 90% of emergency reoperations are needed to stop a postoperative bleeding. Interestingly, most patients will not have an identifiable source of bleeding by the time which they are examined in the operating room. However, these bleeding episodes can be significant and a return to the operating room for a second look may be justified. Intractable pain, hematoma incision, residual hemorrhoidal thrombosis, and sepsis are other possible indications for reoperation.
A network meta-analysis of the trials reporting on reoperation showed that THD/DGHALprocedures were associated with significantly fewer reoperations than open, closed, stapled, and LigaSure™ procedures, in large part due to lower bleeding rate. However, THD had a higher recurrence rate than open, closed, LigaSure, laser, and radiofrequency hemorrhoidectomy, and therefore, the highest probability of being the worst treatments regards recurrence of hemorrhoids. For conventional hemor rhoidectomy (Milligan-Morgan and Ferguson) and bipolar energy device hemorrhoidectomy (LigaSure), rates of bleeding between 0 and 49% have been reported. Clinically significant bleeding has been reported in 0.3-6% of patients, with an average of around 2%, and need of reintervention between 1-2%, without a significant difference in rates of bleeding between the procedures.
Early bleeding was the most common complication after SH, with the overall rate following the procedure ranging from 0 to 68% (median 7.5%) with < 1% of postoperative bleeding requiring treatment.
Bleeding after Doppler-guided hemorrhoidal dearterialization has been reported to be low (0-22%, median 4.3%); however, this needs to be balanced with the chance of long-term recurrence.
Bleeding after RBL normally occurs between 5 and 14 days after treatment, probably due to the sloughing of the ligated hemorrhoids.
However, when RBL was compared to HAL, recurrence rates (if RBL was repeated), symptom scores, complications (such as postoperative bleeding), quality-of-life score, and continence score were similar, although patients had more pain in the early postoperative period after HAL. HAL was also more expensive and was not found to be cost-effective compared with RBL in terms of incremental cost per quality-adjusted life-year.
4. Pain: The higher levels of pain related to OH and SH compared to other techniques resulted in a longer hospital stay and a later return to normal activities. A multimodal pain reliever regimen should be used to promote a faster recovery, prevent urinary retention, and improve patient satisfaction (Level of evidence: 1; Grade of recommendation: B)
Compared to excisional hemorrhoidectomy, THD and SH are followed by less postoperative pain. A number of modifications in surgical and postoperative management have been proposed and attempted to reduce the pain, with variable results.
Topical 2% Diltiazem or GTN ointment demonstrated a significant pain reduction in randomized trials.
Lateral sphincterotomy or botulin toxin injection also demonstrated efficacy in reducing postoperative pain, suggesting a possible role of sphincteric spasm in its pathogenesis. However, the risk of developing temporary or permanent anal continence alterations limits the use of sphincterotomy.
The use of oral metronidazole in controlling postoperative pain was recently evaluated in two meta-analysis with conflicting results.
Several other treatments such as mesoglycanwere recently used for pain after hemorrhoidectomy, but further trials are needed to reach agreement.
## 3
The reported incidence of postoperative pain ranged from 0 to 38% with a pooled value of 15% after THD procedure.
Pain after SH has been attributed to the involvement of the staple line on the sensitive squamous epithelium of the anoderm, inclusion of smooth muscle, or surrounding anorectal tissue in the scar, and induction by the staple line of an inflammatory response in the rectal ampulla, sphincter or rectal spasm, elevated anal resting pressures, retained staples, fibrosis around the staple line, wound dehiscence, and sepsis. Although chronic pain after SH has been variably reported, it is typically experienced by less than 2% of patients.
Treatment of chronic pain following HD surgery should be targeted to the underlying source. However, it is usually quite difficult to manage and cure, which emphasizes the importance of proper knowledge of the anatomy and careful use of surgical techniques.
Warm sitz baths and non-steroidals therapies can relieve mild pain. Antispasmodics such diazepam or cyclobenzaprine may be added if levator spasm is noted. Post evacuatory pain may be treated with oral nifedipine. Anismus may be treated with botulinum toxin injection. For selected cases, sacral neuromodulation has also been described.
In case of chronic pelvic pain after stapler surgery, the removal of staples or staple line excision has been reported. However, the evidence of these treatments is low and effectiveness observed only in a low percentage of patients.
Urinary retention after hemorrhoidectomy is often multifactorial, with pain as one of the major issues, causing symptoms through irritation of pelvic nerves and activation of pain-evoked reflexes.
Some risk factors are not modifiable (age, male sex, and type of surgery).
In general, epidural and spinal anesthesia have been associated with higher rates of urinary retention compared with monitored anesthesia care. Opioids or excess intravenous fluid has also been shown to significantly increase the risk of urinary retention. Usually, most problems with urinary retention are self-limited, and will resolve without major intervention. An adequate control of pain is a key point in prevention and treatment. Patients with mild retention are often counseled to sit in a bath of very warm water, filled above the waist. When this is unsuccessful, patients may require bladder catheterization. This may involve intermittent straight catheterization or a temporary indwelling catheter, which can typically be removed after a few days without further testing. Α1 antagonists such as tamsulosin can be helpful, and attempts to minimize opioid intake is also worthwhile. Severe septic complications have been reported after all types of treatments of hemorrhoids, and their real incidence is probably underestimated.
Complications such as rectal perforation, pelvic sepsis, abdominal peritonitis, pneumo-retroperitoneum or mediastinum, pulmonary septic embolism, liver abscess, and Fournier's gangrene, with several deaths, have been reported.
Several infectious complications have also been reported following office procedures (such as RBL, sclerotherapy, and cryotherapy) including pelvic sepsis, Fournier's gangrene, liver abscesses, tetanus, and bacterial endocarditis. Deaths due to these infectious complications have been reported too.
Even if surgery is usually considered mandatory after serious septic complications, and colostomy often performed, successful conservative treatments (medical, percutaneous drainage) have been reported in selected cases.
The majority of patients in whom these complications occurred were healthy before surgery, and no predisposing factors had been identified. However, it is well known that digital, surgical, or instrumental manipulation of the rectum is associated with a possible 0-9.5% of transient bacteraemia, often with no clinical effects. Escherichia coli and Bacteroides are the predominant organisms that cause infection following hemorrhoidectomy. The efficacy of a routine use of prophylactic antibiotics has yet to be proven, although special consideration should be given in immunocompromised patients.
6. Long-term complications: Anal stenosis, soiling, and alterations of anal continence or residual skin tags have been reported after all the treatments for hemorrhoids, without any significant difference among the surgical treatments (Level of evidence: 1; Grade of recommendation: B)
Complications after hemorrhoid surgery are not always immediate, and can instead take months or years to fully develop. In general, they can be more severe and more difficult to treat than those occurring in the immediate postoperative period.
Fifty-one trials (4793 participants; 11 treatments) reported on the proportion of patients complaining of 1 3 difficulty voiding owing to outlet obstruction or anal stenosis/stricture at follow-up.
Anal stenosis has been reported after stapled or excisional hemorrhoidectomy in 1-7.5% of cases. In these patients, the normal pliable anoderm is replaced by scar tissue due to excessive removal of the anoderm and distal rectal or to other factors that interfere with the normal healing process. Concomitant injury of the underlying anal sphincter muscle may also occur and contribute to the functional and anatomical alteration. A functional stenosis, due to muscle hypertonicity, should be considered when planning treatments.
Patients often report straining at defecation, smaller caliber stools, and pain at defecation. Anal stenosis may also lead to fecal impaction and overflow incontinence.
Anal stenosis may be classified, according to the severity of the stricture, as mild, moderate, or severe, but its management is usually determined by the severity of symptoms rather than the degree of stenosis. Mild strictures can often be treated with dietary modifications, stool softeners, or fiber supplements. Digital dilatation or the use of anal dilators can be part of the treatment plan if medical management is not sufficient. Patients with moderate or severe strictures who have failed conservative management usually require surgical intervention. To determine the proper surgical procedure, the degree of involvement of the anoderm and the sphincter muscle complex must be determined. In case of fibrotic anal sphincter, sphincterotomy (unilateral or bilateral) may be considered. On the contrary, patients with stenosis of the anoderm are usually treated with flap (multiple types) or anoplasty, aiming to replace local fibrosis with healthy, elastic tissue. Flap procedures and sphincteroplasty can be associated, in selected patients, while simple release of a stricture may provide temporary relief of symptoms, but generally should be avoided because of the high rate of recurrence.
Fifty-three trials (3856 participants; 9 treatments) reported on the proportion of patients experiencing soiling or difficulty with hygiene or incontinence at follow-up after different types of treatment for HD.
Incontinence to feces and/or flatus was reported, with an overall incidence rate of 0.1-17.8%. However, whether this complication was transient or permanent was often not clearly specified.
Incontinence after hemorrhoidectomy is usually associated with partial-or full-thickness internal (and occasionally external) anal sphincter injury, but it can occur also with intact sphincters, as the hemorrhoidal cushions are known to provide 15% of the patient's resting anal tone, and their removal can be functionally disadvantageous. Excision of hemorrhoids with secondary healing may also cause decreased sensitivity and reduced capacity for rectoanal discrimination.
Fecal incontinence can also occur after a procedure for prolapse and HD (reported in up to 5% of patients), and it has been related to a low-placed staple line, to an injury to the internal sphincter due to the large diameter of the circular stapler, or to an alteration of anorectal sensitivity or compliance. In a prospective, randomized trial of 134 patients, de novo fecal incontinence at 1 year was reported in 2.5% of patients who had SH compared with 7.5% of patients who had a Milligan-Morgan hemorrhoidectomy.
Compliance with ethical standards.
## Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval Not required.
## Informed consent not required.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.
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Action on diabetic macular oedema: achieving optimal patient management in treating visual impairment due to diabetic eye disease
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Action on diabetic macular oedema: achieving optimal patient management in treating visual impairment due to diabetic eye disease
Eye (2017) 31, S1-S20 Official journal of The Royal College of Ophthalmologists www.nature.com/eye -Consultant Retina Specialist J 'We really need more ability to intervene with diabetes patients to encourage behaviour change, but we just don't have the time or resources or links to other services. All I can really do is tell them what they should be doing and hope they listen.' -Consultant Retina Specialist K Perspectives, in the words of DMO patients J 'The best thing I ever did was the Dose Adjustment For Normal Eating (DAFNE) course. I learnt about diet and exercise and how to manage my insulin and my diabetes.' -Compliant DMO patient J 'I was really upset when I got the diagnosis (of diabetes), I didn't want to have a disease and certainly not one that would ruin my life.' -Non-compliant DMO patient K Experience of the DMO journey, in the words of DMO patients J 'The reaction in my eyes was caused by a dramatic drop in my glucose levels. I was told it may have dropped too quickly and affected the vessels in my eyes.' -Compliant patient J 'I was in bits when they told me I had DMO. It is bad enough being diabetic and now I could go blind! I felt like my life had ended and then they tell me I needed to have an injection in my eye and that was terrifying beyond belief.'-Non-compliant DMO patient Guideline S10 EyeTable 7Online sources of patient information and resources K Diabetes J Diabetes UK. The leading charity that cares for and campaigns for people affected by or at risk of diabetes.J http://www.diabetes.org.uk/ J Following a change in measurement reporting of HbA1c, Diabetes UK has developed an easy-to-use online HbA1c converter, for conversion of old (percentage units) and newer higher order measurements in millimoles per mol (mmol/mol).J http://www.diabetes.org.uk/HbA1c J Leicestershire Diabetes Service provides an extensive online diabetes resource.
# Introduction
Diabetes has been estimated to affect over 8% of the world's population and, as a significant cause of mortality and major morbidity, is now posing one of the greatest challenges for our healthcare systems.The global prevalence of diabetes is set to double over the next 20 years, with the vast majority of this increase related to type 2 diabetes.As such, type 2 diabetes is increasingly recognised as a disease pandemic that is arguably one of the largest global health emergencies of the 21st century.There is therefore an increasing need for knowledge, skills, resources, and infrastructure to deliver the comprehensive healthcare needed to meet the complex demands of this progressive condition. Health policy and interventions should focus on diabetes prevention and early detection, including diabetic eye screening, as well as rehabilitation and long-term care of patients affected by wide-ranging complications of diabetes, such as end organ failure, blindness or amputation.
Healthcare professionals often work in isolation to deliver highly specialised care efficiently and effectively for the individual patient with diabetes and its effects on multiple organ systems. It is not uncommon for a patient to be making frequent visits to community clinics and different hospital clinics to see a variety of specialists and allied healthcare professionals, with seemingly little opportunity for coordination of this complex health management programme between the wider team involved. In a field that is so diverse and rapidly changing, healthcare professionals of all specialties need to be aware of developments across all aspects of diabetes management.
In this article, the authors provide an update for ophthalmologists and allied healthcare professionals on diabetes prevalence, the perspective of the diabetologist on what an ophthalmologist needs to know about diabetes, including developments and challenges in diabetic retinopathy screening. In addition, the paper discusses qualitative research assessment of treatment adherence and patient experience, the role of the diabetes specialist nurse (DSN) and practice principles for the management of people with diabetic eye disease. Summaries with concise 'take home' messages from each topic are provided to enable the reader to easily focus on or refer to specific issues or areas of interest.
## Diabetes is an escalating global health challenge
The World Health Organization (WHO) estimates that the global age-standardised adult prevalence of diabetes has nearly doubled since 1980, rising from a prevalence rate of 4.7% in 1980 to 8.5% of the adult population in 2014 and reflecting an increase in associated risk factors.The rise in the age-standardised adult prevalence of diabetes is compounded by population growth and ageing, with older adults accounting for a larger proportion of the population in developed countries. [bib_ref] Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based..., Ncd-Risc [/bib_ref] Type 2 diabetes, consequent upon complex pathophysiology but effectively driven by defective energy homoeostasis and closely linked with obesity (body mass index ≥ 30 kg/m 2 ) and physical inactivity, accounts for the majority of people with diabetes worldwide.Prevalence data, estimated by the Non-Communicable Diseases (NCD) Risk Factor Collaboration, were pooled from population-based studies that had collected data on diabetes through measurement of its biomarkers to arrive at estimated trends in diabetes prevalence since 1980. [bib_ref] Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based..., Ncd-Risc [/bib_ref] Diabetes was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L; a history of diagnosis with diabetes; or use of insulin or oral hypoglycaemic drugs. The International Diabetes Federation (IDF) estimates there were 415 million adults aged 20-79 years with diabetes worldwide in 2015, including 193 million undiagnosed [fig_ref] Table 1: Global prevalence estimates and healthcare expenditures 2015 and projection for 2040 a [/fig_ref].An estimated 1.5 million deaths in 2012 were directly caused by diabetes, and another 2.2 million deaths were attributable to hyperglycaemia.Diabetes and the management of related complications accounted for 12% of total healthcare expenditure worldwide in 2015, with over 80% of this expenditure being driven by the costs of complications.The direct annual cost of diabetes in the world is estimated at US $825 billion based on diabetes prevalence projections for 2014. [bib_ref] Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based..., Ncd-Risc [/bib_ref] Three-quarters of the global expenditure on diabetes was for people aged between 50 and 79 years, reflecting a higher prevalence of diabetes and of diabetes complications in this burgeoning age group.Prevalence estimates of United Kingdom adult diabetes approach 1 in 10. The WHO estimates a UK diabetes prevalence rate of 7.7% in 2014.The estimated number of UK adults with diabetes in 1980 was 2.3 million, increasing to an estimated 3.8 million adults with diabetes in 2014. [bib_ref] Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based..., Ncd-Risc [/bib_ref] Approximately 90% of people with diabetes have type 2 diabetes. [fig_ref] Table 2: Estimates of diabetes prevalence in the United Kingdom 2016 a [/fig_ref] shows estimates of diabetes prevalence in the adult population across the United Kingdom for 2016: 3.6 million people have diagnosed diabetes and a further 1 million with undiagnosed diabetes.Prevalence estimates prepared by Public Health England's National Cardiovascular Intelligence Network indicate that around 9% of the adult population in England in 2015 has diabetes and this prevalence rate is projected to increase to 9.7% by 2035.Diabetes prevalence rates increase with age, from 9.0% for people aged 45-54 years to 23.8% for people aged 75 years and older [fig_ref] Figure 1: Expected diabetes prevalence [/fig_ref]. According to Public Health England, 2% of adults aged 16-44 years have diabetes, equating to 400 000 people and accounting for 10% of total estimated diabetes cases.Clinical commissioning groups (CCGs) with the highest estimated diabetes prevalence have high proportions of South Asian and black ethnic groups and high levels of deprivation, reflecting the well-recognised association between ethnicity and deprivation with incident diabetes risk. [bib_ref] Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between..., Sharma [/bib_ref] [bib_ref] Predicting risk of type 2 diabetes in England and Wales: prospective derivation..., Hippisley-Cox [/bib_ref] The analysis and comparisons with the 2014/15 Quality and Outcomes Framework suggest that 76% of people with diabetes have been diagnosed and are included on General Practice (GP) registers, that is, 24% of people with diabetes are undiagnosed.
Hamer et al 8 found a nearly doubling in the prevalence rate of diabetes over the 5-year period between 2003 and 2008 in Scotland, which increased from 5.2% in 2003 to 9.4% in 2008. Imkampe and Gulliford 9 similarly identified increasing diabetes prevalence rates in United Kingdom. Prevalence of diagnosed diabetes increased in men from 3.74% in 1994 to 7.25% in 2006 and in women from 2.28 to 4.88% (prevalence based on self-reported diabetes diagnosed by a doctor). The IDF estimates a diabetes prevalence rate in Ireland of 5.3% in adults aged 20-79 years in 2015, 2 with 171 800 adults having diagnosed diabetes Diabetes-related health expenditure in the United Kingdom was estimated at US $13 billion in 2015.The nation is ranked one of the top ten countries for diabetesrelated healthcare expenditure. 2 National Diabetes Audit (United Kingdom and Wales), key findings, and recommendations. The National Diabetes Audit (NDA) provides a comprehensive overview of diabetes care in United Kingdom and Wales. The audit collects information from both primary and secondary care. Participation for the 2014-2015 NDA report was around 4700 GP practices (57%) and 99 specialist services, capturing information on 1.9 million people with diabetes, with the national participation rate lower than in previous years (70.7% national participation rate in the audit year 2012-2013).Annual care processes recommended by the National Institute for Health and Care Excellence (NICE) for all people with diabetes aged 12 years and older encompass blood tests (glycated haemoglobin (HbA1c), serum creatinine, cholesterol), blood pressure, urine albumin, foot surveillance, body mass index, and smoking history, which is the responsibility of Diabetes Care Providers.Annual digital retinal screening, also recommended by NICE, is the responsibility of National Health Service (NHS) Diabetic Eye Screening. The percentage of people with diabetes in United Kingdom and Wales receiving all eight NICE recommended care processes by Diabetes Care Providers in the audit year 2014-15 was 38.7% for people with type 1 diabetes and 58.7% for people with type 2 diabetes.Blood tests and blood pressure checks are more reliably performed than other care processes.Encouraging trends of improvement in blood pressure control for people with type 1 and type 2 diabetes and glucose control for type 1 diabetes were observed in the NDA audit report 2013-2015.However, people aged under 40 are much less likely to receive their care processes and those under 65 with either type 1 or type 2 diabetes are much less likely to achieve recommended treatment targets for HbA1c, blood pressure and cholesterol compared with those aged 65 years and older [fig_ref] Figure 2: Percentage of all people with diabetes in United Kingdom and Wales achieving... [/fig_ref].There remain appreciable variations in care process completion and treatment target achievement between practices, between specialist services and between CCGs and Local Health Boards (LHBs).Furthermore, 75% of people newly diagnosed with diabetes were offered structured education in UnitedChronic hyperglycaemia can seriously affect the cardiovascular system, eyes, kidneys, and nerves, and in almost all high-income countries, diabetes is a major cause of cardiovascular disease, blindness, kidney failure and lower-limb amputation. 2 Report 2 from the National Diabetes Audit for 2012-2013 presents findings on diabetes complications and mortality in United Kingdom and Wales.It shows that people with diabetes are considerably more likely than people without diabetes to be admitted to hospital with angina, myocardial infarction, heart failure and stroke, and are at far greater risk for a major amputation and renal replacement therapy. The risk of a person with diabetes being admitted to hospital for heart failure is 126% greater than among those without diabetes, while the risk of major amputation (above the ankle) is 400% higher.Furthermore, hospital length of stay is considerably greater for people with diabetes than those without, [bib_ref] Healthcare resource implications of hypoglycemiarelated hospital admissions and inpatient hypoglycemia: retrospective record-linked..., Mcewan [/bib_ref] [bib_ref] Associations between adherence and outcomes among older, type 2 diabetes patients: evidence..., Boye [/bib_ref] further compounding the economic and healthcare system implications of the condition.
People diagnosed with diabetes are often active and working, faced with the challenge of attending numerous other medical appointments in cardiology, ophthalmology, renal assessment, endocrinology, and dietetics. Strain et al [bib_ref] Time to do more: Addressing clinical inertia in the management of type..., Strain [/bib_ref] reported survey findings that physicians had low expectations of their diabetic patients in terms of attaining glycaemic control targets and following advice on diet and physical activity. Moreover, only a small proportion of diabetes patients believed lifestyle changes were important and the majority failed to comply. [bib_ref] Time to do more: Addressing clinical inertia in the management of type..., Strain [/bib_ref] In terms of recall, people with diabetes had at best a rudimentary understanding of the risk of complications and the importance of good glycaemic control. Only 25% of patients surveyed in this multicountry evaluation reported being worried about developing type 2 diabetes complications. 15 People with diabetes are encouraged to help manage their own disease through diet and exercise, blood pressure and glucose monitoring and insulin administration where indicated. The primary focus of clinical diabetes care revolves around a multidisciplinary team-based proactive approach to optimise risk factor control and thus minimise the risk of diabetes-related complications.
Early and sustained glycaemic control is important. Longterm prospective studies, some involving follow-up over several decades, underscore the benefit of early and sustained proactive glycaemic control in managing diabetes. These assessments conclusively show that reducing hyperglycaemia decreases the onset and progression of microvascular complications, such as retinopathy and nephropathy, in people with both type 1 and type 2 diabetes. [bib_ref] 10-year follow-up of intensive glucose control in type 2 diabetes, Holman [/bib_ref] [bib_ref] Update to a position statement of the American Diabetes Association and the..., Inzucchi [/bib_ref] The Diabetes Control and Complications Trial (DCCT), a randomised clinical trial with mean follow-up of 6.5 years, showed that intensive glycaemic control effectively delays the onset and slows the progression of clinically important diabetic retinopathy (DR) (change of at least three steps from baseline that was maintained for at least six months), including vision-threatening retinopathy, nephropathy, and neuropathy in patients with insulindependent diabetes.Intensive treatment reduced the mean risk for development of retinopathy by 76% as compared with conventional therapy and slowed the progression of retinopathy by 54%.An observational follow-up study of the DCCT cohort demonstrated a significantly lower incidence of further DR progression in the intensive treatment group (hazard reduction 53-56%). The results indicate a durable beneficial effect, reinforcing the need for optimising glycaemic control as early as possible in patients with diabetes. [bib_ref] Diabetic retinopathy and other ocular findings in the diabetes control and complications..., Aiello [/bib_ref] The landmark UK Prospective Diabetes Study (UKPDS) was a large, multicentre, randomised controlled trial that compared the long-term effects of intensive blood glucose control (aim of fasting plasma glucose of o6 mmol/l) and conventional dietary treatment on the risk of microvascular and macrovascular complications in people with type 2 diabetes. Long-term follow-up resultsshow that: K Haemoglobin A1c was 53 mmol/mol (7.0%) in the intensive group compared with 63 mmol/mol (7.9%) in the conventional group over 10 years.
K Intensive blood glucose control substantially decreased the risk of diabetic microvascular complications in type 2 diabetes.
K Compared with the conventional treatment group, there was a 25% risk reduction (7-40, P = 0.0099) in the intensive group in microvascular endpoints, including the need for retinal photocoagulation.
Another study by the UKPDS Group, involving hypertensive patients with type 2 diabetes and a median follow-up of 8.4 years, showed that tight blood pressure control (144/82 mm Hg) achieved a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of DR, and deterioration in visual acuity.After 9 years of follow-up, the group assigned to tight blood pressure control had a 47% reduced risk (7-70%, P = 0.004) of deterioration in visual acuity by 3 or more lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.Ten-year non-interventional post-trial monitoring was undertaken to determine whether improved glucose control persisted and whether such therapy had a longterm effect on macrovascular outcomes. Results revealed a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause in the patient group originally assigned to receive intensive glucose-lowering therapy. [bib_ref] 10-year follow-up of intensive glucose control in type 2 diabetes, Holman [/bib_ref] Relative risk reductions persisted at 10 years for microvascular disease (24%, P = 0.001). This was despite an early loss of between-group differences in HbA1c levels after the first year of post-trial monitoring. [bib_ref] 10-year follow-up of intensive glucose control in type 2 diabetes, Holman [/bib_ref] Multiple risk factor intervention for hyperglycaemia, hypertension, and dyslipidaemia. Sustained beneficial effects on vascular complications from intensive proactive multiple risk factor intervention was demonstrated in the Steno-2 Study, which involved 160 patients with type 2 diabetes and persistent microalbuminuria. [bib_ref] Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes, Gaede [/bib_ref] With a mean follow-up of 7.8 years, results show that the relative risk of developing kidney, eye, and nerve complications all remained diminished by about 50% for the intensivelytreated group, treated with angiotensin-convertingenzyme (ACE) inhibitors, statins, and glucose-lowering drugs. The impact of such an approach is highlighted by the fact that seven people in the conventional group became blind in one eye, compared with only one person in the group assigned to intensive therapy. [bib_ref] Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes, Gaede [/bib_ref] Patients in the Steno-2 Study were subsequently followed observationally for a mean of 5.5 years. The intensive goal-directed multifactorial intervention group demonstrated sustained beneficial effects with regard to vascular complications as well as all-cause and cardiovascular complications. [bib_ref] Effect of a multifactorial intervention on mortality in type 2 diabetes, Gaede [/bib_ref] These data thus clearly illustrate the benefit of a proactive target driven multifactorial risk modification approach to optimising outcomes in people with type 2 diabetes.
Proactive clinical management of diabetes and co-morbidities, emphasis on patient-centred care. Given the evidence of benefit and supported by both national and international guidelines, a major focus for the care of people with type 2 diabetes is the achievement and maintenance of optimal glucose control early within the natural history of the condition. [bib_ref] Update to a position statement of the American Diabetes Association and the..., Inzucchi [/bib_ref] The clinical paradigm in managing glucose control centres on individualisation of therapy as there are many effective glucose-lowering agents to choose from when tailoring individual antihyperglycaemic treatment strategies for patients with type 2 diabetes. A stepwise approach is typically adopted, advancing from initial single drug therapy to dual combination and triple drug combination therapy when needed. Insulin therapy is considered a key component of any combination regimen when hyperglycaemia is severe. [bib_ref] Update to a position statement of the American Diabetes Association and the..., Inzucchi [/bib_ref] Treatment targets and strategies should be individualised based on a patient-centred approach [fig_ref] Table 3: Recommended approach to the management of hyperglycaemia in patients with type 2... [/fig_ref]. This is reinforced in an updated joint position statement from the American Diabetes Association and the European Association for the Study of Diabetes. [bib_ref] Update to a position statement of the American Diabetes Association and the..., Inzucchi [/bib_ref] Personalisation of treatment is recommended, balancing the benefits and risks of glycaemic control, taking account of the potential risk of hypoglycaemia and other adverse effects and the patient's age and health status. [bib_ref] Update to a position statement of the American Diabetes Association and the..., Inzucchi [/bib_ref] Glycaemic control needs to be combined with a comprehensive cardiovascular risk factor reduction programme, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, and lipid management. [bib_ref] Update to a position statement of the American Diabetes Association and the..., Inzucchi [/bib_ref] Personalised management plans for patients with type 2 diabetes should therefore encompass glycaemic control and effective blood pressure and lipid management.
The initial management of type 2 diabetes involves advice and education about the potential benefits of dietary modification and lifestyle change, including increased physical activity. An early objective is to improve metabolic control through body weight reduction and thereby potentially improve insulin sensitivity.Many patients with diabetes however will require pharmacological therapy over time and often require escalation of treatment intensity. Only one in four patients in the UKPDS trial maintained an HbA1c level below 53 mmol/mol (7%) after 9 years without either oral agents or exogenous insulin.Over one-third of patients taking oral glucose-lowering medications report hypoglycaemic symptoms during the past year, which limited treatment satisfaction and therapy adherence. [bib_ref] Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients..., Peyrot [/bib_ref] [bib_ref] Hypoglycaemic symptoms, treatment satisfaction, adherence and their associations with glycaemic goal in..., Guisasola [/bib_ref] Fear of hypoglycaemia drives poor therapy adherence and is one of the major barriers to the achievement of good glucose control from both a patient and healthcare professional perspective. [bib_ref] Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients..., Peyrot [/bib_ref] In addition, severe hypoglycaemia has been identified as an independent risk factor in the aetiology of diabetesrelated co-morbidities, [bib_ref] Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis, Goto [/bib_ref] while hypoglycaemia along with rapid improvements in glucose control contribute to an increase in retinal complications and blindness. Furthermore, severe hypoglycaemia and unawareness of hypoglycaemia can have serious socioeconomic implications, including suspension of a driving licence and reduced work productivity. [bib_ref] A nine country study of the burden of non-severe nocturnal hypoglycaemic events..., Brod [/bib_ref] A variety of risk factors are related to hypoglycaemia episodes, such as increasing age, longer duration of diabetes (years since diagnosis) and complexity of insulin regimen. Severe hypoglycaemia was found to be prevalent in almost half of people with long-duration type 1 diabetes. [bib_ref] Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies..., Little [/bib_ref] A retrospective cohort study by Bruderer et al 33 found severe hypoglycaemia was recorded in 12 cases per 10 000 person-years in patients with type 2 diabetes in the United Kingdom who were newly treated with anti-diabetic drugs.
Other factors such as treatment complexity, weight gain, and socioeconomic factors can influence therapy adherence and hence glucose control. [bib_ref] Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients..., Peyrot [/bib_ref] Indeed, poor treatment compliance, defined as medication noncompliance and/or non-attendance at medical appointments, was found to be associated with all-cause mortality in people with type 2 diabetes receiving insulin, in a study of patient data extracted from United Kingdom general practice records (n = 15 984). [bib_ref] The impact of treatment noncompliance on mortality in people with type 2..., Currie [/bib_ref] Clinic nonattenders were more likely to be smokers, younger, have higher HbA1c and have more prior primary care contacts and greater morbidity. [bib_ref] The impact of treatment noncompliance on mortality in people with type 2..., Currie [/bib_ref] Patients decline participation in diabetes education programmes for a variety of reasons, commonly for logistical or financial reasons or because there is no perceived benefit. Non-attendance because of healthrelated shame and stigma of diabetes has been identified as a reason for non-attendance at structured education sessions in newly diagnosed type 2 diabetes patients. [bib_ref] Patient explanations for non-attendance at structured diabetes education sessions for newly diagnosed..., Winkley [/bib_ref] Alternative and innovative methods for delivering diabetes education beyond the conventional group format may encourage greater participation and individual empowerment.
Early intervention required to limit risk and progression of complications. Successful diabetes care requires a comprehensive proactive approach. A major objective of effective partnership between local primary care physicians and diabetology services is to maintain patients' quality of life and reduce treatment-related morbidity, such as hypoglycaemia. Patient engagement is central, encouraging individuals to know and own their data so as to maximise and maintain commitment and outcomes. Early and effective glycaemic control reduces microvascular risks and helps prevent later macrovascular complications. [bib_ref] Managing recent-onset diabetes: choosing durable, well-tolerated therapies and understanding the role of..., Shubrook [/bib_ref] People with diabetes often have busy lifestyles and any initiative to reduce the amount of time required for hospital attendance or visits to the doctor's office is beneficial and may contribute to lowering overall healthcare costs.
Summary: What an ophthalmologist and other healthcare professionals need to know about diabetes.
K The primary focus of clinical diabetes care revolves around a multidisciplinary team-based proactive approach to optimise risk factor control and thus minimise the risk of diabetes-related complications.
K In people with diabetes, early optimal glycaemic control reduces the long-term risk of both microvascular and macrovascular complications.
K Fear of hypoglycaemia drives poor therapy adherence and is one of the major barriers to the achievement of good glucose control.
K Glycaemic control needs to be combined with a comprehensive cardiovascular risk factor reduction programme, to include smoking cessation and adoption of other healthy lifestyle habits, blood pressure control, and lipid management. K Insulin therapy: Insulin therapy for adults with type 2 diabetes should be considered if blood glucose levels are inadequately controlled despite dual therapy with metformin plus another oral anti-diabetic drug (if the person is markedly hyperglycaemic and prefers to start insulin rather than adding another drug), or where oral anti-diabetic drugs are contraindicated or not tolerated.
Diabetic retinopathy screening in the United Kingdom: high coverage achieved, challenges and opportunities ahead Screening for sight-threatening DR and maculopathy aims to detect diabetic eye disease at an appropriate stage in the disease process when treatment has a higher likelihood of success. Broad population coverage is essential and all people should be screened promptly and regularly after diagnosis of diabetes.
The rate of detection of referable DR is higher in those who are not screened promptly after diagnosis of type 2 diabetes, illustrating the need for strategies to increase uptake in those with a poor attendance record, [bib_ref] Delay in diabetic retinopathy screening increases the rate of detection of referable..., Scanlon [/bib_ref] for example, use of easy-to-read information and translated letters.Zoega et al 39 described the relationship between non-attendance for diabetic eye disease screening and blind registration (VA o0. [bib_ref] Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based..., Ncd-Risc [/bib_ref] in a small sample of diabetes patients in Iceland, observing a significant relationship between screening compliance and visual outcome. Those people aged 18-34 years are least likely to attend promptly for screening after registration, with a higher risk of referable DR being present at first screen. [bib_ref] Screening attendance, age group and diabetic retinopathy level at first screen, Scanlon [/bib_ref] Success in tackling vision impairment and blindness from DR in people of working age. The NHS Diabetic Eye Screening Programme involves a systematic approach designed to capture all people with diabetes for photographic screening once each year. People newly diagnosed with diabetes are invited annually for digital retinal photography screening and images are subjected to feature-based grading [fig_ref] Figure 3: Retinal screening grading pathway, NHS England [/fig_ref] outlines the retinal screening grading pathway).Assessments demonstrate the effectiveness of screening for DR by 2-field mydriatic digital photography, with good levels of sensitivity (87.8%) and specificity (86.1%) that compare well with seven field stereophotography and an ophthalmologist's examination using slit lamp biomicroscopy. [bib_ref] The effectiveness of screening for diabetic retinopathy by digital imaging photography and..., Scanlon [/bib_ref] [bib_ref] Comparison of two reference standards in validating two field mydriatic digital photography..., Scanlon [/bib_ref] Those found to have potentially sight-threatening DR are referred to surveillance clinics or the NHS Hospital Eye Service.
The national screening programme has progressively evolved to achieve high population coverage in excess of 80% in United Kingdom. In 2014-2015, there were 83 local screening programmes involving both NHS and private providers in United Kingdom. That year, 2.5 million people with known diabetes were offered screening appointments and 2.1 million people were screened (84%). In the last 10 years, the epidemic of diabetes has seen an increase of 120 000 cases every 12 months. Of the 1.89 million people screened in United Kingdom in 2012-2013, 5.6% were graded background DR with maculopathy, 0.61% preproliferative DR without maculopathy, 0.59% preproliferative DR with maculopathy, 0.32% proliferative DR without maculopathy and 0.42% proliferative DR with maculopathy.
Similarly, the national Diabetic Retinopathy Screening Programme in Scotland screened 78.7% (201 299 individuals) of eligible people in 2014-2015, just below the Scottish national target of 80%.The national trend for 2014 was 8 916 new diabetes patients becoming eligible for screening across Scotland through 12 months. The annual percentage of referrals to ophthalmology on account of retinopathy is around 3.5%.Many people with diabetes have been prevented from losing vision through early detection and timely intervention. Liew et al [bib_ref] A comparison of the causes of blindness certifications in England and Wales..., Liew [/bib_ref] 10% of eyes have centre-involving diabetic macular oedema (DMO) and around 20% have proliferative disease.Vitrectomy surgery for the late complications of proliferative DR continues to be required for some patients. [bib_ref] Why do patients still require surgery for the late complications of proliferative..., Scanlon [/bib_ref] New challenges and opportunities to improve screening performance and referral refinement Risk stratification and personalised screening intervals. Duration of diabetes is independently associated with microvascular events in type 2 diabetes, an effect that is greatest at younger age. [bib_ref] Impact of age, age at diagnosis and duration of diabetes on the..., Zoungas [/bib_ref] The more prolonged the diabetes, the higher the prevalence of DR. However, the duration of diabetes is generally inconsistently documented and collated in clinical practice.
Better glycaemic control and to a lesser extent blood pressure control may be beneficial in reducing the incidence of proliferative DR and increasing the odds of improvement of DR. [bib_ref] The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of..., Klein [/bib_ref] The 25-year cumulative rate of progression of DR was 83% and the rate of progression to proliferative DR was 42% in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. [bib_ref] The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of..., Klein [/bib_ref] Less severe DR, male gender, higher HbA1c, an increase in HbA1c level and an increase in diastolic blood pressure from the baseline to the 4-year follow-up increased the likelihood of progression of DR. [bib_ref] The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of..., Klein [/bib_ref] The risk of progression of DR is significantly higher for those with background DR in both eyes than for those with background retinopathy in only one eye or in neither eye. [bib_ref] The influence of background diabetic retinopathy in the second eye on rates..., Scanlon [/bib_ref] The cumulative 4-year risk of development of referable DR was 1 in 3 for those with bilateral background DR, compared with less than 1 in 10 and 1 in 20 for those with only one eye or neither eye affected, respectively. With respect to the ETDRS severity scale, mild or non-proliferative DR or background DR (R1) identifies a minimum of at least the presence of one microaneurysm and/or retinal haemorrhage, equivalent to ETDRS levels 20-35; R1b defines the presence of these features in both eyes. [bib_ref] The influence of background diabetic retinopathy in the second eye on rates..., Scanlon [/bib_ref] Two risk stratification models, one incorporating results from a single screening episode plus clinical information (HbA1c in the twelve months prior to screening and duration of diabetes) and another the results from two screening episodes alone, have been developed and validated. [bib_ref] Development of a cost-effectiveness model for optimisation of the screening interval in..., Scanlon [/bib_ref] [bib_ref] A simple risk stratification for time to development of sight threatening diabetic..., Stratton [/bib_ref] These models discriminate well between those with very low and with high risk of progression to sight-threatening DR, which includes the risk of developing maculopathy as well as the risk of development of pre-proliferative DR or proliferative DR. Experience from the Diabetic Eye Screening Programme has helped develop risk stratification showing the risk for sight-threatening DR after 6 years is 1.7% compared with a risk for any retinopathy of 39%. [bib_ref] Development of a cost-effectiveness model for optimisation of the screening interval in..., Scanlon [/bib_ref] The increasing numbers of people with diabetes presents challenges in maintaining a yearly screening service for all eligible diabetes patients. Following consultation, the UK National Screening Committee has recommended that in people at low risk of sight loss, the interval between screening tests should be changed from one year to two years. Extending the screening interval in selected low-risk cases is expected to reduce the number of unnecessary referrals to specialist eye services. Further outstanding questions need to be addressed however before implementation of these policy proposals. While observational studies in low-risk patients show little difference in clinical outcomes between 1 and 2-year screening intervals, Taylor-Phillips et al [bib_ref] Extending the diabetic retinopathy screening interval beyond 1 year: systematic review, Taylor-Phillips [/bib_ref] have argued there is insufficient evidence currently to support recommendations to extend the screening interval beyond one year.
Using optical coherence tomography as a second-line screening tool for those who are screen positive for maculopathy on 2-dimensional photographic markers: helping address over-referrals. The English Diabetic Eye Screening Programme has introduced surveillance into the approved service pathway standard. Cases that are classified as background DR with maculopathy (R1M1) in one or both eyes are also classified as having sightthreatening DR but are sometimes offered interim review appointments in surveillance clinics, depending on severity and circumstances.
Spectral domain optical coherence tomography (SD-OCT) imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy. [bib_ref] SDOCT imaging to identify macular pathology in patients diagnosed with diabetic maculopathy..., Mackenzie [/bib_ref] A prospective audit was performed of patients referred from the diabetic eye screening programme with mild to moderate non-proliferative DR (R1) and maculopathy in either eye attending an OCT-guided surveillance clinic. Results showed such cases had a 42.1% chance of having no DMO on SD-OCT imaging when graded by a retina specialist. [bib_ref] SDOCT imaging to identify macular pathology in patients diagnosed with diabetic maculopathy..., Mackenzie [/bib_ref] In the Gloucestershire Diabetic Eye Screening Programme, the service pathway includes a surveillance clinic for certain cases that are classified on screening episode by digital photography as background DR and maculopathy in one or both eyes. Spectral domain OCT is utilised to grade and identify macular pathology. An audit of a consecutive case series (n = 724) referred from the screening programme with background DR and maculopathy found only 20% needed to be referred to the NHS Hospital Eye Service for further review by an ophthalmologist, avoiding unnecessary hospital referral in 80% of screen-positive maculopathy cases [fig_ref] Table 4: Referral decisions in a consecutive case series of diabetes patients following OCT-guided... [/fig_ref]. Optical coherence tomography criteria and definitions used to grade scans as positive for referable diabetic maculopathy and borderline criteria are detailed in [fig_ref] Table 5: Criteria utilising spectral domain optical coherence tomography [/fig_ref]. Abbreviation: OCT, optical coherence tomography.
## Guideline
## S8
Eye Automated image analysis software systems to augment manual graders. Manual grading is labour and capital intensive and requires trained, qualified graders. Systematic telemedicine digital retinal screening programmes have been introduced in a number of countries aiming to reach all people with diabetes.
Automated retinal image analysis systems may complement pure human grading, for example as an initial filter in routine screening prior to primary human grading or as a quality assurance tool, with manual grading as the reference standard.Studies are ongoing comparing the performance and economic costs of manual versus automated DR image assessment. Preliminary observational study results confirm that automated image assessment software systems provide acceptable sensitivity for referable retinopathy when compared with human graders, with sufficient specificity to make them costeffective alternatives to manual grading alone.Summary: Retinal screening in the United Kingdom: progress and challenges.
K Although DR is no longer the leading cause of severe sight impairment among working age adults in the United Kingdom, it remains a major cause of registrable blindness.
K Strategies are needed to increase uptake in those with a poor attendance record.
K Risk stratification using one screening episode plus clinical risk factors (HbA1c in the twelve months prior to screening and duration of diabetes) or the results from two screening episodes alone can be used to identify lowrisk groups who may require less frequent screening.
K Using OCT as a second-line screening tool in a screening surveillance clinic for those who are screen positive for maculopathy on photographic imaging may help reduce unnecessary referrals to the NHS Hospital Eye Service.
K Automated retinal image analysis systems may complement manual grading, providing an initial filter in routine screening prior to primary human grading or as a quality assurance tool.
Patient experience and adherence with intravitreal injection therapy for visual impairment due to DMO: results of a qualitative research study DMO is a common complication of DR. The risk for developing DMO is associated with duration of diabetes and severity of DR. Estimates of the DMO prevalence rate range from around 1 to 12% of all people with diabetes. [bib_ref] Burden of illness of diabetic macular edema: literature review, Chen [/bib_ref] A study estimated 7% of people with diabetes in United Kingdom had DMO, and of these, more than one-third (39%) had clinically significant macular oedema with visual impairment (visual acuity o6/6 in at least one eye). [bib_ref] Prevalence of diabetic macular oedema and related health and social care resource..., Minassian [/bib_ref] Therapeutic options for the management of DMO include laser photocoagulation, vitrectomy, corticosteroid therapy, and intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment. Macular laser photocoagulation has been the historic mainstay treatment for DMO over the past several decades. Intravitreal corticosteroid therapy has shown efficacy in improving VA in patients with DMO and may play a role in the treatment of adult pseudophakic DMO patients who fail to respond sufficiently to prior non-corticosteroid therapy, or are considered unsuitable for noncorticosteroid therapy. [bib_ref] Current treatments in diabetic macular oedema: systematic review and meta-analysis, Ford [/bib_ref] Anti-VEGF therapy, associated with substantially improved visual and anatomic outcomes compared with laser photocoagulation in patients with DMO, 62 is considered the standard of care for initial management of eyes with visual impairment from central-involved DMO. [bib_ref] Current treatments in diabetic macular oedema: systematic review and meta-analysis, Ford [/bib_ref] [bib_ref] Anti-vascular endothelial growth factor therapy for diabetic macular edema, Boyer [/bib_ref] [bib_ref] New approaches for the treatment of diabetic macular oedema: recommendations by an..., Bandello [/bib_ref] Focal laser is an option for cases of non centre-involving DMO.Anecdotal evidence suggests that treatment adherence for some patients with intravitreal injection therapy for DMO is not optimal. A qualitative research study, commissioned by Bayer, was undertaken to elucidate patient experience and treatment adherence patterns amongst a diverse range of patients with DMO. The research programme also assessed patient compliance from the perspective of healthcare professionals and explored clinical and practical solutions that may help improve compliance, including clinic attendance. See Supplementary Information-Patient Experience and Adherence in DMO.
Individual in-depth interviews were conducted with 18 DMO patients being treated with licensed anti-VEGF therapy within the NHS Hospital Eye Service. Ten of 18 Eye patients were regarded as non-compliant with treatment, defined as any missed appointment. The patient sample, drawn from ten different clinical centres in United Kingdom, Scotland, and Wales, was broadly mixed by age (range and socioeconomic grouping. The majority (15/18) were men. Ten healthcare professionals (six consultant medical retina specialists, one advanced nurse practitioner and three nurse practitioners) from UK ophthalmology centres and all having experience in the management of both compliant and non-compliant DMO patients were also interviewed. Extracts are reproduced in [fig_ref] Table 6: Revealing extracts, see Supplementary Information-Patient Experience and Adherence in DMO K Perspectives,... [/fig_ref].
Perspectives of the healthcare professional: proactive support may help improve health outcomes. Many patients do not immediately associate sight-threatening DMO with diabetes and time is required to explain the implications of their diabetic eye disease. People with diabetes need to be informed of the risks to their sight early on in their care pathway. Although it cannot be achieved in all patient groups, healthcare professionals should counsel patients on diabetes control, encourage them to understand the threat of vision loss from DMO and to manage their diabetes. Ethnic, cultural and language barriers however can make this approach difficult to achieve in all cases. The thought of intravitreal injections and an intensive appointment schedule can be stressful for patients. The burden of treatment for bilateral DMO in particular can present challenges for patients who are coping with other diabetes-related co-morbidities. Anxiety often can persist throughout treatment and may be addressed with appropriate educational interventions.
Wilful or deliberate non-compliance was generally found to be rare. According to healthcare professionals interviewed, education about diabetes control could be better addressed, individually tailored to take account of ethnicity, age, and social needs. The introduction of a DSN in a dedicated pathway for patients with DMO may help to improve outcomes, [bib_ref] Diabetic retinopathy: role of the diabetes specialist eye nurse, Khan [/bib_ref] generating positive patient experience and awareness and potentially improve individual motivation towards participation in structured education programmes and for attaining and maintaining good blood glucose and blood pressure targets.
Patients' perspectives. At the time of a diagnosis of DMO, patients typically experience worry, concern, and fear. For patients, fear of intravitreal injections and uncertainty over a proposed treatment plan without a determinate end often overshadow all other concerns. Explanations at the time of consultation about the importance of regular retreatment to avoid deterioration of vision and the association between diabetes, glycaemic control, and sight loss may be obscured by needle phobia or general treatment anxiety.
A lack of awareness of DMO, the risk of visual impairment if left unchecked, and the link to chronic diabetes was common. This dilutes the important communication that is required between doctor and patient in a DMO clinic. Patients require access to up-todate educational materials about DMO, including useful signposting to authoritative sources, both before and at the point of diagnosis, to reinforce and encourage better diabetic control. Nine in ten adults report going online every day, reflecting the fact that internet use is an integral part of many people's daily lives.Multichannel access to educational materials increases awareness and involvement and may motivate the patient with regard to DMO treatment compliance and prioritisation of lifestyle modification to better control modifiable risk factors. Three psychological profiles were identified in the research study that characterise the main differences amongst people with diabetic macular oedema attending DMO clinics: 'evangelists', the 'generally sensible' and 'those not always well behaved' [fig_ref] Figure 4: Characteristic psychological profiles of diabetes patients, covering attitudes to diabetes and its... [/fig_ref]. The evangelical patient takes a keen interest in the condition, focused on adjusting lifestyle to help achieve better management of diabetes. They are disciplined and very compliant. The generally sensible profile probably covers the majority of patients, who listen, are interested, have good intentions and achieve good compliance most of the time, with occasional lapses in clinic attendance. Then there are patients who are not always well behaved, embracing a range of behaviours: past non-compliance, those in denial of their condition, or preoccupied with 'chaotic' and busy lifestyles.
Attitudes towards DMO treatment adherence were found to mirror patients' views and behaviours in relation to the management and care of their own diabetes. Fear of visual impairment from DMO added a further patient profile: the 'transformed'. These are patients who previously have not always been well behaved, but whose diabetic compliance has been markedly improved (transformed) by the diagnosis of DMO and resulting fear of blindness.
Experience of the DMO journey. Patients appreciate the explanation and reassurance provided by healthcare professionals at the time of commencing DMO treatment. However, they are aware of time and resource pressures within NHS hospital clinics. A perception of busy clinics can make patients reluctant to ask too many questions or take up too much time with clinicians. Not all patients want information upfront about DMO, preferring a stepwise approach one appointment at a time. Others prefer to absorb as much information as possible at the outset.
Compliant patients are more likely to understand the need for good diabetic control and are encouraged by threat or symptoms of sight loss. For such patients, explanation and counselling by healthcare professionals acts to support or reinforce compliance.
Not all patients with DMO receiving intravitreal anti-VEGF therapy are aware of the nature of the treatment regimen or understand the importance of the treatment intervals involved. Non-compliant patients are often least aware of the need to have repeat injections at prescribed intervals. This could be addressed by providing newly diagnosed DMO patients with good website links or patient information leaflets providing useful guidance about the course of treatment involved and about how treatment frequency typically peaks in the first year and diminishes over subsequent years. [bib_ref] Diabetic Retinopathy Clinical Research Network. Intravitreal Ranibizumab for diabetic macular edema with..., Elman [/bib_ref] Mobile text messaging may encourage improved compliance with scheduled clinic visits. There were 91.5 million United Kingdom mobile subscriptions at the end of 2015.Seventy-one per cent of all UK adults own a smartphone, up from 66% in 2015.Ofcom research shows that 66% of adults claimed to access data services on a mobile phone in 2016, with a significant increase since 2015 noted for users aged 55 and older (20% of respondents aged 55+ in 2016 compared with 11% in 2015).Hence, text message reminders could be more widely utilised to reinforce and encourage good patient attendance for scheduled appointments and minimise 'did not attend' rates, particularly for those who might be reluctant to turn up. A systematic literature review of studies on mobile telephone message reminders in healthcare services found 70% of the studies showed improved outcomes. [bib_ref] Use of mobile phone text message reminders in health care services: a..., Kannisto [/bib_ref] Mobile phone text messaging reminders have been shown to increase attendance at healthcare appointments when compared to no reminders or postal reminders. [bib_ref] Mobile phone messaging reminders for attendance at healthcare appointments, Gurol-Urganci [/bib_ref] Message content and timing in relation to an appointment should be carefully considered. The ideal may be a letter some weeks beforehand, so that time off work can be booked, followed by a simple text message reminder a couple of days prior to the appointment.
Summary: Qualitative research study exploring patient treatment adherence patterns with intravitreal injection therapy for DMO.
K People with diabetes need to be informed of the risks to their sight early on in the management of their diabetes care.
K Attitudes towards DMO treatment adherence appear to mirror patients' views and health behaviours in relation to the management and care of their own diabetes. K Patients require access to up-to-date educational materials about DMO and the importance of adherence to treatment schedules, both before and at the point of diagnosis.
K Text message reminders could be more widely utilised to reinforce and encourage good patient attendance for scheduled appointments and minimise 'did not attend' rates.
Expanding the role of the diabetes specialist nurse in diabetic eye clinics Practice interventions by a DSN promotes proactive modification of lifestyle behaviours and may improve glycaemic status and overall metabolic control. A randomised study in Sweden, involving data collection in 2010 and 2011, found nurse-led intervention focused on patient-centred self-management support lowered HbA1c among patients with type 2 diabetes at 12 months' followup. [bib_ref] Nurse-led patient-centered self-management support improves HbA1c in patients with type 2 diabetes-A..., Jutterström [/bib_ref] Glycated haemoglobin level significantly decreased from baseline in patient groups randomised to group intervention and individual intervention by 5 and 4 mmol/mol, respectively. An external control group recruited from another county council showed increased HbA1c from baseline. An earlier published report from practitioners at University of Hospitals of Leicester NHS Trust showed positive results in an audit of a service pathway involving a diabetes specialist eye nurse working in both the diabetes and ophthalmology clinics [fig_ref] Figure 5: Type 1 and type 2 diabetes [/fig_ref] shows the care pathway and protocol). [bib_ref] Diabetic retinopathy: role of the diabetes specialist eye nurse, Khan [/bib_ref] Khan et al 65 reported improved glycaemic control and reductions in mean cholesterol levels at 12 months' follow-up in a cohort of 100 people with diabetic eye disease. For the full audited cohort, mean HbA1c level reduced from 71 mmol/mol (8.67%) at baseline to 60 mmol/mol (7.64%) at 12 months' follow-up examination.
A majority of diabetes patients with severe DMO (78-82% of 52 patients) failed to achieve a glycaemic control target of ≤ 48 mmol/mol (6.5%), in a retrospective audit of results from a regional hospital eye clinic in United Kingdom with conventional treatment without direct DSN intervention.The data suggest there is room for improvement in the management of diabetes patients being treated for DMO.
Exploring the role of the DSN in diabetic ophthalmic practice. The DSN role exists to educate and support people living with diabetes and their families at all stages of their lives, motivating people to self-manage their diabetes as effectively as possible. The DSN provides expertise as part of dedicated diabetes teams and assists other healthcare professionals in the care they provide. Considered the patient's advocate, the DSN can act as a valuable bridge between healthcare professionals and services in primary, secondary and integrated care. Nurse-led structured education programmes encourage people to manage modifiable risk factors for onset and progression of diabetic eye disease, by optimising control of blood glucose levels, blood pressure and lipid management.
Careful instructions are provided on when and how to self-test blood glucose and what to do with the results.
Smoking cessation is stressed, as is the importance of regular eye examination for early identification and initiation of care for patients with retinopathy. The main modifiable risk factors for type 2 diabetes are overweight and obesity, insufficient physical activity and unhealthy dietary practices.Results of a parallel-group, randomised controlled trial at 56 primary care practices in Central and South United Kingdom found that an internet-based intervention with brief practice nurse support helped people maintain clinically important weight reductions over 12 months. [bib_ref] An internet-based intervention with brief nurse support to manage obesity in primary..., Little [/bib_ref] Patients with diabetes require access to concise written material and online educational resources. Often there appears to be a lack of emphasis at the time of diabetes diagnosis on the relationship between managing known risk factors and development of diabetic eye disease. Diabetes patients should understand the need for good glycaemic control, as progression of eye disease is associated with the severity and duration of hyperglycaemia, and for effective treatment of hypertension. [bib_ref] The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression..., Klein [/bib_ref] [bib_ref] Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies, Ciulla [/bib_ref] [bib_ref] Additive effects of glycaemia and blood pressure exposure on risk of complications..., Stratton [/bib_ref] Stratton et al 76 found that development of retinopathy in type 2 diabetes over 6 years from diagnosis was strongly associated with baseline glycaemia, glycaemic exposure over 6 years and higher blood pressure. Progression of existing retinopathy was associated with older age, male gender and hyperglycaemia. Intensive treatment of both hyperglycaemia and hypertension is advisable to help minimise the incidence of diabetes complications. [bib_ref] Additive effects of glycaemia and blood pressure exposure on risk of complications..., Stratton [/bib_ref] Vision impairment negatively impacts quality of life and may restrict independence and mobility. Even mild impairment (near-normal vision) has a tangible influence on quality of life. Cumberland et al 77 reported that, in a gradient of increasing severity, all-cause impaired visual function was associated with adverse social outcomes and impaired general and mental health. Vision-reliant tasks are required for good chronic disease management, including self-care (eg, foot checks in diabetes) and getting to and from clinic visits.Vision loss also may complicate the management of other conditions by creating difficulties in medication adherence and management, for example, administering insulin or eye drops.
The DSN can ensure baseline investigations for risk factors are completed at time of initial assessment for patients with DMO, refer patients at high risk of visual loss to a diabetologist (eg, poorly controlled hypertension, raised lipid parameters, microalbuminuria) and encourage good follow-up attendance for patients at risk of visual deterioration.
Summary: Expanding the role of the diabetes specialist nurse in dedicated eye clinics for patients with diabetic macular oedema.
K Often there appears to be a lack of emphasis at the time of diabetes diagnosis on the relationship between managing known risk factors and development of diabetic eye disease.
K Practice interventions by a diabetes specialist nurse (DSN) promotes proactive modification of lifestyle behaviours and may improve glycaemic status and overall metabolic control.
K Wherever feasible, the introduction of a DSN in a dedicated DMO eye clinic may help to improve care outcomes.
K The DSN can ensure baseline investigations for risk factors are completed at time of initial assessment following referral, direct patients at high risk of visual loss to a diabetologist and encourage good follow-up clinic attendance and treatment adherence.
## Practice principles and clinical considerations
In diabetes management, commitment of patients can deteriorate over time. People generally are more willing to consider behavioural change at the time of diabetes diagnosis. But enthusiasm typically wanes, with condition fatigue emerging with therapy escalation. Poor glucose control is often explained by clinical inertia, which limits or delays intensification of treatment when needed in the management of diabetes. [bib_ref] Clinical inertia in people with type 2 diabetes: a retrospective cohort study..., Khunti [/bib_ref] Diabetic retinopathy and DMO are the two major retinal complications that account for most diabetesrelated vision loss. [bib_ref] Diabetic retinopathy and angiogenesis, Crawford [/bib_ref] Left unchecked, approximately half of people with DMO at baseline lose 2 or more lines of visual acuity within 2 years. [bib_ref] Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies, Ciulla [/bib_ref] Hyperglycaemia, hypertension and dyslipidaemia are risk factors for both the development and progression of DR/DMO and there is substantial evidence that control over metabolic factors can effectively prevent development and progression of potentially blinding diabetic eye disease. [bib_ref] Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies, Ciulla [/bib_ref] For optimal clinical care of patients with visual impairment due to DMO, several practice-based principles merit consideration in NHS ophthalmic service provision and care pathway redesign.
Practice-based principles for optimal clinical care Principle 1. Foster closer working relationships between diabetes management, general practitioners, and ophthalmology specialties. Closer clinical collaboration between diabetology, primary care, and ophthalmology services may enhance patient experience.
The ophthalmologist should establish who is taking care of the individual patient's diabetes and, as emphasised in clinical guidelines for DR from the Royal College of Ophthalmologists, 64 develop strong links with local primary care and diabetology services to ensure that patients have effective integrated care plans for the management of their condition.The aim is to achieve closer working relationships so that patients with DMO or advanced or progressive retinopathy are appropriately managed from both the perspective of ophthalmology and diabetes management.
Much of the clinical focus in diabetes management is to limit the burden of diabetes-related complications. A structured approach to education concerning health behaviours and health promotion is beneficial and higher uptake should be encouraged. Multiple risk factor intervention is required to reduce disease burden and improve clinical outcomes, generating value at the individual, clinical and health system level.
In tailoring diabetes management to individual patients who are being treated for DMO, the diabetologist would benefit from knowing the patient's degree of sight loss, frequency of current treatment and expected prognosis. The diabetes management team should be aware of the main prognostic factors for increased risk of development and progression of sight-threatening DMO. This would enable the diabetes care team to identify high-risk patients at an early stage, for example, obesity, sleep apnoea, and elevated risk of progression of DR. [bib_ref] Obstructive sleep apnea syndrome. Is it a risk factor for diabetic retinopathy?, Baba [/bib_ref] Principle 2. Consider the benefits of establishing a dedicated clinic service for the management and followup of patients with DMO. Consider streamlining the pathway of diagnosis and treatment of DMO, with an emphasis on improving education and awareness, multidisciplinary working, expanding the role of the DSN in dedicated DMO clinics, and ensuring communication/ liaison with colleagues beyond ophthalmology is effective and sufficient.
More time during consultation is needed for patients, to educate them about their diagnosis, treatment, outcomes, and diabetes control. Dedicated service provision for DMO would also facilitate integration of a DSN-led review service thus enhancing efficiency of diabetes care. The English Diabetic Retinopathy Screening Programme and guidance on retinal screening from the Royal College of Ophthalmologists have for a long time recommended dedicated assessment clinics in the NHS Hospital Eye Service for people with diabetic eye disease referred for ophthalmologist review.
Dedicated clinics for patients with diabetic eye disease would help promote: K The value of early detection and intervention; K Delivery of sustained education and health promotion; K Multidisciplinary working and engagement with other healthcare professionals working with diabetes patients;
K Flexible service provision and clinics for greater patient engagement; and K Identification of high-risk patients.
Practice varies across the United Kingdom with regard to injection treatment clinics for DMO. While many centres choose to treat all eligible patients with retinal disease during a combined medical retina injection treatment service for example, other clinical centres prefer to maintain separate assessment and injection clinics for patients with DMO. Protocols for assessment and monitoring, as well as the recommended treatment posology with intravitreal anti-VEGF therapy, vary for different retinal disease entities.
Principle 3. Explore aspirations and opportunities to expand the role of the DSN in the hospital eye clinic, with the nurse specialist acting as the main hub between ophthalmology, endocrinology, diabetology, and primary care services/support. Specialist input from a diabetes expert is required when dealing with DMO patients coping with established diabetes-related complications and who may be at risk of mild or moderate vision impairment and of other later macrovascular complications because of poor metabolic control. Diabetes experts urge ophthalmologists to make better use of the specialist diabetes services available. Commissioners investing in local services should also support expansion and strengthen DSN recruitment so they may logistically be in a position to provide further coverage within hospital eye departments.
Principle 4. Tailor clinical practice and follow-up initiatives to improve treatment adherence in DMO. A wide range of appointment times should be available for patients with diabetes. Afternoon, evening or weekend appointments for working diabetic patients are often preferred, with experience suggesting only minor nonattendance rates for evening DMO clinics. Messaging beyond letter notification could be considered to reinforce the importance of a scheduled clinic appointment, for instance with follow-up text messaging. Text messaging can be quite effective for younger adults for example. For DR screening programmes, the regular non-attenders need to be vigorously chased.
Principle 5. Set realistic patient expectations when initiating treatment of DMO. Adequate support should be provided to ensure that patients understand the treatment they are being given and why that particular treatment is right for them, the treatment response they might expect, the most common side effects and the options that might be available if the initial treatment does not work well or does not suit them.
Where the treatment choice for DMO is intravitreal ant-VEGF therapy, patients should understand the goal of treatment, the need for regular repeat therapy, the treatment plan including follow-up regimen and be aware also that the frequency of injections may diminish after the first year of treatment.
Regular clinical attendance is required to resolve macular oedema and to ensure maintenance and/or improvement of vision long-term. Inadequate or delayed treatment may result in irreversible vision loss. The potential need for additional or substitute treatments should be discussed at the outset as there may be some cases of refractory macular oedema. Patients are reminded of the need to be proactive in optimising control of modifiable systemic risk factors. Several online sources of patient information and resources are outlined in .
Principle 6. Perform a regular audit of practice outcomes and benchmark performance, preferably using an electronic medical record (EMR) system. Audit and benchmark the key performance indicators of efficacy, safety, and treatment burden in the management and treatment of DMO. Development of a nationally agreed DMO outcome data set for EMR reporting will facilitate national audit data collection and shared learning.
## Best practice
Best practice models illustrate progress in strengthening service capacity and referral refinement of DR, including the use of OCT imaging as a second-line surveillance tool for evaluating referrals of screen-positive maculopathy. Illustrative examples include: K Refinement of screening referrals. Consider establishing a second-line surveillance service for screen-positive maculopathy and/or pre-proliferative DR. OCTguided surveillance clinics for screen-positive maculopathy and/or pre-proliferative DR provide additional flexibility in DMO management by helping minimise or limit false positive referrals to the Hospital Eye Service. 82 K Evening technician-led imaging clinics. Evening technician-led OCT imaging clinics for DMO patients being treated with intravitreal anti-VEGF therapy have been introduced successfully within ophthalmology departments, uplifting capacity and allowing high-speed decision-making based on ophthalmologist review of acquired OCT scans. This frees up additional time for direct ophthalmologist review of more complex cases and for patient cases that may benefit from a treatment switch.
K DSN-led reviews of initial referrals of background DR or diabetic maculopathy after brief medical history and fundoscopy carried out by the eye clinic ophthalmologist, covering key baseline diabetes investigations and onward referral to the eye care service or discharge to primary care diabetes care.
K Virtual review clinics utilising OCT imaging combined with fundus photography. For patients with established DMO on regular intravitreal treatment and follow-up, a virtual OCT review clinic allows for separate assessment and grading of OCT images and fundus photographs by trained hospital technicians and nurses. Patients with stable disease are taken out of the existing DMO clinic service, releasing additional front-line treatment capacity.
# Conclusion
Findings from the Diabetic Retinopathy Clinical Research Network (DRCR.net) reiterate that long-term success in optimisation of glycaemic control as measured by HbA1c can be challenging. [bib_ref] Diabetic Retinopathy Clinical Research Network. Assessing the effect of personalized diabetes risk..., Aiello [/bib_ref] Investigators from DRCR.net identified a need for frequent educational interaction and additional communication with local primary diabetes care providers, as part of a comprehensive approach to the management of vision loss due to DR and DMO. [bib_ref] Diabetic Retinopathy Clinical Research Network. Assessing the effect of personalized diabetes risk..., Aiello [/bib_ref] People with diabetes need education to manage their condition and need to be informed of the risks to their sight early in the management of their diabetes care to ensure good compliance with regular eye checks. Greater collaboration between eye health professionals and general practitioners, practice nurses and community-based diabetes care providers is recommended in order to ensure better coordinated follow-up and timely assessment of diabetes patients with related eye disease. Broader utilisation of and access to community-based diabetes care regimens can be expected to improve standards of patient care, and contribute to greater awareness of the need for improved glycaemic control to reduce diabetes-related complications and morbidity.
Evidence from randomised controlled trials supports treatment of proliferative DR and DMO to prevent progressive vision loss and imaging plays a valuable role in surveillance. [bib_ref] Anti-vascular endothelial growth factor therapy for diabetic macular edema, Boyer [/bib_ref] Diabetes specialist nurses can help allay patient anxiety, reinforce knowledge of the value of adherence to treatment regimens and encourage appropriate health behaviours.
As an integral part of the patient pathway, ophthalmologists and other healthcare professionals play a vital role in disease management by encouraging and educating patients with DR and/or DMO to achieve important health targets, particularly for blood glucose and blood pressure control, to reduce the risk of progression of vascular complications and preserve visual function.
Summary: Action on DMO: best practice principles.
K Foster closer working relationships between diabetes management, general practitioners, and ophthalmology specialties.
K Consider the benefits of establishing a dedicated DMO eye clinic service for management and follow-up of patients with diabetic eye disease, for example, facilitate integration of a DSN-led review service and enhance efficiency of diabetes care.
[fig] Figure 1: Expected diabetes prevalence (diagnosed and undiagnosed) for England in 2015 by gender, ethnicity, and age group. 5 A Public Health England (PHE). Diabetes Prevalence Model. Public Health England, September 2016. Contains public sector information licensed under the Open Government Licence v3.0. The 2016 PHE diabetes prevalence model incorporates more up-to-date data sources and population estimates than previously published diabetes prevalence models. The previous model published in 2012 underestimated undiagnosed diabetes, suggesting that the overall prevalence estimates were probably low. [/fig]
[fig] Figure 2: Percentage of all people with diabetes in United Kingdom and Wales achieving all three treatment targets (HbA1c ≤ 58 mmol/mol (7.5%), blood pressure ≤ 140/80 mm Hg, and cholesterol o5 mmol/l) by diabetes type and age group, 2014-2015. 10 National Diabetes Audit 2013-2014 and 2014-2015. Report 1: Care Processes and Treatment Targets. Published 28 January 2016 by the Health and Social Care Information Centre (HSCIC), also known as NHS Digital. Contains public sector information licensed under the Open Government Licence v3.0. [/fig]
[fig] Figure 3: Retinal screening grading pathway, NHS England. Public Health England. 41 Public health functions to be exercised by NHS England. Service specification No 22. NHS Diabetic Eye Screening Programme. Department of Health, NHS England, November 2013. Contains public sector information licensed under the Open Government Licence v3.0. Abbreviations: M0, no maculopathy; M1, maculopathy; R0, no retinopathy; R1, background retinopathy; R2, pre-proliferative retinopathy; R3a, active proliferative retinopathy; R3s, stable proliferative retinopathy. [/fig]
[fig] Figure 4: Characteristic psychological profiles of diabetes patients, covering attitudes to diabetes and its treatment. Three distinct types of diabetes patient were identified, which match DMO patient profiles, with the threat of blindness or experience of visual impairment creating an additional profile -'Transformed'. [/fig]
[fig] Figure 5: Type 1 and type 2 diabetes: diabetes specialist eye nurse care pathway, University Hospitals of Leicester. Abbreviations: BMI, body mass index; CK, creatine kinase; DR, diabetic retinopathy; FFA, fundus fluorescein angiography; F/U, follow-up; HbA1c, haemoglobin A1c; LDH, lactate dehydrogenase; OHAs, ocular hypertensive agents; TFTs, thyroid function tests; U&E, urea and electrolytes; VA, visual acuity. Reproduced with permission from UHL ophthalmology department. [/fig]
[table] Table 1: Global prevalence estimates and healthcare expenditures 2015 and projection for 2040 a [/table]
[table] Table 2: Estimates of diabetes prevalence in the United Kingdom 2016 a [/table]
[table] Table 3: Recommended approach to the management of hyperglycaemia in patients with type 2 diabetes: modulation of the intensiveness of glucose lowering based on patient and disease features, a broad construct to guide clinical decision-making a [/table]
[table] Table 4: Referral decisions in a consecutive case series of diabetes patients following OCT-guided assessment in Gloucestershire Diabetic Eye Screening surveillance clinic (n = 724) [/table]
[table] Table 5: Criteria utilising spectral domain optical coherence tomography (OCT) as an adjunct to colour fundus photography in diabetic eye screening surveillance clinic [/table]
[table] Table 6: Revealing extracts, see Supplementary Information-Patient Experience and Adherence in DMO K Perspectives, in the words of consultant retina specialists J 'I always look to see what kind of diabetic patient they are. Their treatment history, how their HbA1c is controlled and what they do for themselves to manage their diabetes. It will tell me a lot about their diabetic macular oedema.' [/table]
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https://www.nature.com/articles/eye201753.pdf
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Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF‐PH inhibitors
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Recommendations by the Asian Pacific society of nephrology (APSN) on the appropriate use of HIF‐PH inhibitors
Renal anaemia is a common and important complication in patients with chronic kidney disease (CKD). The current standard-of-care treatment for renal anaemia in CKD patients involves ensuring adequate iron stores and administration of erythropoietin stimulating agents (ESA). Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery. Manipulation of the HIF pathway by the use of HIF-prolyl hydroxylase inhibitors (HIF-PHI) has emerged as a novel approach for renal anaemia management. Despite it being approved for clinical use in various Asia-Pacific countries, its novelty mandates the need for nephrologists and clinicians generally in the region to well understand potential benefits and harms when prescribing this class of drug. The Asian Pacific society of nephrology HIF-PHI Recommendation Committee, formed by a panel of 11 nephrologists from the Asia-Pacific region who have clinical experience or have been investigators in HIF-PHI studies, reviewed and deliberated on the clinical and preclinical data concerning HIF-PHI. This recommendation summarizes the consensus
views of the committee regarding the use of HIF-PHI, taking into account both available data and expert opinion in areas where evidence remains scarce.
## K e y w o r d s
anaemia, Asian Pacific, chronic kidney disease, hypoxia inducible factor, prolyl hydroxylase inhibitor Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery.
Its preliminary state comprises a constitutively expressed, nucleusbound β-subunit and three isoforms of a cytoplasmic α-subunit (HIF-1α, HIF-2α and HIF-3α). HIF-1α and HIF-2α are master regulators of defensive mechanisms against hypoxia and enhance oxygen delivery by stimulating a variety of genes. Representative target genes are erythropoietin (EPO) and those that optimize iron utilization.
When oxygen availability is normal, the α-subunit is sequentially degraded: first by prolyl hydroxylation by HIF-prolyl hydroxylase (HIF-PH), followed by ubiquitination via the Von-Hippel Lindau (VHL) gene and the E3 ubiquitin ligase complex, which facilitates proteosomal degradation. However, prolyl hydroxylation is oxygendependent; hence, during periods of hypoxia HIF-PH loses its activity, resulting in stabilization of the α-subunit before it undergoes nuclear translocation and formation of a heterodimer with the β-subunit. As the oxygen sensing mechanism and the adaptive response against hypoxia is so important and essential, three great scientists who elucidated this mechanism, Peter Ratcliffe, Gregg Semenza, and William Kaelin Jr., were awarded the Nobel Prize in Physiology and Medicine in 2019.
The current standard-of-care treatments for anaemia in chronic kidney disease (CKD) is intravenous (IV) or subcutaneous (SC) administration of human recombinant EPO or its derivatives, known as erythropoiesis stimulating agents (ESA) which stimulate the haematopoietic system specifically. HIF-PH inhibitors (HIF-PHI) are now approved and available in some countries as an oral drug of a completely new mechanism to treat anaemia in CKD.HIF-PHI work systemically and may exert some effects outside the haematopoietic system. Being a relatively novel therapy that was first approved in various Asia-Pacific countries, it is important for nephrologists and clinicians within the region to well understand the potential benefits and harms when prescribing this class of drug. Physician can consider HIF-PHI as alternatives to ESAs in correcting and maintaining haemoglobin (Hb) for renal anaemia both in dialysis-dependent (DD) and non-dialysis-dependent (NDD) CKD patients based on the new data concerning its efficacy and safety from several recent clinical trials.These trials show that the efficacy and safety of HIF-PHI are comparable to ESAs in treating renal anaemia in the short term, although the long-term risks and benefits of HIF-PHIs in treating renal anaemia remains to be assessed.
Physicians should recognize that HIF-PHI are very different in its mechanism of action of erythropoiesis compared to ESAs. ESAs stimulate erythropoiesis by acting specifically on the erythropoietin receptor that expressed on red blood cell precursors.In clinical studies, HIF-PHIs have been shown to increase blood TIBC with no significant changes in serum iron levels, resulting in reduced TSAT.Treatment with HIF-PHI is also associated with decreased blood ferritin level and hepcidin level.Iron deficiency is associated with thromboembolic events, and clinical trials of roxadustat in Japan have reported increased incidence of thromboembolic events.As treatment with HIF-PHIs may decrease serum iron levels due to increased availability of iron for erythropoiesis, one T A B L E 1 Pharmacologic profiles of HIF-PHIs in phase III development* should pay attention to avoid treatment-induced reduction in serum iron levels. Apart from increasing EPO transcription and inhibiting hepcidin production, HIF also induces transcription of genes relating to neovascularization and tumour growth (specific to tumour type). These include vascular endothelial growth factor (VEGF), nitric oxide, TWIST gene, metalloproteinase and mitogen-activated protein kinase, among others. Importantly, HIF-1α (rather than HIF-2α) appears related to tumour gene activity and associated with metastatic spread for breast, prostate, lung, bone and colorectal cancers.Nonetheless, HIF-2α has also been identified in in vitro malignant hepatocellular lines, is involved in the activation of cancer stem cells factor and is strongly associated with various tumour metastases, as well as a poor prognosis.The relevance of HIF activation on the potential for malignancy is evident in conditions such as VHL disease, where the incidence of several tumours, including renal cell carcinoma (RCC) is increased.
Conversely, most RCCs display somatic mutations in the VHL gene, reducing proteolysis of the HIF α-subunit and increasing HIF activity.Solid tumours have a poorer prognosis when HIF activity is increasedAt least two agents have been assessed regarding their potential for cancer development in longer-term murine studies: roxadustat and daprodustat.Roxadustat is usually administered to humans at doses up to 1.5 mg/kg daily or thrice-weekly (TIW). At doses of up to 10 (rats) and 60 (mice) mg/kg administered TIW and followed for up to 104 weeks, there was no effect in either animal on survival or on the development of neoplastic lesions.Similarly, daprodustat was administered to a cohort of mice and Sprague-Dawley rats for up to 2 years at ≥143-fold the predicted maximal human clinical exposure.
Again, no neoplastic changes were observed, although (male) rat lifespan was curtailed due erythrocytosis, aortic thrombosis and/or associated cardiomyopathy.
In summary, from the available animal and short-term human data, so far there is no evidence of tumour risk with the use of PHIs.
Whether the same can be said for humans, and whether there is a difference between primary oncogenesis and enhancing known tumour growth and spread is unclear. Some idea of the relative risk of malignancy will be available following publication of current studies, but since patients with known tumours were unlikely to be enrolled, it is probable such questions will not be fully addressed. Given broad marketing approval ensues, or in Japan maintained, it will be essential to maintain post-marketing surveillance for a substantive period-at least 5 years-given the theoretical and experimental concerns associated with increased HIF activity, as well as the long-term malignancy risk posed by related genetic diseases.
## | retinopathy <recommendation>
- Retinopathy is a theoretical concern of HIF-PHI in CKD patients.
Early referral for ophthalmologic assessment is warranted in patients who report visual disturbance after drug initiation.
Retinopathy is a sight-threatening condition and remains a serious concern in the use of HIF-stabilizer in CKD patients. Theoretically, activation of the HIF pathway may enhance retinal angiogenesis and predispose patients to retinal complications such as haemorrhage.The overall incidence of retinal adverse events is low. While the cur-
## | liver dysfunction <recommendation>
- Liver dysfunction is relatively uncommon in CKD patients receiving HIF-PHI. Regular monitoring of liver function may facilitate early detection of HIF-PHI -related hepatic dysfunction.
The effect of HIF on liver and hepatic diseases remains elusive.
Animal data suggest that HIF confers protective effect on ischaemic-
reperfusion injury of liver but shows pathogenic roles in the progression of hepatic fibrosis and fatty liver.In an open-label randomized study in dialysis patients, transient elevation of liver biochemistries was noted in two roxadustat-treated patients (3.3%) during the 12-week treatment period and both showed normalization of liver function without drug discontinuation.In a phase 3 study of roxadustat in Chinese patients receiving dialysis, two subjects (1%)
showed liver dysfunction which was mild or moderate in severity.The derangement in liver function test, however, was not observed in another phase 3 study of roxadustat conducted in NDD Chinese CKD patients.Correction of renal anaemia has been shown to reduce incidence of heart failure and improve cardiac function. However, there were a series of reports on reduced cardiac function following sustained activation of HIF or inhibition of prolyl hydroxylase.Studies of HIF deletion in a model of heart failure reported discrepant results.The molecular mechanism of this effect is not clearly defined. Basic science studies suggested that this might be associated with the extent of HIF activation, where over-activation of HIF might lead to defective energy utilisation of the cardiac myocytes.
This highlights the importance of the fine balance between prolyl hydroxylase inhibition to stimulate erythropoiesis for correction of renal anaemia and modest HIF activation at the heart to prevent deterioration of cardiac function. One should also pay attention to the experimental study which showed that HIF-1 directly upregulated BNP, a marker of heart failure.The potential benefits of HIF-PHIs on improving myocardial ischaemia and the potential risks of compromising cardiac function need to be further studied in RCTs.
## | concerns from basic studies
Basic studies have shown that HIF pathway is associated with thrombosis and plaque stability. In this context, hypoxia and HIF target and also increase in plasminogen activator inhibitor 1, which in turn inhibits fibrinolysis.Plaque stability is related to the expression of HIF within the plaque, specifically its expression in vascular smooth muscle cells (VSMCs), endothelial cells (ECs) and more importantly foam cells. HIF can also stimulate destabilised angiogenesis occurring in the ischaemic and necrotic atherosclerotic lesion. HIF and HIFinduced genes, especially VEGF, can enhance the haemodynamic instability and fragility of the plaque, thus allows further infiltration of inflammatory cells.Basic studies have also shown that HIF pathway may be associ- and 4B.In DD patients, the incidence of CV events was low (42/1741 [2.4%]).
HIF-PH inhibitors were associated with higher incidence of all-cause mortality, hyperkalemia and CV events . In NDD patients, the incidence of CV events was even lower (21/1871 [1.1%]). HIF-PHI were associated with insignificantly higher incidence of all-cause mortality, hyperkalaemia and CV events ( This is mainly due to regional hypoxia as a consequence of compression by enlarged cysts and a mismatch between expanding cysts and the vascularization of cyst walls, but not the genetic defects.Data from animal models further support this idea. Tissue PO 2 in cortical surface of Lewis polycystic kidney rats is approximately half of that in control rats. Moreover, renal blood flow and oxygen delivery in the polycystic rats are 60% and 80% lower than control rats.Overproduction of EPO by increased HIF-2α in chronic hypoxia may explain why patients with autosomal dominant polycystic kidney disease (ADPKD) present with less severe anaemia than patients with other end-stage kidney disease (ESKD).Indeed, serum levels of EPO in ESKD patients due to ADPKD are on average 2-fold higher than in ESKD of other causes.However, the stabilization of HIF in the polycystic disease confers not only such beneficial outcome but also deleterious effects in cyst enlargement. Recent study with mouse ADPKD models in combination with genetic and pharmacological approaches clearly demonstrated that increased levels of HIF-1α due to chronic hypoxia promote cyst progression.HIF-1α-dependent apical Ca2 + -activated Cl − secretion is known as a major driving force for cyst fluid secretion.This study also identified the Ca 2+ -activated Clchannel 'anoctamin 1' and the purinergic receptor 'P2Y2R' as 2 major molecular players in the HIF-1α-mediated cyst growth.Although the erythropoietic dosage of a HIF-PHI for CKD patients might be different from that used for the animal experiments, undesirable action of HIF-1α on cyst expansion should be taken into consideration in long-term administration of HIF-PHI to treat anaemia in ADPKD patients.
## | seizure or neurological complications <recommendation>
- Clinical studies have no signals that suggest seizure or neurological complications as an adverse event by HIF-PHI.
HIF is involved in transcriptional responses to hypoxia of many genes, and hence its systemic effect on the cerebrovascular system is of potential concern. In theory, HIF-PHI may increase thromboem- (0.9%) occurred after 19 weeks of roxadustat in ESKD patients receiving maintenance HD, and such adverse events were not observed in the epoetin alfa group.Cerebral infarction (0.7%) was also reported in a study of Japanese population after 24 weeks treatment with roxadustat compared to none in the darbopoietin alfa group.One study reported that vadadustat treatment in NDD CKD patients was associated with slightly higher incidence of headache and dizziness compared with placebo during the 20 weeks of treatment.Headache was also more common in NDD CKD patients treated with daprodustat for 1 month compared with placebo,although adverse cerebrovascular event did not occur in another study where NDD patients had received 4 weeks of daprodustat.There was no cerebrovascular adverse events or stroke reported In CKD stage 3 to 5 NDD patients treated with molidustat for 16 weeks. 88,89
## | potential benefits in addition to improvement of anaemia
One potential benefits of HIF-PHI is that HIF-PHI may stimulate erythropoiesis by an increase in circulating EPO levels within a physiological range. However, many clinical studies did not employ time points at which circulating EPO levels reach the peak by administration of HIF-PHI.
As hypoxia is a final common pathway to ESKD, HIF-PHI may preserve kidney function in CKD patients.In addition, HIF is a master regulator of defensive mechanisms against hypoxia, HIF-PHI may provide protection against ischaemic diseases such as ischemic heart disease, stroke, peripheral arterial disease and acute kidney injury.However, there is no solid clinical evidence to support these expectations, and clinical studies to clarify these issues are awaited.
Previous clinical trials showed a decrease in lipids after HIF-PHI treatment. However, treatment with HIF-PHI decreased both LDLcholesterol and HDL-cholesterol in these trials. In addition, while some HIF-PHI showed lipid-lowering effects, others did not. Therefore, this effect may be agent specific, and long-term consequences of metabolic changes induced by HIF-PHI remain to be elucidated.
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https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/nep.13835
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Renal anaemia is a common and important complication in patients with chronic kidney disease (CKD). The current standard‐of‐care treatment for renal anaemia in CKD patients involves ensuring adequate iron stores and administration of erythropoietin stimulating agents (ESA). Hypoxia inducible factor (HIF) is a key transcription factor primarily involved in the cellular regulation and efficiency of oxygen delivery. Manipulation of the HIF pathway by the use of HIF‐prolyl hydroxylase inhibitors (HIF‐PHI) has emerged as a novel approach for renal anaemia management. Despite it being approved for clinical use in various Asia‐Pacific countries, its novelty mandates the need for nephrologists and clinicians generally in the region to well understand potential benefits and harms when prescribing this class of drug. The Asian Pacific society of nephrology HIF‐PHI Recommendation Committee, formed by a panel of 11 nephrologists from the Asia‐Pacific region who have clinical experience or have been investigators in HIF‐PHI studies, reviewed and deliberated on the clinical and preclinical data concerning HIF‐PHI. This recommendation summarizes the consensus views of the committee regarding the use of HIF‐PHI, taking into account both available data and expert opinion in areas where evidence remains scarce.
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Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients
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Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients
CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation have cosponsored these guidelines for preventing opportunistic infections (OIs) among hematopoietic stem cell transplant (HSCT) recipients. The guidelines were drafted with the assistance of a working group of experts in infectious diseases, transplantation, and public health. For the purposes of this report, HSCT is defined as any transplantation of blood-or marrow-derived hematopoietic stem cells, regardless of transplant type (i.e., allogeneic or autologous) or cell source (i.e., bone marrow, peripheral blood, or placental or umbilical cord blood). Such OIs as bacterial, viral, fungal, protozoal, and helminth infections occur with increased frequency or severity among HSCT recipients. These evidence-based guidelines contain information regarding preventing OIs, hospital infection control, strategies for safe living after transplantation, vaccinations, and hematopoietic stem cell safety. The disease-specific sections address preventing exposure and disease for pediatric and adult and autologous and allogeneic HSCT recipients. The goal of these guidelines is twofold: to summarize current data and provide evidence-based recommendations regarding preventing OIs among HSCT patients. The guidelines were developed for use by HSCT recipients, their household and close contacts, transplant and infectious diseases physicians, HSCT center personnel, and public health professionals. For all recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation. Adhering to these guidelines should reduce the number and severity of OIs among HSCT recipients.
# Introduction
In 1992, the Institute of Medicine (1 ) recommended that CDC lead a global effort to detect and control emerging infectious agents. In response, CDC published a plan (2 ) that outlined national disease prevention priorities, including the development of guidelines for preventing opportunistic infections (OIs) among immunosuppressed persons. During 1995, CDC published guidelines for preventing OIs among persons infected with human immunodeficiency virus (HIV) and revised those guidelines during 1997 and 1999 . Because of the success of those guidelines, CDC sought to determine the need for expanding OI prevention activities to other immunosuppressed populations. An informal survey of hematology, oncology, and infectious disease specialists at transplant centers and a working group formed by CDC determined that guidelines were needed to help prevent OIs among hematopoietic stem cell transplant (HSCT)* recipients.
The working group defined OIs as infections that occur with increased frequency or severity among HSCT recipients, and they drafted evidence-based recommendations for preventing exposure to and disease caused by bacterial, fungal, viral, protozoal, or helminthic pathogens. During March 1997, the working group presented the first draft of these guidelines at a meeting of representatives from public and private health organizations. After review by that group and other experts, these guidelines were revised and made available during September 1999 for a 45-day public comment period after notification in the Federal Register. Public comments were added when feasible, and the report was approved by CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. The pediatric content of these guidelines has been endorsed also by the American Academy of Pediatrics. The hematopoietic stem cell safety section was endorsed by the International Society of Hematotherapy and Graft Engineering.
The first recommendations presented in this report are followed by recommendations for hospital infection control, strategies for safe living, vaccinations, and hema-topoietic stem cell safety. Unless otherwise noted, these recommendations address allogeneic and autologous and pediatric and adult HSCT recipients. Additionally, these recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HSCT center personnel, and public health professionals. *For this report, HSCT is defined as any transplantation of blood-or marrow-derived hematopoietic stem cells, regardless of transplant type (e.g., allogeneic or autologous) or cell source (e.g., bone marrow, peripheral blood, or placental/umbilical cord blood). In addition, HSCT recipients are presumed immunocompetent at ≈24 months after HSCT if they are not on immunosuppressive therapy and do not have graft-versus-host disease (GVHD), a condition that occurs when the transplanted cells recognize that the recipient's cells are not the same cells and attack them.
## Using these guidelines
For all recommendations, prevention strategies are rated by the strength of the recommendation [fig_ref] TABLE 1: Evidence-based rating system used to determine strength of recommendations [/fig_ref] and the quality of the evidence [fig_ref] TABLE 2: Evidence-based rating system used to determine quality of evidence supporting recommendation [/fig_ref] supporting the recommendation. The principles of this rating system were developed by the Infectious Disease Society of America and the U.S. Public Health Service for use in the guidelines for preventing OIs among HIVinfected persons . This rating system allows assessments of recommendations to which adherence is critical.
# Background
HSCT is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., systemic lupus erythematosus or multiple sclerosis) [bib_ref] Use of peripheral stem cell support of high-dose chemotherapy, Kessinger [/bib_ref] [bib_ref] Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s, Bortin [/bib_ref]. Moreover, HSCT has become standard treatment for selected conditions . HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia and offer the only curative therapy for persons with chronic myelogenous leukemia . Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. However, for allogeneic candidates who lack such a donor, registry organizations (e.g., the National Marrow Donor Program) maintain computerized databases that store information regarding HLA type from millions of volunteer donors [bib_ref] Bone marrow transplantation for chronic myeloid leukemia: the use of histocompatible unrelated..., Mackinnon [/bib_ref] [bib_ref] Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow..., Kernan [/bib_ref] [bib_ref] Outcome of matched unrelated donor bone marrow transplantation in patients with hematologic..., Nademanee [/bib_ref]. Another source of stem cells for allogeneic candidates without an HLA-matched sibling is a mismatched family member [bib_ref] Marrow transplantation from donors other than HLA-identical siblings, Clift [/bib_ref]. However, persons who receive allogeneic grafts from donors who are not HLA-matched siblings are at a substantially greater risk for graft-versus-host disease (GVHD). These persons are also at increased risk for suboptimal graft function and delayed immune system recovery. To reduce GVHD among allogeneic HSCTs, techniques have been developed to remove T-lymphocytes, the principal effectors of GVHD, from the donor graft. Although the recipients of T-lymphocyte-depleted marrow grafts generally have lower rates of GVHD, they also have greater rates of graft rejection, cytomegalovirus (CMV) infection, invasive fungal infection, and Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease [bib_ref] T-cell depletion of HLA-identical transplants in leukemia, Marmont [/bib_ref].
The patient's own cells are used in an autologous HSCT. Similar to autologous transplants are syngeneic transplants, among whom the HLA-identical twin serves as the donor. Autologous HSCTs are preferred for patients who require highlevel or marrow-ablative chemotherapy to eradicate an underlying malignancy but have healthy, undiseased bone marrows. Autologous HSCTs are also preferred when the immunologic antitumor effect of an allograft is not beneficial. Autologous HSCTs are used most frequently to treat breast cancer, non-Hodgkin's lymphoma, and Hodgkin's disease . Neither autologous nor syngeneic HSCTs confer a risk for chronic GVHD.
Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. Early results demonstrate that greater degrees of histoincompatibility between donor and recipient might be tolerated without graft rejection or GVHD when UCB hematopoietic cells are used . However, immune system function after UCB transplants has not been well-studied.
HSCT is also evolving rapidly in other areas. For example, hematopoietic stem cells harvested from the patient's peripheral blood after treatment with hematopoietic colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF or filgastrim] or granulocyte-macrophage colony-stimulating factor [GM-CSF or sargramostim]) are being used increasingly among autologous recipients and are under investigation for use among allogeneic HSCT. Peripheral blood has largely replaced bone marrow as a source of stem cells for autologous recipients. A benefit of harvesting such cells from the donor's peripheral blood instead of bone marrow is that it eliminates the need for general anesthesia associated with bone marrow aspiration.
GVHD is a condition in which the donated cells recognize the recipient's cells as nonself and attack them. Although the use of intravenous immunoglobulin (IVIG) in the routine management of allogeneic patients was common in the past as a means of producing immune modulation among patients with GVHD, this practice has declined because of cost factors and because of the development of other strategies for GVHD prophylaxis. For example, use of cyclosporine GVHD prophylaxis has become commonplace since its introduction during the early 1980s. Most frequently, cyclosporine or tacrolimus (FK506) is administered in combination with other immunosuppressive agents (e.g., methotrexate or corticosteroids). Although cyclosporine is effective in preventing GVHD, its use entails greater hazards for infectious complications and relapse of the underlying neoplastic disease for which the transplant was performed.
Although survival rates for certain autologous recipients have improved , infection remains a leading cause of death among allogeneic transplants and is a major cause of morbidity among autologous HSCTs . Researchers from the National Marrow Donor Program reported that, of 462 persons receiving unrelated allogeneic HSCTs during December 1987-November 1990, a total of 66% had died by 1991 [bib_ref] Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow..., Kernan [/bib_ref]. Among primary and secondary causes of death, the most common cause was infection, which occurred among 37% of 307 patients [bib_ref] Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow..., Kernan [/bib_ref].* Despite high morbidity and mortality after HSCT, recipients who survive long-term are likely to enjoy good health. A survey of 798 persons who had received an HSCT before 1985 and who had survived for >5 years after HSCT, determined that 93% were in good health and that 89% had returned to work or school full time . In another survey of 125 adults who had survived a mean of 10 years after HSCT, 88% responded that the benefits of transplantation outweighed the side effects .
## Immune system recovery after hsct
During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteriacarrying sources (e.g., skin or mucosa) becomes a reservoir of potential pathogens. Virtually all HSCT recipients rapidly lose all T-and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients.
During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci ) .
Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm 3 and sustained platelet count of ≈20,000, lasting ≈3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6-84 days) [bib_ref] Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow..., Kernan [/bib_ref]. In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. For example, although allogeneic recipients might have normal total lymphocyte counts within ≈2 months after HSCT, they have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts. They might also have immunoglobulin G (IgG) 2 , IgG 4 , and immunoglobulin A (IgA) deficiencies for months after HSCT and have difficulty switching from immunoglobulin M (IgM) to IgG production after antigen exposure . Immune system recovery might be delayed further by CMV infection .
During the first ≈2 months after HSCT, recipients might experience acute GVHD that manifests as skin, gastrointestinal, and liver injury, and is graded on a scale of I-IV . Although autologous or syngeneic recipients might occasionally experience a mild, self-limited illness that is acute GVHDlike [bib_ref] Induction of cutaneous graft-versus-host disease by administration of cyclosporine to patients undergoing..., Yeager [/bib_ref] , GVHD occurs primarily among allogeneic recipients, particularly those receiving matched, unrelated donor transplants. GVHD is a substantial risk factor for infection among HSCT recipients because it is associated with a delayed immunologic recovery and prolonged immunodeficiency. Additionally, the immunosuppressive agents used for GVHD prophylaxis and treatment might make the HSCT recipient more vulnerable to opportunistic viral and fungal pathogens .
Certain patients, particularly adult allogeneic recipients, might also experience chronic GVHD, which is graded as either limited or extensive chronic GVHD [bib_ref] Consensus among bone marrow transplanters for diagnosis, grading and treatment of chronic..., Atkinson [/bib_ref]. Chronic GVHD appears similar to autoimmune, connective-tissue disorders (e.g., scleroderma or systemic lupus erythematosus) [bib_ref] Chronic graft-versus-host disease and other late complications of bone marrow transplantation, Sullivan [/bib_ref] and is associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis [bib_ref] Recovery of antibody production in human allogeneic marrow graft recipients: influence of..., Witherspoon [/bib_ref] , poor response to vaccination [bib_ref] Detection of specific antibody formation to recall antigens after human bone marrow..., Lum [/bib_ref] [bib_ref] Kinetics of immune reconstitution after human marrow transplantation, Lum [/bib_ref] , and severe mucositis. Risk factors for chronic GVHD include increasing age, allogeneic HSCT (particularly those among whom the donor is unrelated or a non-HLA identical family member) [bib_ref] Chronic graft-versus-host disease and other late complications of bone marrow transplantation, Sullivan [/bib_ref] , and a history of acute GVHD [bib_ref] Chronic graft-versushost syndrome in man: a long-term clinicopathologic study of 20 Seattle..., Shulman [/bib_ref]. Chronic GVHD was first described as occurring >100 days after HSCT but can occur 40 days after HSCT. Although allogeneic recipients with chronic GVHD have normal or high total serum immunoglobulin levels [bib_ref] Recovery of antibody production in human allogeneic marrow graft recipients: influence of..., Witherspoon [/bib_ref] , they experience long-lasting IgA, IgG, and IgG subclass deficiencies [bib_ref] Recovery of antibody production in human allogeneic marrow graft recipients: influence of..., Witherspoon [/bib_ref] [bib_ref] Disordered salivary immunoglobulin secretion and sodium transport in human chronic graft-versus-host disease, Izutsu [/bib_ref] [bib_ref] Long lasting IgG subclass and antibacterial polysaccharide antibody deficiency after allogeneic bone..., Aucouturier [/bib_ref] and poor opsonization and impaired reticuloendothelial function. Consequently, they are at even greater risk for infections [bib_ref] Consensus among bone marrow transplanters for diagnosis, grading and treatment of chronic..., Atkinson [/bib_ref] , particularly life-threatening bacterial infections from encapsulated organisms (e.g., Stre. pneumoniae , Ha. influenzae , or Ne. meningitidis ). After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored.
## Opportunistic pathogens after hsct
HSCT recipients experience certain infections at different times posttransplant, reflecting the predominant host-defense defect(s) . Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); phase II, the postengraftment phase (30-100 days after HSCT); and phase III, the late phase (>100 days after HSCT). Prevention strategies should be based on these three phases and the following information: *Presently, no updated data have been published. .
## Figure. phases of opportunistic infections among allogeneic hsct recipients
- Phase I, preengraftment. During the first month posttransplant, HSCT recipients have two critical risk factors for infection -prolonged neutropenia and breaks in the mucocutaneous barrier resulting from the HSCT preparative regimens and frequent vascular access required for patient care. Consequently, oral, gastrointestinal, and skin flora are sources of infection. Prevalent pathogens include Candida species, and as neutropenia continues, Aspergillus species. Additionally, herpes simplex virus (HSV) reactivation can occur during this phase. During preengraftment, the risks for infection are the same for autologous or allogeneic patients, and OIs can appear as febrile neutropenia. Although a recipient's first fever during preengraftment is probably caused by a bacterial pathogen, rarely is an organism or site of infection identified. Instead, such infections are usually treated preemptively or empiricallyuntil the neutropenia resolves [bib_ref] Randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients..., Pizzo [/bib_ref]. Growth factors can be administered during phase I to decrease neutropenia duration and complications (e.g., febrile neutropenia).
- Phase II, postengraftment. Phase II is dominated by impaired cell-mediated immunity for allogeneic or autologous recipients. Scope and impact of this defect for allogeneic recipients are determined by the extent of GVHD and its immunosuppressive therapy. After engraftment, the herpes viruses, particularly CMV, are critical pathogens. At 30-100 days after HSCT, CMV causes pneumonia, hepatitis, and colitis and potentiates superinfection with opportunistic pathogens, particularly among patients with active GVHD. Other dominant pathogens during this phase include Pneumocystis carinii and Aspergillus species.
- Phase III, late phase. During phase III, autologous recipients usually have more rapid recovery of immune system function and, therefore, a lower risk for OIs than do allogeneic recipients. Because of cell-mediated and humoral immunity defects and impaired reticuloendothelial system function, allogeneic patients with chronic GVHD and recipients of alternate donor allogeneic transplants are at risk for certain infections during this phase. Alternate donors include matched unrelated, UCB, or mismatched family-related donors. These patients are at risk for infections that include CMV, varicella-zoster virus (VZV), EBV-related posttransplant lymphoproliferative disease, communityacquired respiratory viruses (CRV), and infections with encapsulated bacteria (e.g., Ha. influenzae and Stre. pneumoniae). Risk for these infections is approximately proportional to the severity of the patient's GVHD during phases II and III. Patients receiving mismatched allogeneic transplants have a higher attack rate and severity of GVHD and, therefore, a higher risk for OIs during phases II and III than do patients receiving matched allogeneic HSCTs. In contrast, patients undergoing autologous transplantation are primarily at risk for infection during phase I. Preventing infections among HSCT recipients is preferable to treating infections. However, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histoincompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients. susceptibility profiles, particularly when using a single antibiotic for antibacterial prophylaxis (BIII). The emergence of fluoquinolone-resistant coagulase-negative Staphylococci and Es. coli (51,52 ), vancomycin-intermediate Sta. aureus and vancomycin-resistant Enterococcus (VRE) are increasing concerns [bib_ref] Outbreak of vancomycin-dependent Enterococcus faecium in a bone marrow transplant unit, Kirkpatrick [/bib_ref]. Vancomycin should not be used as an agent for routine bacterial prophylaxis (DIII). Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT [bib_ref] Clinical applications of hematopoietic growth factors, Vose [/bib_ref] ; however, no data were found that indicate whether growth factors effectively reduce the attack rate of invasive bacterial disease.
Physicians should not routinely administer IVIG products to HSCT recipients for bacterial infection prophylaxis (DII), although IVIG has been recommended for use in producing immune system modulation for GVHD prevention. Researchers have recommended routine IVIG* use to prevent bacterial infections among the approximately 20%-25% of HSCT recipients with unrelated marrow grafts who experience severe hypogammaglobulinemia (e.g., IgG < 400 mg/dl) within the first 100 days after transplant (CIII). For example, recipients who are hypogammaglobulinemic might receive prophylactic IVIG to prevent bacterial sinopulmonary infections (e.g., from Stre. pneumoniae ) (8 ) (CIII). For hypogammaglobulinemic allogeneic recipients, physicians can use a higher and more frequent dose of IVIG than is standard for non-HSCT recipients because the IVIG half-life among HSCT recipients (generally 1-10 days) is much shorter than the half-life among healthy adults (generally 18-23 days) [bib_ref] Pharmacokinetics of cytomegalovirus specific IgG antibody following intravenous immunoglobulin in bone marrow..., Rand [/bib_ref] [bib_ref] Kinetics of anti-CMV antibodies after administration of intravenous immunoglobulins to bone marrow..., Bosi [/bib_ref] [bib_ref] Use of intravenous immune globulin in immunodeficiency diseases, Buckley [/bib_ref]. Additionally, infections might accelerate IgG catabolism; therefore, the IVIG dose for a hypogammaglobulinemic recipient should be individualized to maintain trough serum IgG concentrations >400-500 mg/dl (58 ) (BII). Consequently, physicians should monitor trough serum IgG concentrations among these patients approximately every 2 weeks and adjust IVIG doses as needed (BIII) (Appendix).
Preventing Late Disease (>100 Days After HSCT). Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae, Ha. influenzae, or Ne. meningitidis ) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59 ) (BIII). Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe demonstrable hypogammaglobulinemia (e.g., IgG levels < 400 mg/dl, which might be associated with recurrent sinopulmonary infections), routine monthly IVIG administration to HSCT recipients >90 days after HSCT is not recommended (60 ) (DI) as a means of preventing bacterial infections.
Other Disease Prevention Recommendations. Routine use of IVIG among autologous recipients is not recommended (61 ) (DII). Recommendations for preventing bacterial infections are the same among pediatric or adult HSCT recipients.
## Recommendations regarding stre. pneumoniae
## Preventing exposure
Appropriate care precautions should be taken with hospitalized patients infected with Stre. pneumoniae [bib_ref] Hospital Infection Control Practices Advisory Committee, Garner [/bib_ref] (BIII) to prevent exposure among HSCT recipients.
## Preventing disease
Information regarding the currently available 23-valent pneu-mococcal polysaccharide vaccine indicates limited immunogenicity among HSCT recipients. However, because of its potential benefit to certain patients, it should be administered to HSCT recipients at 12 and 24 months after HSCT (64-66 ) (BIII). No data were found regarding safety and immunogenicity of the 7valent conjugate pneumococcal vaccine among HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made. Antibiotic prophylaxis is recommended for preventing infection with encapsulated organisms (e.g., Stre. pneumoniae , Ha. influenzae , and Ne. meningitidis ) among allogeneic recipients with chronic GVHD for as long as active chronic GVHD treatment is administered (59 ) (BIII). Trimethoprim-sulfamethasaxole (TMP-SMZ) administered for Pneumocystis carinii pneumonia (PCP) prophylaxis will also provide protection against pneumococcal infections. However, no data were found to support using TMP-SMZ prophylaxis among HSCT recipients solely for the purpose of preventing Stre. pneumoniae disease. Certain strains of Stre. pneumoniae are resistant to TMP-SMZ and penicillin. Recommendations for preventing pneumococcal infections are the same for allogeneic or autologous recipients.
As with adults, pediatric HSCT recipients aged ≈2 years should be administered the current 23-valent pneumococcal polysaccharide vaccine because the vaccine can be effective (BIII). However, this vaccine should not be administered to children aged <2 years because it is not effective among that age population (DI). No data were found regarding safety and immunogenicity of the 7-valent conjugate pneumococcal vaccine among pediatric HSCT recipients; therefore, no recommendation regarding use of this vaccine can be made.
The induction course is usually started at engraftment (AI), although physicians can add a brief prophylactic course during HSCT preconditioning (CIII) (Appendix).
Preemptive strategy against early CMV (i.e., <100 days after HSCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HSCT recipients of seropositive donor cells (i.e., D-positive or R-negative) because of the low attack rate of active CMV infection if screened or filtered blood product support is used (BII). Preemptive strategy restricts ganciclovir use for those patients who have evidence of CMV infection after HSCT. It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV infection after HSCT and to enable immediate administration of ganciclovir after CMV infection has been detected. Allogeneic recipients at risk should be screened ≈1 times/week from 10 days to 100 days after HSCT (i.e., phase II) for the presence of CMV viremia or antigenemia (AIII).
HSCT physicians should select one of two diagnostic tests to determine the need for preemptive treatment. Currently, the detection of CMV pp65 antigen in leukocytes (antigenemia) (79,80 ) is preferred for screening for preemptive treatment because it is more rapid and sensitive than culture and has good positive predictive value (79-81 ). Direct detection of CMV-DNA (deoxyribonucleic acid) by polymerase chain reaction (PCR) (82 ) is very sensitive but has a low positive predictive value (79 ). Although CMV-DNA PCR is less sensitive than whole blood or leukocyte PCR, plasma CMV-DNA PCR is useful during neutropenia, when the number of leukocytes/slide is too low to allow CMV pp65 antigenemia testing.
Virus culture of urine, saliva, blood, or bronchoalveolar washings by rapid shell-vial culture (83 ) or routine culture (84,85 ) can be used; however, viral culture techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. Also, rapid shell-viral cultures require ≈48 hours and routine viral cultures can require weeks to obtain final results. Thus, viral culture techniques are less satisfactory than PCR or antigenemia tests. HSCT centers without access to PCR or antigenemia tests should use prophylaxis rather than preemptive therapy for CMV disease prevention (86 ) (BII). Physicians do use other diagnostic tests (e.g., hybrid capture CMV-DNA assay, Version 2.0 [87 ] or CMV pp67 viral RNA [ribonucleic acid] detection) (88 ); however, limited data were found regarding use among HSCT recipients, and therefore, no recommendation for use can be made.
Allogeneic recipients £100 days after HSCT (i.e., during phase II) should begin preemptive treatment with ganciclovir if CMV viremia or any antigenemia is detected or if the recipient has ≈2 consecutively positive CMV-DNA PCR tests (BIII). After preemptive treatment has been started, maintenance ganciclovir is usually continued until 100 days after HSCT or for a minimum of 3 weeks, whichever is longer (AI) (Appendix). Antigen or PCR tests should be negative when ganciclovir is stopped. Studies report that a shorter course of ganciclovir (e.g., for 3 weeks or until negative PCR or antigenemia occurs) (89-91 ) might provide adequate CMV prevention with less toxicity, but routine weekly screening by pp65 antigen or PCR test is necessary after stopping ganciclovir because CMV reactivation can occur (BIII).
Presently, only the intravenous formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (BIII). No recommendation for oral ganciclovir use among HSCT recipients can be made because clinical trials evaluating its efficacy are still in progress. One group has used ganciclovir and foscarnet on alternate days for CMV prevention (92 ), but no recommendation can be made regarding this strategy because of limited data. Patients who are ganciclovirintolerant should be administered foscarnet instead (93 ) (BII) (Appendix). HSCT recipients receiving ganciclovir should have ANCs checked ≈2 times/week (BIII). Researchers report managing ganciclovir-associated neutropenia by adding G-CSF (94 ) or temporarily stopping ganciclovir for ≈2 days if the patient's ANC is <1,000 (CIII). Ganciclovir can be restarted when the patient's ANC is ≈1,000 for 2 consecutive days. Alternatively, researchers report substituting foscarnet for ganciclovir if a) the HSCT recipient is still CMV viremic or antigenemic or b) the ANC remains <1,000 for >5 days after ganciclovir has been stopped (CIII) (Appendix). Because neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII).
Currently, no benefit has been reported from routinely administering ganciclovir prophylaxis to all HSCT recipients at >100 days after HSCT (i.e., during phase III). However, persons with high risk for late CMV disease should be routinely screened biweekly for evidence of CMV reactivation as long as substantial immunocompromise persists (BIII). Risk factors for late CMV disease include allogeneic HSCT accompanied by chronic GVHD, steroid use, low CD4 counts, delay in high avidity anti-CMV antibody, and recipients of matched unrelated or T-cell-depleted HSCTs who are at high risk (95-99 ). If CMV is still detectable by routine screening ≈100 days after HSCT, ganciclovir should be continued until CMV is no longer detectable (AI). If low-grade CMV antigenemia (<5 positive cells/slide) is detected on routine screening, the antigenemia test should be repeated in 3 days (BIII). If CMV antigenemia indicates ≈5 cells/slide, PCR is positive, or the shell-vial culture detects CMV viremia, a 3-week course of preemptive ganciclovir treatment should be administered (BIII) (Appendix). Ganciclovir should also be started if the patient has had ≈2 consecutively positive viremia or PCR tests (e.g., in a person receiving steroids for GVHD or who received ganciclovir or foscarnet at <100 days after HSCT). Current investigational strategies for preventing late CMV disease include the use of targeted prophylaxis with antiviral drugs and cellular immunotherapy for those with deficient or absent CMV-specific immune system function.
If viremia persists after 4 weeks of ganciclovir preemptive therapy or if the level of antigenemia continues to rise after 3 weeks of therapy, ganciclovir-resistant CMV should be suspected. If CMV viremia recurs during continuous treatment with ganciclovir, researchers report restarting ganciclovir induction (100 ) or stopping ganciclovir and starting foscarnet (CIII). Limited data were found regarding the use of foscarnet among HSCT recipients for either CMV prophylaxis or preemptive therapy (92,93 ).
Infusion of donor-derived CMV-specific clones of CD8+ T-cells into the transplant recipient is being evaluated under FDA Investigational New Drug authorization; therefore, no recommendation can be made. Although, in a substantial cooperative study, high-dose acyclovir has had certain efficacy for preventing CMV disease (101 ), its utility is limited in a setting where more potent anti-CMV agents (e.g., ganciclovir) are used (102 ). Acyclovir is not effective in preventing CMV disease af-ter autologous HSCT (103 ) and is, therefore, not recommended for CMV preemptive therapy (DII). Consequently, valacyclovir, although under study for use among HSCT recipients, is presumed to be less effective than ganciclovir against CMV and is currently not recommended for CMV disease prevention (DII).
Although HSCT physicians continue to use IVIG for immune system modulation, IVIG is not recommended for CMV disease prophylaxis among HSCT recipients (DI). Cidofovir, a nucleoside analog, is approved by FDA for the treatment of AIDS-associated CMV retinitis. The drug's major disadvantage is nephrotoxicity. Cidofovir is currently in FDA phase 1 trial for use among HSCT recipients; therefore, recommendations for its use cannot be made.
Use of CMV-negative or leukocyte-reduced blood products is not routinely required for all autologous recipients because most have a substantially lower risk for CMV disease. However, CMV-negative or leukocyte-reduced blood products can be used for CMV-seronegative autologous recipients (CIII). Researchers report that CMV seropositive autologous recipients be evaluated for preemptive therapy if they have underlying hematologic malignancies (e.g., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-chlorodeoxyadenosine (CDA) (CIII). This subpopulation of autologous recipients should be monitored weekly from time of engraftment until 60 days after HSCT for CMV reactivation, preferably with quantitative CMV pp65 antigen (80 ) or quantitative PCR (BII).
Autologous recipients at high risk who experience CMV antigenemia (i.e., blood levels of ≈5 positive cells/slide) should receive 3 weeks of preemptive treatment with ganciclovir or foscarnet (80 ), but CD34+-selected patients should be treated at any level of antigenemia (BII) (Appendix). Prophylactic approach to CMV disease prevention is not appropriate for CMV-seropositive autologous recipients. Indications for the use of CMV prophylaxis or preemptive treatment are the same for children or adults.
## Recommendations regarding ebv
## Preventing exposure
All transplant candidates, particularly those who are EBV-seronegative, should be advised of behaviors that could decrease the likelihood of EBV exposure (AII). For example, HSCT recipients and candidates should follow safe hygiene practices (e.g., frequent hand washing [AIII] and avoiding the sharing of cups, glasses, and eating utensils with others) (104 ) (BIII), and they should avoid contact with potentially infected respiratory secretions and saliva (104 ) (AII).
## Preventing disease
Infusion of donor-derived, EBV-specific cytotoxic Tlymphocytes has demonstrated promise in the prophylaxis of EBV-lymphoma among recipients of T-cell-depleted unrelated or mismatched allogeneic recipients (105,106 ). However, insufficient data were found to recommend its use. Prophylaxis or preemptive therapy with acyclovir is not recommended because of lack of efficacy (107,108 ) (DII).
## Recommendations regarding hsv
## Preventing exposure
HSCT candidates should be tested for serum anti-HSV IgG before transplant (AIII); however, type-specific anti-HSV IgG serology testing is not necessary. Only FDA-licensed or approved tests should be used. All HSCT candidates, particularly those who are HSV-seronegative, should be informed of the importance of avoiding HSV infection while immunocompromised and should be advised of behaviors that will decrease the likelihood of HSV exposure (AII). HSCT recipients and candidates should avoid sharing cups, glasses, and eating utensils with others (BIII). Sexually active patients who are not in a long-term monogamous relationship should always use latex condoms during sexual contact to reduce the risk for exposure to HSV as well as other sexually transmitted pathogens (AII). However, even long-time monogamous pairs can be discordant for HSV infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should ask partners to be tested for serum HSV IgG antibody. If the partners are discordant, they should consider using latex condoms during sexual contact to reduce the risk for exposure to this sexually transmitted OI (CIII). Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (62 ) (AI) to prevent transmission of HSV to HSCT recipients.
## Preventing disease and disease recurrence
Acyclovir. Acyclovir prophylaxis should be offered to all HSVseropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant period (109-113 ) (AI). Standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HSCT (BIII) (Appendix). Without supportive data from controlled studies, routine use of antiviral prophylaxis for >30 days after HSCT to prevent HSV is not recommended (DIII). Routine acyclovir prophylaxis is not indicated for HSV-seronegative HSCT recipients, even if the donors are HSV-seropositive (DIII). Researchers have proposed administration of ganciclovir prophylaxis alone (86 ) to HSCT recipients who required simultaneous prophylaxis for CMV and HSV after HSCT (CIII) because ganciclovir has in vitro activity against CMV and HSV 1 and 2, although ganciclovir has not been approved for use against HSV.
Valacyclovir. Researchers have reported valacyclovir use for preventing HSV among HSCT recipients (CIII); however, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients [bib_ref] Long-term safety of valaciclovir for suppression of herpes simplex virus infections, Chulay [/bib_ref]. Controlled trial data among HSCT recipients are limited [bib_ref] Long-term safety of valaciclovir for suppression of herpes simplex virus infections, Chulay [/bib_ref] , and the FDA has not approved valacyclovir for use among recipients. Physicians wishing to use valacyclovir among recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix).
Foscarnet. Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HSCT recipients (DIII).
Famciclovir. Presently, data regarding safety and efficacy of famciclovir among HSCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made.
## Other recommendations
HSV prophylaxis lasting >30 days after HSCT might be considered for persons with frequent recurrent HSV (CIII) (Appendix). Acyclovir can be used during phase I for administration to HSV-seropositive autologous recipients who are likely to experience substantial mucositis from the conditioning regimen (CIII). Antiviral prophylaxis doses should be modified for use among children (Appendix), but no published data were found regarding valacyclovir safety and efficacy among children.
## Recommendations regarding vzv
## Preventing exposure
HSCT candidates should be tested for the presence of serum anti-VZV IgG antibodies (AIII). However, these tests are not 100% reliable, particularly among severely immunosuppressed patients. Researchers recommend that a past history of varicella accompanied by a positive titer is more likely to indicate the presence of immunity to VZV than a low positive titer alone. All HSCT candidates and recipients, particularly those who are VZV-seronegative, should be informed of the potential seriousness of VZV disease among immunocompromised persons and advised of strategies to decrease their risk for VZV exposure (116-122 ) (AII).
Although researchers report that the majority of VZV disease after HSCT is caused by reactivation of endogenous VZV, HSCT candidates and recipients who are VZVseronegative, or VZV-seropositive and immunocompromised, should avoid exposure to persons with active VZV infections (123 ) (AII). HCWs, family members, household contacts, and visitors who are healthy and do not have a reported history of varicella infection or who are VZV-seronegative should receive VZV vaccination before being allowed to visit or have direct contact with an HSCT recipient (AIII). Ideally, VZV-susceptible family members, household contacts, and potential visitors of immunocompromised HSCT recipients should be vaccinated as soon as the decision is made to perform HSCT. The vaccination dose or doses should be completed ≈4 weeks before the conditioning regimen begins or ≈6 weeks (42 days) before the HSCT is performed (BIII).
HSCT recipients and candidates undergoing conditioning therapy should avoid contact with any VZV vaccine recipient who experiences a rash after vaccination (BIII). When this rash occurs, it usually appears 14-21 days after VZV vaccination (median: 22 days; range: 5-35 days) (personal communication from Robert G. Sharrar, M.D., Merck & Co., Inc.). However, to date, no serious disease has been reported among immuno-compromised patients from transmission of VZV vaccine virus, and the VZV vaccine strain is susceptible to acyclovir.
All HSCT recipients with VZV disease should be placed under airborne and contact precautions (62 ) (AII) to prevent transmission to other HSCT recipients. Contact precautions should be continued until all skin lesions are crusted. Airborne precautions should be instituted 10 days after exposure to VZV and continued until 21 days after last exposure or 28 days postexposure if the patient received varicella-zoster immunoglobulin (VZIG)* (62 ) (AI) because a person infected with VZV can be infectious before the rash appears.
## Preventing disease
VZIG. VZV-seronegative HSCT recipients should be administered VZIG as soon as possible but ideally within 96 hours after close or household contact with a person having either chickenpox or shingles if the HSCT recipient is not immunocompetent (i.e., allogeneic patient <24 months after HSCT, ≈24 months after HSCT and on immunosuppressive therapy, or having chronic GVHD) (AII). Researchers report VZIG administration for VZV exposure as described for HSCT recipients who were VZV-seropositive before HSCT (CIII).
Because of the high morbidity of VZV-associated disease among severely immunocompromised HSCT recipients and until further data are published, HSCT physicians should administer VZIG to all VZV-seronegative HSCT recipients or candidates undergoing conditioning therapy who are exposed to a VZV vaccinee having a varicella-like rash (BIII). Researchers also report VZIG administration for this situation for VZV-seropositive HSCT recipients and candidates undergoing conditioning therapy (CIII). These recommendations are made because the vaccinee might be unknowingly incubating wild-type varicella, particularly during the first 14 days after varicella vaccination, and because vaccine-strain VZV has been rarely transmitted by VZV vaccinees with vesicular rashes postvaccination.
If VZV-seronegative HSCT recipients or candidates undergoing conditioning therapy are closely exposed to varicella >3 weeks after receiving VZIG, they should be administered another dose of VZIG (120 ) (BIII). Researchers also recommend VZIG administration for this condition for VZV-seropositive HSCT recipients and candidates undergoing conditioning therapy (CIII). Antiviral Drugs. Any HSCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash (particularly after exposure to a person with wild-type varicella or shingles) should receive preemptive intravenous acyclovir until ≈2 days after all lesions have crusted (BIII) (Appendix). Any HSCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash after exposure to a VZV vaccinee with a rash should be administered intravenous acyclovir preemptively to prevent severe, disseminated VZV disease (BII). Acyclovir should be administered until 2 days after all lesions have crusted. Long-term acyclovir prophylaxis to prevent recurrent VZV infection (e.g., during the first 6 months after HSCT) is not routinely recommended (124-126 ) (DIII); however, this therapy could be considered for use among HSCT recipients with severe, long-term immunodeficiency (CIII). When acyclovir resistance occurs among patients, HSCT physicians should use foscarnet for preemptive treatment of VZV disease (127 ) (BIII). Researchers report valacyclovir use for preventing HSV among HSCT recipients (CIII). However, preliminary data demonstrate that very high doses of valacyclovir (8 g/day) were associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome among HSCT recipients [bib_ref] Long-term safety of valaciclovir for suppression of herpes simplex virus infections, Chulay [/bib_ref]. Controlled trial data regarding HSCT recipients are limited [bib_ref] Long-term safety of valaciclovir for suppression of herpes simplex virus infections, Chulay [/bib_ref] , and the FDA has not approved valacyclovir for use among HSCT recipients. Physicians wishing to use valacyclovir among HSCT recipients with renal impairment should exercise caution and decrease doses as needed (BIII) (Appendix). No data were found demonstrating safety and efficacy of preemptive treatment of famciclovir against herpes zoster among HSCT recipients. Consequently, no recommendation for its use can be made.
Live-Attenuated VZV Vaccine. VZV vaccine use is contraindicated among HSCT recipients <24 months after HSCT (128 ) (EIII). Use of VZV vaccine among HSCT recipients is restricted to research protocols for recipients ≈24 months after HSCT who are presumed immunocompetent. Further research is needed to determine the safety, immunogenicity, and efficacy of VZV vaccine among HSCT recipients.
## Other recommendations
An inactivated VZV vaccine has been used investigationally among HSCT recipients [bib_ref] Early reconstitution of immunity and decreased severity of herpes zoster in bone..., Redman [/bib_ref] ; however, more studies are needed before a recommendation regarding its use can be made. Recommendations for VZV prevention are the same for allogeneic or autologous recipients. Recommendations for preventing VZV disease among pediatric or adult HSCT recipients are the same, except that appropriate dose adjustments for VZIG should be made for pediatric HSCT recipients (AIII) (Appendix).
## Recommendations regarding crv infections: influenza, respiratory syncytial virus, parainfluenza virus, and adenovirus
## Preventing exposure
Preventing CRV exposure is critical in preventing CRV disease [bib_ref] Nosocomial respiratory syncytial virus infections: prevention and control in bone marrow transplant..., Garcia [/bib_ref] [bib_ref] Infection control of nosocomial respiratory viral disease in the immunocompromised host, Raad [/bib_ref]. To prevent nosocomial CRV transmission, HSCT recipients and their HCWs should always follow HSCT infection control guidelines (AIII). To minimize the risk for CRV transmission, HCWs and visitors with upper respiratory infection (URI) symptoms should be restricted from contact with HSCT recipients and HSCT candidates undergoing conditioning therapy (AIII). At a minimum, active clinical surveillance for CRV disease should be conducted on all hospitalized HSCT recipients and candidates undergoing conditioning therapy; this clinical surveillance should include daily screening for signs and symptoms of CRV (e.g., URI or lower respiratory infection [LRI]) (AIII). Viral cultures of asymptomatic HSCT candidates are unlikely to be useful. HSCT recipients with URI or LRI symptoms should be placed under contact precautions to avoid transmitting infection to other HSCT candidates and recipients, HCWs, and visitors until the etiology of illness is identified (62 ) (BIII). Optimal isolation precautions should be modified as needed after the etiology is identified (AIII). HSCT recipients and candidates, their family members and visitors, and all HCWs should be informed regarding CRV infection control measures and the potential severity of CRV infections among HSCT recipients (130-140 ) (BIII). Physicians have routinely conducted culturebased CRV surveillance among HSCT recipients; however, the cost effectiveness of this approach has not been evaluated.
Influenza vaccination of family members and close or household contacts is strongly recommended during each influenza season (i.e., October-May) starting the season before HSCT and continuing ≈24 months after HSCT (141 ) (AI) to prevent influenza exposure among the recipients or candidates. All family members and close or household contacts of HSCT recipients who remain immunocompromised ≈24 months after HSCT should continue to be vaccinated annually as long as the HSCT recipient's immuno-compromise persists (141 ) (AI). Seasonal influenza vaccination is strongly recommended for all HCWs of HSCT recipients (142,143 ) (AI).
If HCWs, family members, or other close contacts of HSCT recipients receive influenza vaccination during an influenza A outbreak, they should receive amantadine or rimantadine chemoprophylaxis for 2 weeks after influenza vaccination (BI) while the vaccinee experiences an immunologic response to the vaccine. Such a strategy is likely to prevent transmission of influenza A to HCWs and other close contacts of HSCT recipients, which could prevent influenza A transmission to HSCT recipients themselves. However, if a nosocomial outbreak occurs with an influenza A strain that is not contained in the available influenza vaccine, all healthy family members, close and household contacts, and HCWs of HSCT recipients and candidates should be administered influenza A chemoprophylaxis with amantadine or rimantadine until the end of the outbreak (141 ) (BIII).
In 1999, two neuroaminidase inhibitors (zanamivir and oseltamivir) were approved for treatment of influenza, but are not currently approved for prophylaxis. To date, experience is limited regarding use of zanamivir or oseltamivir in the treatment or prophylaxis of influenza among HSCT settings. However, HCWs, family members, or other close contacts can be offered a neuroaminidase inhibitor (e.g., zanamivir or oseltamivir) using the same strategies outlined previously, if a) rimantadine or amantadine cannot be tolerated, b) the outbreak strain of influenza A is amantadine or rimantadine-resistant, or c) the outbreak strain is influenza B (144-147 ) (BI). Zanamivir can be administered to persons aged ≈12 years, and oseltamivir can be administered to persons aged ≈18 years. Patients with influenza should be placed under droplet and standard precautions (AIII) to prevent transmission of influenza to HSCT recipients. HCWs with influenza should be excused from patient care until they are no longer infectious (AIII).
## Preventing disease
HSCT physicians should determine the etiology of a URI in an HSCT recipient or candidate undergoing conditioning therapy, if possible, because respiratory syncytial virus (RSV), influenza, parainfluenza, and adenovirus URIs can progress to more serious LRI, and certain CRVs can be treated (BIII). Appropriate diagnostic samples include nasopharyngeal washes, swabs or aspirates, throat swabs, and bronchoalveolar lavage (BAL) fluid. HSCT candidates with URI symptoms at the time conditioning therapy is scheduled to start should postpone their conditioning regimen until the URIs resolve, if possible, because certain URIs might progress to LRI during immunosuppression [bib_ref] Infection control of nosocomial respiratory viral disease in the immunocompromised host, Raad [/bib_ref] [bib_ref] Community respiratory virus infections among hospitalized adult bone marrow transplant recipients, Whimbey [/bib_ref] [bib_ref] Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus..., Whimbey [/bib_ref] [bib_ref] Coronavirus pneumonia following autologous bone marrow transplantation for breast cancer, Folz [/bib_ref] (BIII).
## Recommendations regarding influenza.
Life-long seasonal influenza vaccination is recommended for all HSCT candidates and recipients, beginning during the influenza season before HSCT and resuming ≈6 months after HSCT (142 ) (BIII). Influenza vaccinations administered to HSCT recipients <6 months after HSCT are unlikely to be beneficial and are not recommended (142 ) (DII). HSCT recipients <6 months after HSCT should receive chemoprophylaxis with amantadine or rimantadine during community or nosocomial influenza A outbreaks (BIII). These drugs are not effective against influenza B. Additionally, antiviral-resistant strains of influenza can emerge during treatment with amantadine or rimantadine and transmission of resistant strains can occur [bib_ref] Common emergence of amantadine-and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults, Englund [/bib_ref] [bib_ref] Prolonged shedding of amantadine-resistant influenzae A viruses by immunodeficient patients: detection by..., Klimov [/bib_ref]. During such outbreaks, HSCT recipients 6-24 months after HSCT, or >24 months after HSCT and still substantially immunocompromised (i.e., receiving immunosuppressive therapy, have had a relapse of their underlying disease, or have GVHD) and who have not yet received a current influenza vaccination, should be vaccinated against influenza immediately (BIII). Additionally, to allow sufficient time for the patient to experience an immunologic response to influenza vaccine, chemoprophylaxis with amantadine or rimantadine can be used for these HSCT recipients for 2 weeks after vaccination during a nosocomial or community influenza A outbreak (CIII). Influenza A chemoprophylaxis with amantadine or rimantadine has been recommended for all influenza A-exposed HSCT recipients <24 months after HSCT or ≈24 months after HSCT and substantially immunocompromised regardless of vaccination history, because of their likely suboptimal immunologic response to influenza vaccine [bib_ref] Antibody response to a twodose regimen of influenza vaccine in allogeneic T..., Engelhard [/bib_ref] [bib_ref] Prevention and treatment of influenza in immunocompromised patients, Hayden [/bib_ref]. However, no recommendation regarding such chemoprophylaxis can be made because of lack of data.
To prevent severe disease, early preemptive therapy with amantadine or rimantadine has been reported for HSCT recipients with unexplained acute URI or LRI symptoms during a community or nosocomial outbreak of influenza A. However, the effectiveness in preventing influenza-related complications and the safety of this strategy have not been evaluated among HSCT recipients. Therefore, data are insufficient to make a recommendation.
Neuroaminidase inhibitors (zanimivir and oseltamivir), intravenous and aerosol ribavirin, and combination drug therapy (e.g., rimantadine or amantadine with ribavirin or interferon) [bib_ref] Prevention and treatment of influenza in immunocompromised patients, Hayden [/bib_ref] [bib_ref] Intravenous ribavirin by constant infusion for serious influenza and parainfluenza virus infection, Hayden [/bib_ref] [bib_ref] Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza, Hayden [/bib_ref] [bib_ref] Combination antiviral therapy for respiratory virus infections, Hayden [/bib_ref] have been proposed for investigational, preemptive treatment to prevent severe influenza disease among HSCT recipients. However, because of lack of data, no recommendation for use of these strategies among HSCT recipients can be made.
## Recommendations regarding rsv.
Respiratory secretions of any hospitalized HSCT candidate or recipient who experiences signs or␣ symptoms of CRV infection should be tested promptly by viral culture and rapid diagnostic tests for RSV (BIII). If two diagnostic samples taken ≈2 days apart do not identify a respiratory pathogen despite persistence of respiratory symptoms, BAL and further testing are advised (BIII). This testing is critical because of the high morbidity and case fatality of RSV disease among HSCT recipients [bib_ref] Respiratory syncytial virus infections in adult bone marrow transplant recipients, Martin [/bib_ref] [bib_ref] Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow..., Hertz [/bib_ref]. HSCT recipients, particularly those who are preengraftment and at highest risk for severe RSV pneumonia, should have their illness diagnosed early (i.e., during RSV URI), and their illness should be treated aggressively to prevent fatal RSV disease (BIII).
Although a definitive, uniformly effective preemptive therapy for RSV infection among HSCT recipients has not been identified, certain strategies have been proposed, including use of aerosolized ribavirin [bib_ref] Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow..., Hertz [/bib_ref] [bib_ref] Successful therapy with ribavirin of late onset respiratory syncytial virus pneumonitis complicating..., Win [/bib_ref] , RSV antibodies (i.e., passive immunization with high RSV-titered IVIG or RSV immunoglobulin) in combination with aerosolized ribavirin [bib_ref] Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus..., Whimbey [/bib_ref] [bib_ref] Immunotherapy of respiratory syncytial virus pneumonia following bone marrow transplantation, Devincenzo [/bib_ref] , and RSV monoclonal antibody. Clinical trials are currently underway to evaluate the efficacy of these strategies. No recommendation regarding the optimal method for RSV prevention and preemptive therapy can be made because of limited data. Further, current data do not support use of intravenous ribavirin for preemptive therapy for RSV pneumonia among HSCT recipients (60 ) (DIII), and nocommercially licensed vaccines against RSV are currently available.
## Recommendations regarding parainfluenza virus and
Adenovirus. Immuno-prophylaxis, chemoprophylaxis, and preemptive treatment for parainfluenza virus and adenovirus infections among HSCT recipients have been proposed [bib_ref] Increasing incidence of adenovirus disease in bone marrow transplant recipients, Flomenberg [/bib_ref] [bib_ref] Prevention and treatment of respiratory syncytial virus and parainfluenza viruses in immunocompromised..., Englund [/bib_ref]. However, no recommendation can be made in these guidelines because of insufficient data. No commercially licensed vaccines against parainfluenza or adenovirus are currently available.
## Other disease prevention recommendations
The recommendations for preventing CRV infections and their recurrence are the same for allogeneic or autologous recipients. Generally, these recommendations apply to children or adults, but with appropriate adjustments in antiviral drug and influenza vaccine doses for children (Appendix).
For pediatric HSCT recipients and candidates aged >6 months, annual seasonal influenza vaccination is recommended HSCT (BIII). Children aged <9 years who are receiving influenza vaccination for the first time require two doses administered ≈1 months apart (AI). Healthy children who receive influenza vaccination for the first time might not generate protective antibodies until 2 weeks after receipt of the second dose of influenza vaccine. Therefore, during an influenza A outbreak, pediatric recipients aged <9 years, ≈6 months after HSCT, and receiving their first influenza vaccination, should be administered ≈6 weeks of influenza A chemoprophylaxis after the first dose of influenza vaccine (141 ) (BIII) (Appendix). Amantadine and rimantadine are not FDA-approved for children aged <1 year (141,161 ) (DIII).
To prevent RSV disease, researchers report substituting RSV-IVIG for IVIG during RSV season (i.e., November-April) for pediatric recipients (i.e., children aged <18 years) who receive routine IVIG therapy (164 ) (i.e., those with hypogammaglobulinemia) (CIII) (Appendix). Other researchers report that pediatric recipients with RSV can be considered for preemptive therapy (e.g., during URI or early LRI) with aerosolized ribavirin (CIII), although this therapy remains controversial (164 ) (Appendix). Droplet and contact precautions for the duration of illness are required for pediatric recipients for the duration of adenovirus (62 ) (AIII).
## Fungal infections
## General recommendations
## Preventing exposure
Limited data were found that demonstrate to what extent preventing fungal exposures is effective in preventing infection and disease. However, HSCT recipients and candidates undergoing conditioning therapy have been advised to avoid contact with certain areas and substances, including foods, that might increase a patient's risk for fungal exposures (CII). Specific precautions have included avoiding areas of high dust exposure (e.g., excavation sites, areas of building construction or renovation, chicken coops, and caves), occupations involving soil, and foods that contain molds (e.g., blue cheese).
## Preventing disease
Growth factors (e.g., GM-CSF and G-CSF) shorten the duration of neutropenia after HSCT [bib_ref] Clinical applications of hematopoietic growth factors, Vose [/bib_ref] ; however, no data were found that indicate which growth factors effectively reduce the attack rate of invasive fungal disease. Therefore, no recommendation for use of growth factors solely for prophylaxis against invasive fungal disease can be made.
Topical antifungal drugs, which are applied to the skin or mucosa (e.g., nystatin or clotrimazole), might reduce fungal colonization in the area of application. However, these agents have not been proven to prevent generation of locally invasive or disseminated yeast infections (e.g., candidiasis) or mold infections (e.g., aspergillosis) and are not recommended for their prophylaxis (DII). Performing fungal surveillance cultures is not indicated for asymptomatic HSCT recipients (166,167 ) (DII), but cultures should be obtained from symptomatic HSCT recipients (BIII).
## Recommendations regarding yeast infections
## Preventing exposure
Invasive candidiasis is usually caused by dissemination of endogenous Candida species that have colonized a patient's gastrointestinal tract [bib_ref] Bone-marrow transplantation and related infections, Crawford [/bib_ref]. Consequently, methods of preventing exogenous yeast exposure usually do not prevent invasive yeast infections after HSCT. However, because Candida species can be carried on the hands, HCWs and others in contact with HSCT recipients should follow appropriate hand-washing practices to safeguard patients from exposure (AIII).
## Preventing disease
Allogeneic recipients should be administered fluconazole prophylaxis to prevent invasive disease with fluconazole-susceptible Candida species during neutropenia, particularly among centers where Can. albicans is the predominant cause of invasive fungal disease preengraftment (AI) (Appendix). Because candidiasis occurs during phase I (169 ), fluconazole (400 mg/day by mouth or intravenously) should be administered [bib_ref] Controlled trial of fluconazole to prevent fungal infections in patients undergoing bone..., Goodman [/bib_ref] [bib_ref] Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation-a..., Slavin [/bib_ref] from the day of HSCT until engraftment (AII). However, fluconazole is not effective against certain Candida species, including Can. kruseiand Can. glabrata and is, therefore, not recommended for their prevention (DI). Further studies are needed to determine the optimal duration of fluconazole prophylaxis. Preliminary studies have reported that low-dose fluconazole prophylaxis (100-200 mg/day by mouth) among neutropenic patients has variable efficacy in preventing candidiasis [bib_ref] Low dose fluconazole prophylaxis in neutropenia, Donowitz [/bib_ref]. Therefore, this therapy is not recommended for HSCT recipients (DII). Oral, nonabsorbable antifungal drugs, including oral amphotericin B (500 mg suspension every 6 hours), nystatin, and clotrimazole troches, might reduce superficial colonization and control local mucosal candidiasis, but have not been demonstrated to reduce invasive candidiasis (CIII).
## Other recommendations
HSCT candidates with candidemia or invasive candidiasis can safely receive transplants (173 ) if a) their infection was diagnosed early and treated immediately and aggressively with amphotericin B or alternatively with appropriate doses of fluconazole if the organism is susceptible; and b) evidence of disease control is reported (e.g., by serial computed tomography scans) before the transplant (BIII). Such patients should continue receiving therapeutic doses of an appropriate antifungal drug throughout phase I (BII) and until a careful review of clinical, laboratory, and serial computed tomography scans verifies resolution of candidiasis (BII).
Because autologous recipients generally have an overall lower risk for invasive fungal infection than allogeneic recipients, certain autologous recipients do not require routine antiyeast prophylaxis (DIII). However, researchers recommend administering antiyeast prophylaxis to a subpopulation of autologous recipients with underlying hematologic malignancies (e.g., lymphoma or leukemia) and who have or will have prolonged neutropenia and mucosal damage from intense conditioning regimens or graft manipulation, or have received fludarabine or 2-CDA recently (BIII). Recommendations regarding preventing invasive yeast infections among pediatric or adult HSCT recipients are the same, except that appropriate dose adjustments for prophylactic drugs should be made for pediatric recipients (Appendix).
## Recommendations regarding mold infections
## Preventing exposure
Nosocomial mold infections among HSCT recipients result primarily from respiratory exposure to and direct contact with fungal spores [bib_ref] Nosocomial aspergillosis: environmental microbiology, hospital epidemiology, diagnosis and treatment, Walsh [/bib_ref]. Ongoing hospital construction and renovation have been associated with an increased risk for nosocomial mold infection, particularly aspergillosis, among severely immunocompromised patients [bib_ref] Construction activity: an independent risk factor for invasive aspergillosis and zygomycosis in..., Weems [/bib_ref] [bib_ref] Nosocomial fungal infection during hospital renovation, Krasinski [/bib_ref] [bib_ref] Refinements of environmental assessment during an outbreak investigation of invasive aspergillosis in..., Thio [/bib_ref]. Therefore, whenever possible, HSCT recipients who remain immunocompromised should avoid hospital construction or renovation areas (AIII). When constructing new HSCT centers or renovating old ones, hospital planners should ensure that rooms for HSCT patients have an adequate capacity to minimize fungal spore counts through use of - high-efficiency (>90%) particulate air (HEPA) filtration [bib_ref] Hammer PG 2 nd . Efficacy of infection control measures during a..., Opal [/bib_ref] (BIII);
- directed room airflow (i.e., positive air pressure in patient rooms in relation to corridor air pressure) so that air from patient rooms flows into the corridor (180 ) (BIII);
- correctly sealed rooms, including correctly sealed windows and electrical outlets (140 ) (BIII);
- high rates of room air exchange (i.e., >12 air changes/ hour) (140,178 ) (BIII); and
- barriers between patient care and renovation or construction areas (e.g., sealed plastic) that prevent dust from entering patient care areas and that are impermeable to Aspergillus species (175,179 ) (BIII).
Additionally, HSCT centers should be cleaned with care, particularly after hospital renovation or construction, to avoid exposing HSCT recipients and candidates to mold spores (174,176 ) (BIII).
## Preventing disease
No regimen has been reported to be clearly effective or superior in preventing aspergillosis, and therefore, no recommendation can be made. Further studies are needed to determine the optimal strategy for aspergillosis prevention. Moderate-dose (0.5 mg/kg/day) amphotericin B (181-184 ), low-dose (0.1-0.25 mg/kg/day) amphotericin B [bib_ref] Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin..., O'donnell [/bib_ref] [bib_ref] Low-dose amphotericin B prophylaxis against invasive Aspergillus infections in allogeneic marrow transplantation, Rousey [/bib_ref] [bib_ref] Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients, Perfect [/bib_ref] , intranasal amphotericin B spray, lipid formulations of amphotericin B [bib_ref] Experience with liposomal amphotericin-B in 60 patients undergoing high-dose therapy and bone..., Kruger [/bib_ref] [bib_ref] Prophylactic use of liposomal amphotericin B (AmBisome) against fungal infections: a randomized..., Tollemar [/bib_ref] , and aerosolized amphotericin B [bib_ref] Nebulized amphotericin B as prophylaxis against invasive aspergillosis in granulocytopenic patients, Conneally [/bib_ref] have been administered for aspergillosis prophylaxis, but data are limited regarding the safety and efficacy of these formulations among HSCT recipients. Additionally, itraconazole capsules are not recommended for fungal prophylaxis among HSCT recipients [bib_ref] Itraconazole in antifungal therapy, Cleary [/bib_ref] (DII) for three reasons. First, itraconazole capsules are poorly absorbed gastrointestinally, particularly among patients who are fasting [bib_ref] Treatment of aspergillosis with itraconazole, Jennings [/bib_ref] or receiving cytotoxic agents [bib_ref] Marked intra-and interpatient variability of itraconazole steady state plasma concentrations, Poirier [/bib_ref]. Second, persons taking itraconazole capsules do not achieve steady-state serum levels for 2 weeks [bib_ref] Multiple dose pharmacokinetics of an oral solution of itraconazole in autologous bone..., Prentice [/bib_ref] , and when achieved, these levels are lower than the average Aspergillus species minimum inhibitory concentration (MIC) among HSCT recipients [bib_ref] Use of itraconazole in treatment of prevention of invasive aspergillosis in bone..., Tam [/bib_ref]. Third, itraconazole has adverse interactions with other drugs (e.g., antiepileptics, rifampin, oral hypoglycemics, protease inhibitors, vinca alkaloids, cyclosporine, methylprednisolone, and warfarin-like anticoagulants) [bib_ref] In: Physician's desk reference (PDR), Biotech [/bib_ref]. Trials assessing the efficacy of the recently licensed cyclodextrin oral solution and intravenous formulations of itraconazole in preventing invasive fungal disease among HSCT recipients are in progress; however, no recommendations regarding its use for Aspergillus species infection prophylaxis can be made. For HSCT recipients whose respiratory specimens are culture positive for Aspergillus species, acute invasive aspergillosis should be diagnosed presumptivelyand treated preemptively and aggressively (e.g., with intravenous amphotericin) (AIII).
The risk for aspergillosis recurrence has been high among allogeneic recipients with preexisting invasive aspergillosis. Previously, allogeneic HSCTs were avoided among persons with uncontrolled, proven aspergillosis. However, HSCT cen-ter personnel have recently reported successful allogeneic or autologous HSCT among a limited number of persons who have had successfully treated, prior invasive pulmonary aspergillosis [bib_ref] Progress in the diagnosis and management of aspergillosis in bone marrow transplantation:..., Mcwhinney [/bib_ref] [bib_ref] Pulmonary resection for fungal infection in children undergoing bone marrow transplantation, Lupinetti [/bib_ref] [bib_ref] Invasive pulmonary aspergillosis prior to BMT in acute leukemia patients does not..., Richard [/bib_ref]. Because of limited data, no recommendations regarding strategies for preventing aspergillosis recurrence can be made.
## Protozoal and helminthic infections
## Recommendations regarding pcp
## Preventing exposure
Although a possible cause of PCP is reactivation of latent infection among immunocompromised persons, cases of person-to-person transmission of PCP have been reported [bib_ref] Transmission of Pneumocystic carinii from AIDS patients to other immunosuppressed patients: a..., Chave [/bib_ref] [bib_ref] Possible transfer of Pneumocystis carinii between immunodeficient patients, Goesch [/bib_ref] [bib_ref] Possible transfer of Pneumocystic carinii between kidney transplant recipients, Bensousan [/bib_ref] [bib_ref] Compromised host and infection. I: Pneumocystic carinii pneumonia, Ruskin [/bib_ref] [bib_ref] Pneumocystis carinii pneumonia in a family, Watanabe [/bib_ref]. Generally, standard precautions should be used for patients with PCP (62 ) (BIII), but researchers have reported patients with PCP being isolated (201,204 ) and contact precautions being used if evidence existed of person-to-person transmission in the institution (CIII). This subject remains controversial, and until further data are published, HSCT recipients should avoid exposure to persons with PCP (62 ) (CIII).
## Preventing disease and disease recurrence
Physicians should prescribe PCP prophylaxis for allogeneic recipients throughout all periods of immunocompromise [bib_ref] Pneumocystis carinii pneumonitis following bone marrow transplantation, Tuan [/bib_ref] after engraftment. Prophylaxis should be administered from engraftment until 6 months after HSCT (AII) for all patients, and >6 months after HSCT for the duration of immunosuppression for those who a) are receiving immunosuppressive therapy (e.g. prednisone or cyclosporine) (AI), or b) have chronic GVHD (BII). However, PCP prophylaxis can be initiated before engraftment if engraftment is delayed (CIII). Researchers report an additional 1-to 2-week course of PCP prophylaxis before HSCT (i.e., day -14 to day -2) (CIII).
Preferred PCP prophylaxis is TMP-SMZ (AII); however, if TMP-SMZ is administered before engraftment, the associated myelosuppression could delay engraftment, and patients might experience sensitivity to the drug. Every effort should be made to keep such patients on the drug, including assessment of desensitization therapy, although data regarding this technique among HSCT recipients are limited. For patients who cannot tolerate TMP-SMZ, physicians can choose to use alternative PCP prophylaxis regimens (e.g., dapsone) (208 ) (BIII). Use of aerosolized pentamidine [bib_ref] Pentamidine aerosol prophylaxis of Pneumocystis carinii pneumonia after BMT, Link [/bib_ref] is associated with the lowest PCP prevention rates and should only be used if other agents cannot be tolerated. Atovaquone is a possible alternative drug for PCP prophylaxis among dapsone intolerant persons with HIV infection [bib_ref] Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia..., Chan [/bib_ref] ; however, no recommendation regarding use of atovaquone among HSCT recipients can be made because of lack of data. Although data are limited, concomitant use of leucovorin (folinic acid) and TMP-SMZ is not recommended (211,212 ) (DIII). A patient's history of PCP should not be regarded as a contraindication to HSCT (213 ) (DIII).
Recurrent PCP among HSCT recipients is rare; however, patients with continued immunosuppression should remain on PCP prophylaxis until their immunosuppression is resolved (AI). The regimen recommended for preventing toxoplasmosis recurrence among HSCT recipients (i.e., TMP-SMZ) will also prevent PCP recurrence.
## Other recommendations
PCP prophylaxis should be considered for autologous recipients who have underlying hematologic malignancies (i.e., lymphoma or leukemia), are receiving intense conditioning regimens or graft manipulation, or have recently received fludarabine or 2-CDA (207,214 ) (BIII). PCP prophylaxis should be administered ≈6 months after HSCT if substantial immunosuppression or immunosuppressive therapy (e.g., steroids) persists (CIII). Use of PCP prophylaxis among other autologous recipients is controversial (CIII). Generally, indications for PCP prophylaxis are the same among children or adults, but pediatric doses should be used (Appendix).
## Recommendations regarding toxoplasma gondii preventing exposure
All HSCT recipients should be provided information regarding strategies to reduce their risk for Toxoplasma species exposure. Researchers report that potential donors for allogeneic HSCT be tested for To. gondii antibodies (215,216 ) by using FDA-licensed or -approved screening tests that include IgG antibody testing because To. gondii has been reported to be transmitted by leukocyte transfusion [bib_ref] Transmission of toxoplasmosis by leukocyte transfusion, Siegel [/bib_ref] and HSCT (218,219 ) (CIII).
## Preventing disease and disease recurrence
Because most toxoplasmosis among HSCT recipients is caused by disease reactivation, researchers report that candidates for allogeneic HSCT can be tested for IgG antibody to determine whether they are at risk for disease reactivation after HSCT (215,216,218 ) (CIII). However, the value of such testing is controversial because a limited number of patients who were seronegative for To. gondii pretransplant experienced the infection posttransplant [bib_ref] Bone Marrow Transplant Team. Disseminated toxoplasmosis in marrow recipients: a report of..., Chandrasekar [/bib_ref]. If testing is performed, only FDA-licensed or approved screening tests should be used.
Researchers recommend toxoplasmosis prophylaxis for seropositive allogeneic recipients with active GVHD or a prior history of toxoplasmic chorioretinitis [bib_ref] Prophylaxis of toxoplasmosis with pyrimethamine/sulfadoxine (Fansidar) in bone marrow transplant recipients, Foot [/bib_ref] [bib_ref] Fansidar: reactivation toxoplasmic retinochoroiditis in patients undergoing bone marrow transplantation: is there..., Peacock [/bib_ref] , but data demonstrating efficacy are limited (CIII). The optimal prophylactic regimen for toxoplasmosis among HSCT recipients has not been determined, but a proposed drug is TMP-SMZ (BII), although allogeneic recipients have experienced break-through clinical disease despite TMP-SMZ prophylaxis [bib_ref] Toxoplasma gondii infection in marrow transplant recipients: a 20 year experience, Slavin [/bib_ref]. For patients who are TMP-SMZ-intolerant, a combination of clindamycin, pyramethamine, and leucovorin can be substituted for To. gondii prophylaxis (Appendix). After therapy for toxoplasmosis, HSCT recipients should continue receiving suppressive doses of TMP-SMZ or an alternate regimen for the duration of their immunosuppression (BIII) (Appendix).
## Other recommendations
Recipients of autologous transplants are at negligible risk for toxoplasmosis reactivation [bib_ref] Toxoplasma gondii infection in marrow transplant recipients: a 20 year experience, Slavin [/bib_ref]. No prophylaxis or screening for toxoplasmosis infection is recommended for such patients (DIII). Indications for toxoplasmosis prophylaxis are the same among children or adults, but pediatric doses should be used among children (Appendix).
## Recommendations regarding strongyloides stercoralis preventing exposure
Allogeneic recipients should avoid contact with outhouses and cutaneous exposure to soil or other surfaces that might be contaminated with human feces (223 ) (AIII). Allogeneic recipients who work in settings (e.g., hospitals or institutions) where they could be exposed to fecal matter should wear gloves when working with patients or in areas with potential fecal contamination (AIII).
## Preventing disease and disease recurrence
Travel and residence histories should be obtained for all patients before HSCT to determine any exposures to highrisk areas (e.g., such moist temperate areas as the tropics, subtropics, or the southeastern United States and Europe) (223 ) (BIII). HSCT candidates who have unexplained peripheral eosinophilia or who have resided in or traveled to areas endemic for strongyloidiasis, even during the distant past, should be screened for asymptomatic strongyloidiasis before HSCT (BIII). Serologic testing with an enzymelinked immunosorbent assay is the preferred screening method and has a sensitivity and specificity of >90% (223,224 ) (BIII). FDA-licensed or -approved screening tests should be used. Although stool examinations for strongyloidiasis are specific, the sensitivity obtained from ≈3 stool examinations is 60%-70%; the sensitivity obtained from concentrated stool exams is, at best, 80%. A total of ≈3 stool examinations should be performed if serologic tests are unavailable or if strongyloidiasis is clinically suspected in a seronegative patient (BIII).
HSCT candidates whose screening tests before HSCT are positive for Strongyloides species, and those with an unexplained eosinophilia and a travel or residence history indicative of exposure to Strongyloides stercoralis should be empirically treated before transplantation [bib_ref] Pneumocystis carinii and parasitic infections in transplantation, Fishman [/bib_ref] , preferably with ivermectin (BIII), even if seronegative or stool-negative (Appendix).
To prevent recurrence among HSCT candidates with parasitologically confirmed strongyloidiasis, cure after therapy should be verified with ≈3 consecutive negative stool examinations before proceeding with HSCT (AIII). Data are insufficient to recommend a drug prophylaxis regimen after HSCT to prevent recurrence of strongyloidiasis. HSCT recipients who had strongyloidiasis before or after HSCT should be monitored carefully for signs and symptoms of recurrent infection for 6 months after treatment (BIII).
## Other recommendations
Hyperinfection strongyloidiasis has not been reported after autologous HSCT; however, the same screening precautions should be used among autologous recipients (BIII). Indications for empiric treatment for strongyloidiasis before HSCT are the same among children or adults except for children weighing <15 kg, for whom the preferred drug is thiabendazole (BIII) (Appendix).
## Recommendations regarding trypanosoma cruzi preventing exposure
HSCT physicians should be aware that Trypanosoma cruzi , the etiologic agent of Chagas' disease, can be transmitted congenitally, through blood transfusion [bib_ref] Trypanosoma cruzi in a low-to moderate-risk blood donor population: seroprevalence and possible..., Leiby [/bib_ref] , and possibly through HSCT. Additionally, treatment for persons infected with Tr. cruzi is not always effective, even during the acute stage of infection [bib_ref] Trypanosoma cruzi in a low-to moderate-risk blood donor population: seroprevalence and possible..., Leiby [/bib_ref]. Therefore, potential donors who were born, received a blood transfusion, or ever lived for ≈6 months in a Chagas' disease endemic area (e.g., parts of South and Central America and Mexico) should be screened serologically for anti-Tr. cruzi serum IgG antibody (228 ) (BIII). Persons who lived <6 months in a Chagas'-endemic area but who had high-risk living conditions (e.g., having had extensive exposure to the Chagas' disease vector -the reduviid bug -or having lived in dwellings with mud walls, unmilled logs and sticks, or a thatched roof) should also be screened for evidence of Tr. cruzi infection (BIII). Because Chagas' disease can be transmitted congenitally, researchers report that any person with extensive multigenerational maternal family histories of cardiac disease (e.g., cardiomegaly and arrhythmias) should be screened serologically for serum IgG anti-Tr. cruzi antibodies (227 ) (CIII). To decrease the risk for misdiagnosis by false-positive or false-negative serologic tests, Tr. cruzi screening should consist of ≈2 conventional serologic tests (e.g., enzyme immunoassay, indirect hemagglutination, indirect fluorescent antibody) or ≈1 conventional serologic tests, followed by a confirmatory serologic test (e.g., radioimmunoprecipitation assay) (229 ) (BIII). Persons with active Chagas' disease should not serve as HSCT donors (DIII). Researchers also recommend deferral of HSCT donation for a past history of Chagas' disease (CIII).
## Preventing disease
HSCT candidates who are at risk for being infected with Tr. cruzi should be screened for serum IgG anti-Tr. cruzi antibody (228 ) (BIII). Tr. cruzi seropositivity is not a contraindication to HSCT [bib_ref] Recipients and donors of bone marrow transplants suffering from Chagas' disease: management..., Dictar [/bib_ref] [bib_ref] Reactivation of chronic Chagas' disease following allogeneic bone marrow transplantation and successful..., Altclas [/bib_ref]. However, if an acute illness occurs in a Tr. cruzi-seropositive HSCT recipient, particularly during neutropenia, Tr. cruzi reactivation should be included in the differential diagnosis (230 ) (BIII). Researchers have proposed use of beznidazole or nifurtimox for preemptive therapy or prophylaxis of recurrent Tr. cruzi among seropositive HSCT recipients [bib_ref] Reactivation of chronic Chagas' disease following allogeneic bone marrow transplantation and successful..., Altclas [/bib_ref] [bib_ref] Chagas' disease after bone marrow transplantation, Altclas [/bib_ref] , but insufficient data were found to make a recommendation.*
## Other recommendations
Recommendations are the same for autologous or allogeneic recipients. However, recurrence of Chagas' disease is probably less likely to occur among autologous recipients because of the shorter duration of immunosuppression. Recommendations are the same among children or adults.
## Hospital infection control
## Room ventilation
HSCT center personnel should follow published guidelines for hospital room design and ventilation (140,180 ) (BIII). HSCT centers should also prevent birds from gaining access to hospital air-intake ducts (140,174 ) (AII). All allogeneic recipients should be placed in rooms with >12 air exchanges/ hour [bib_ref] Design, construction, and operation of healthy buildings; solutions to global and regional..., Streifel [/bib_ref] and point-of-use HEPA filters that are capable of removing particles ≈0.3 µm in diameter [bib_ref] Design, construction, and operation of healthy buildings; solutions to global and regional..., Streifel [/bib_ref] (AIII). Correct filtration is critical in HSCT centers with ongoing construction and renovation [bib_ref] Hammer PG 2 nd . Efficacy of infection control measures during a..., Opal [/bib_ref]. When portable HEPA filters are used as adjuncts to the primary ventilation system, they must be placed centrally in patient rooms so that space is available around all surfaces to allow free air circulation (BIII). The need for environmental HEPA filtration for autologous recipients has not been established. However, HEPA-filtered rooms should be evaluated for autologous recipients if they experience prolonged neutropenia, a substantial risk factor for nosocomial aspergillosis (CIII).
A laminar air flow (LAF) room contains filtered air that moves in parallel, unidirectional flow -the air enters the room from one wall and exits the room on the opposite wall. Although LAF has been demonstrated to protect patients from infection during aspergillosis outbreaks related to hospital construction [bib_ref] Control of an outbreak of nosocomial aspergillosis by laminar airflow isolation, Barnes [/bib_ref] [bib_ref] Impact of air filtration on nosocomial Aspergillus infections: unique risk to bone..., Sheretz [/bib_ref] , the value of routine LAF room use for all HSCT recipients is doubtful because substantial overall survival benefit has not been reported. During 1983, LAF rooms were preferred for allogeneic recipients with aplastic anemia and HLA-identical sibling donors because use of regular rooms was associated with a mortality rate that was approximately four times higher than for those recipients treated in LAF rooms [bib_ref] Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow..., Storb [/bib_ref]. However, the survival of aplastic anemia HSCT recipients during the late 1990s exceeds that reported during the early 1980s, and no studies have been done to determine whether HSCT recipients with aplastic anemia still have an improved survival rate when treated in an LAF room. Therefore, HSCT centers need not construct LAF rooms for each HSCT recipient. Use of LAF rooms, if available, is optional (CII).
Hospital rooms should have directed airflow so that air intake occurs at one side of the room and air exhaust occurs at the opposite side (140 ) (BIII). Each hospital room should also be well-sealed (e.g, around windows and electrical outlets) (140 ) (BIII). To provide consistent positive pressure in the recipient's room, HSCT centers should maintain consistent pressure differentials between the patient's room and the hallway or anteroom at >2.5 Pa (i.e., 0.01 inches by water gauge) (232,233 ) (BIII). Generally, hospital rooms for HSCT recipients should have positive room air pressure when compared with any adjoining hallways, toilets, and anterooms, if present.
Anterooms should have positive air pressure compared with hallways. An exception is the HSCT recipient with an active disease that has airborne transmission (e.g., pulmonary or laryngeal Mycobacteria tuberculosis or measles). These HSCT patients should be placed in negative isolation rooms (62 ) (BIII), and a room with an anteroom is recommended for such patients (180 ) (BIII). Whenever possible, HSCT centers should have self-closing doors to maintain constant pressure differentials among the HSCT recipients' room and anterooms, if available, and hallways (233 ) (BIII). To enable the nursing staff to observe the HSCT recipient even when the doors are closed, windows can be installed in either the door or the wall of the HSCT recipient's room (233 ) (CIII).
HSCT centers should provide backup emergency power and redundant air-handling and pressurization systems to maintain a constant number of air exchanges and room pressurization in the center when the central ventilation system is shut off for maintenance and repair (238 ) (BIII). Additionally, infection control personnel should work with maintenance personnel to develop protocols to protect HSCT centers at all times from bursts of mold spores that might occur when airhandling systems are restarted after routine maintenance shutdowns (BIII).
## Construction, renovation, and building cleaning
## Construction and renovation
Hospital construction and renovation have been associated with an increased risk for nosocomial fungal infection, particularly aspergillosis, among severely immuno-compromised patients [bib_ref] Construction activity: an independent risk factor for invasive aspergillosis and zygomycosis in..., Weems [/bib_ref] [bib_ref] Nosocomial fungal infection during hospital renovation, Krasinski [/bib_ref]. Therefore, persons responsible for HSCT center construction or renovation should consult published recommendations regarding environmental controls during construction (239,240 ) (AIII).
Whenever possible, HSCT recipients, HCWs, and visitors should avoid construction or renovation areas (240 ) (AIII). Also, equipment and supplies used by HSCT recipients or their HCWs should not be exposed to construction or renovation areas [bib_ref] Infection control issues in construction and renovation, Carter [/bib_ref]. When planning for construction or renovation, the HSCT center should include plans for intensified aspergillosis-control measures (AIII). Construction and renovation infection control planning committees should include engineers, architects, housekeeping staff, infection control personnel, the director of the HSCT center, the administration, and safety officers (241 ) (BIII).
When constructing new HSCT centers, planners should ensure that patient rooms will have adequate capacity to minimize fungal spore counts by following room ventilation recommendations. During outdoor construction and demolition, the intake air should be sealed (BIII), if possible; if not, filters should be checked frequently. Additionally, to protect HSCT patient care areas during fire drills and emergencies, weather stripping should be placed around stairwell doors, or alternatively, the stairwell air should be filtered to the level of safety of the adjacent hospital air (BIII). False ceilings should be avoided whenever possible (174 ) (BII). If use of false ceilings cannot be avoided, the area above false ceilings should be vacuumed routinely to minimize dust and, therefore, fungal exposure to patients (174 ) (BIII).
During hospital construction or renovation, hospitals should construct rigid, dust-proof barriers with airtight sealsbetween patient care and construction or renovation areas to prevent dust from entering patient care areas; these barriers (i.e., sealed drywall) should be impermeable to Aspergillus species [bib_ref] Construction activity: an independent risk factor for invasive aspergillosis and zygomycosis in..., Weems [/bib_ref] [bib_ref] Nosocomial fungal infection during hospital renovation, Krasinski [/bib_ref] [bib_ref] Hammer PG 2 nd . Efficacy of infection control measures during a..., Opal [/bib_ref] [bib_ref] Infection control issues in construction and renovation, Carter [/bib_ref] (BIII). If impervious barriers cannot be created around the construction or renovation area, patients should be moved from the area until renovation or construction is complete and the area has been cleaned appropriately (176 ) (BIII). HSCT centers should direct pedestrian traffic occurring near construction or renovation areas away from patient care areas to limit the opening and closing of doors or other barriers that might cause dust dispersion, entry of contaminated air, or tracking of dust into patient areas, particularly those in the HSCT center (176 ) (BIII). If possible, specific corridors, entrances, and exits should be dedicated to construction use only [bib_ref] Infection control issues in construction and renovation, Carter [/bib_ref]. An elevator to which patients do not have access also should be dedicated to construction use only [bib_ref] Infection control issues in construction and renovation, Carter [/bib_ref]. Construction workers, whose clothing might be contaminated with Aspergillus species spores, should use the construction elevator and avoid contact with patients, patient care areas, other elevators, and nonconstruction areas (BIII).
Hospital construction or renovation areas should have negative air pressure relative to that in adjacent patient care areas, if no contraindications exist for such pressure differential [bib_ref] Nosocomial fungal infection during hospital renovation, Krasinski [/bib_ref] [bib_ref] Hammer PG 2 nd . Efficacy of infection control measures during a..., Opal [/bib_ref] [bib_ref] Infection control issues in construction and renovation, Carter [/bib_ref] (BIII). Ideally, air from the construction or renovation areas should be exhausted to the outside of the hospital (176 ) (BIII) or if recirculated, it should be HEPA-filtered first (BIII).
Researchers have proposed that HSCT recipients wear the N95 respirator to prevent mold exposure during transportation near hospital construction or renovation areas (CIII) because the N95 respirators are regarded as effective against any aerosol. However, to be maximally effective, N95 respirators must be fit-tested and all users must be trained. With correct personnel fit-testing and training, N95 respirators reliably reduce aerosol exposure by 90%. Without fittesting and training, aerosol exposure would be reduced but not necessarily by 90%. For patients who cannot use or tolerate an N95 respirator, researchers have proposed using the powered air purifying respirator, which can be used by patients in wheelchairs. Limitations of the powered air purifying respirator include its cost and that it is not appropriate for young children and infants. General limitations of using respirators are that no commercially available respirator, including N95, has been tested specifically for its efficacy in reducing exposure to Aspergillus species in hospital construction or renovation areas, and no studies have been done that assess the usefulness and acceptability of using respirators among HSCT recipients. Standard surgical masks provide negligible protection against mold spores and are not recommended for this indication (DIII).
Newly constructed or renovated areas should be cleaned before patients are allowed to enter them (140,176 ) (AIII). Decontamination of fungal-contaminated areas that cannot be extracted and replaced should be done using copper-8-quinolate (179 ) (BIII). Also, areas above false ceilings located under or adjacent to construction areas should be vacuumed (174 ) (BIII). Additionally, the ventilation, direction of airflow, and room pressurization should be tested and correctly adjusted before patients are allowed to enter (BIII).
## Cleaning
HSCT centers should be cleaned ≈1 times/day with special attention to dust control (BIII). Exhaust vents, window sills, and all horizontal surfaces should be cleaned with cloths and mop heads that have been premoistened with an FDA-or Environmental Protection Agency (EPA)-registered hospital disinfectant (BIII). Thorough cleaning during and after any construction activity, including minor renovation projects, is critical (BIII).
HSCT center personnel should prohibit exposures of patients to such activities as vacuuming or other floor or carpet vacuuming that could cause aerosolization of fungal spores (e.g., Aspergillus species) (140 ) (AIII). Accordingly, doors to patient rooms should be closed when vacuuming HSCT center corridors. All vacuum cleaners used in the HSCT center should be fitted with HEPA filters. An FDA-or EPA-registered disinfectant [bib_ref] APIC guideline for selection and use of disinfectants, Rutala [/bib_ref] should be used daily for environmental disinfection and when wet vacuuming is performed in the HSCT center (BIII). If an HSCT center provides care for infants, phenolic disinfectants can be used to clean the floors only if the compound is diluted according to the product label; but phenolic compounds should not be used to clean basinets or incubators (246 ) (DIII).
Water leaks should be cleaned up and repaired as soon as possible but within 72 hours to prevent mold proliferation in floor and wall coverings, ceiling tiles, and cabinetry in and around all HSCT patients care areas (BIII). If cleanup and repair are delayed ≈72 hours after the water leak, the involved materials should be assumed to contain fungi and handled accordingly. Use of a moisture meter to detect water penetration of walls should be used whenever possible to guide decisionmaking (238 ) (BIII). For example, if the wall does not have <20% moisture content ≈72 hours after water penetration, it should be removed (BIII). Design and selection of furnishings should focus on creating and maintaining a dust-free environment. Flooring and finishes (i.e., wall coverings, window shades, and countertops) used in HSCT centers should be scrubbable, nonporous, easily disinfected, and they should collect minimal dust (BIII).
## Isolation and barrier precautions
HSCT center personnel should follow published guidelines for hospital isolation practices, including CDC guidelines for preventing nosocomial infections (62,140,248 ) (AIII). However, the efficacy of specific isolation and barrier precautions in preventing noso-comial infections among HSCT recipients has not been evaluated.
HSCT recipients should be placed in private (i.e., singlepatient) rooms (BIII). If contact with body fluids is anticipated, standard precautions should be followed (AIII). These precautions include hand washing and wearing appropriate gloves, surgical masks or eye and face protection, and gowns during procedures and activities that are likely to generate splashes or sprays of blood, body fluids, secretions or excretions, or cause soiling of clothing [bib_ref] Hospital Infection Control Practices Advisory Committee, Garner [/bib_ref]. When indicated, HSCT recipients should also be placed on airborne, droplet, or contact precautions in addition to standard precautions (62 ) (AIII). Careful observation of isolation precautions is critical in preventing transmission of infectious agents among HSCT recipients, HCWs, visitors, and other HSCT recipients. Physicians are cautioned that HSCT recipients might have a prolonged or episodic excretion of organisms (e.g., CMV).
Researchers have proposed that HSCT recipients wear surgical mask and gloves when exiting their hospital rooms before engraftment (CIII). All HSCT recipients who are immunocompromised (phases I-III of immune system recovery) and candidates undergoing conditioning therapy should minimize the time spent in crowded areas of the hospital (e.g., waiting areas and elevators) (BIII) to minimize potential exposure to persons with CRV infections.
## Hand hygiene
Hand washing is the single-most critical and effective procedure for preventing nosocomial infection [bib_ref] Hospital Infection Control Practices Advisory Committee, Garner [/bib_ref]. All persons, but particularly HCWs, should wash their hands before entering and after leaving the rooms of HSCT recipients and candidates undergoing conditioning therapy [bib_ref] Hospital Infection Control Practices Advisory Committee, Garner [/bib_ref] or before and after any direct contact with patients regardless of whether they were soiled from the patient, environment, or objects (AI). HSCT recipients should be encouraged to practice safe hand hygiene (e.g., washing hands before eating, after using the toilet, and before and after touching a wound) (BIII). Hand washing should be done with an antimicrobial soap and water (AIII); alternatively, use of hygienic hand rubs is another acceptable means of maintaining hand hygiene [bib_ref] APIC guideline for handwashing and hand antisepsis in health care settings, Larson [/bib_ref]. If gloves are worn, HCWs should put them on in the patient's room after hand washing and then discard them in the same patient's room before washing hands again after exiting the room. When worn, gloves should always be changed between patients or when soiled before touching a clean area (e.g., change gloves after touching the perineum and before going to a "clean" area) (AIII). Appropriate gloves should be used by all persons when handling potentially contaminated biological materials (AII). Items worn on the hands and fingers (e.g., rings or artificial nails [bib_ref] Hospital Infection Control Practices Advisory Committee, Mangram [/bib_ref] [bib_ref] Effect of hand cleansing with antimicrobial soap gel on microbial colonization of..., Mcneil [/bib_ref] and adhesive bandage strips, can create a nidus for pathogenic organisms that is difficult to clean. Thus, HCWs should avoid wearing such items whenever possible (BII).
## Equipment
All HSCT center personnel should sterilize or disinfect and maintain equipment and devices using only EPA-registered compounds as directed by established guidelines [bib_ref] APIC guideline for selection and use of disinfectants, Rutala [/bib_ref] [bib_ref] Disinfection of endoscopes: review of new chemical sterilants used for high-level disinfection, Rutala [/bib_ref] (AIII). HSCT center personnel should monitor opened and unopened wound-dressing supplies (e.g., adhesive bandagesand surgical and elastic adhesive tape [bib_ref] Outbreak of cutaneous aspergillosis in a tertiary-care hospital, Bryce [/bib_ref] to detect mold contamination and prevent subsequent cutaneous transmission to patients (BII).
Monitoring should consist of discarding all bandages and wound dressings that are out of date, have damaged packaging, or are visually contaminated by construction debris or moisture (BIII). When arm boards are used to provide support for intravenous lines, only sterile dressing materials should be used [bib_ref] Outbreak of primary cutaneous aspergillosis related to intravenous arm boards, Mccarty [/bib_ref] , and arm boards should be changed frequently (e.g., daily) (BIII). Additionally, unsterile tongue depressors inserted into a piece of foam tubing should not be used as splints for intravenous and arterial catheter sites because these have been associated with an outbreak of fatal invasive nosocomial Rhizopus microsporus among preterm (i.e., very low-birth-weight) infants (261 ) (DII). HSCT centers should not install carpeting in hallways outside (DII) or in patient rooms (DIII) because contaminated carpeting has been associated with outbreaks of aspergillosis among HSCT recipients [bib_ref] Aspergillosis due to carpet contamination, Gerson [/bib_ref] [bib_ref] Aspergillus flavus in a bone marrow transplant unit (BMTU): pseudofungemia traced to..., Richet [/bib_ref].
## Plants, play areas, and toys
Although to date, exposure to plants and flowers has not been conclusively reported to cause fungal infections among HSCT recipients, most researchers strongly recommend that plants and dried or fresh flowers should not be allowed in the rooms of hospitalized HSCT candidates undergoing conditioning therapy and HSCT recipients (phases I-III of immune system recovery) because Aspergillus species have been isolated from the soil of potted ornamental plants (e.g., cacti), the surface of dried flower arrangements, and fresh flowers [bib_ref] Nosocomial aspergillosis: environmental microbiology, hospital epidemiology, diagnosis and treatment, Walsh [/bib_ref]
[formula] (BIII). [/formula]
Play areas for pediatric HSCT recipients and candidates undergoing conditioning therapy should be cleaned and disinfected ≈1 times/week and as needed (BIII). Only toys, games, and videos that can be kept clean and disinfected should be allowed in the HSCT center (BIII). HSCT centers should follow published recommendations for washing and disinfecting toys (265 ) (BIII). All HSCT center toys, games, and videos should be routinely and thoroughly washed or wiped down when brought into the HSCT center and thereafter ≈1 times/ week and as needed by using a nontoxic FDA-or EPA-registered disinfectant [bib_ref] APIC guideline for selection and use of disinfectants, Rutala [/bib_ref] followed by a water rinse (BIII). Cloth or plush toys should be washed in a hot cycle of a washing machine or dry-cleaned ≈1 times/week and as needed (BIII). Alternatively, machine washing in a cold cycle is acceptable if laundry chemicals for cold water washing are used in proper concentration. Hard plastic toys should be scrubbed with warm soapy water using a brush to clean crevices, rinsed in clean water, immersed in a mild bleach solution, which should be made fresh daily, for 10-20 minutes, rinsed again, and allowed to air dry [bib_ref] APIC guideline for selection and use of disinfectants, Rutala [/bib_ref]. Alternatively, hard plastic toys can be washed in a dishwasher or hot cycle of a washing machine (BIII). Broviac dolls* should be disassembled upon completion of play and washed with a nontoxic FDA-or EPAregistered disinfectant [bib_ref] APIC guideline for selection and use of disinfectants, Rutala [/bib_ref] , rinsed with tap water, and allowed to air dry before other children are allowed to play with them (BIII). Toys that cannot be washed, disinfected, or dry-cleaned after use should be avoided (BIII). Infants, toddlers, and children who put toys in their mouths should not share toys (265 ) (DIII). For children in isolation, researchers recommend the following:
- Disposable play items should be offered whenever possible (BIII).
- Before returning a washable toy used in an isolation room to the pediatric play room for use by another child, it should be cleaned again as previously described (BIII).
- When a child is taken out of isolation, toys, games, and videos used during the period of isolation and that might serve as fomites for infection should be thoroughly disinfected with a nontoxic FDA-or EPA-registered disinfectant [bib_ref] APIC guideline for selection and use of disinfectants, Rutala [/bib_ref] (BIII). After use in isolation rooms, cloth or plush toys should be placed in a plastic bag and separated from unused toys. All cloth or plush toys used in isolation rooms should be washed in a washing machine or dry-cleaned before being used in a nonisolation room (BIII). Toys that cannot be disinfected or dry-cleaned after use in an isolation room should be discarded (BIII).
Water-retaining bath toys have been associated with an outbreak of Pseudomonas aeruginosa in a pediatric oncology ward [bib_ref] Multiresistant Pseudomonas aeruginosa outbreak in a pediatric oncology ward related to bath..., Buttery [/bib_ref] ; therefore, these toys should not be used by immunocompromised HSCT recipients and candidates (DII). Occupational and physical therapy items should be cleaned and disinfected as previously described (BIII). Soilbased materials (e.g., clay or potting soil) should be avoided (BIII).
## Hcws
HSCT center personnel should have a written comprehensive policy regarding their immunizations and vaccinations, and that policy should meet current CDC, Advisory Committee on Immunization Practices, and Healthcare Infection Control Practices Advisory Committee recommendations (267 ) (BIII). Immunizations are needed to prevent transmission of vaccine-preventable diseases to HSCT recipients and candidates undergoing conditioning therapy. All HCWs with diseases transmissible by air, droplet, and direct contact (e.g., VZV, infectious gastroenteritis, HSV lesions of lips or fingers, and URIs) should be restricted from patient contact and temporarily reassigned to other duties (AI). HSCT center personnel should follow published recommendations regarding the duration of work restrictions for HCWs with infectious diseases (268,269 ) (BIII). HSCT center HCWs with bloodborne viruses (e.g., HIV or hepatitis B or C viruses) should not be restricted from patient contact (DIII) as long as they do not perform procedures that pose a high risk for injury that could result in patient exposure to the HCW's blood or body fluids. Work exclusion policies should be designed to encourage HCWs to report their illnesses or exposures (AII).
## Hsct center visitors
Hospitals should have written policies for screening HSCT center visitors, particularly children, for potentially infectious conditions. Such screening should be performed by clinically trained HCWs (BII). Visitors who might have communicable infectious diseases (e.g., URIs, flu-like illnesses, recent exposure to communicable diseases, an active shingles rash whether covered or not, a VZV-like rash within 6 weeks of receiving a live attenuated VZV vaccine, or a history of receiving an oral polio vaccine within the previous 3-6 weeks) should not be allowed in the HSCT center or allowed to have direct contact with HSCT recipients or candidates undergoing conditioning therapy (AII). No absolute minimum age requirement for HSCT center visitors exists; however, all visitors must be able to understand and follow appropriate hand *Broviac dolls are used to demonstrate medical procedures (e.g., insertion of catheters) to children to lessen their fears.
washing and isolation precautions (AIII). The number of HSCT center visitors at any one time should be restricted to a number that permits the nursing staff to perform appropriate screening for contagious diseases and adequate instruction and supervision of hand washing, glove and mask use, and biosafety precautions (BIII).
## Patient skin and oral care
To optimize skin care, HSCT recipients should take daily showers or baths during and after transplantation (BIII), using a mild soap (BIII). Skin care during neutropenia should also include daily inspection of skin sites likely to be portals of infection (e.g., the perineum and intravascular access sites) (BIII). HSCT recipients and candidates undergoing conditioning therapy should maintain good perineal hygiene to minimize loss of skin integrity and risk for infection (BIII). To facilitate this precaution, HSCT center personnel should develop protocols for patient perineal care, including recommendations for gentle but thorough perineal cleaning after each bowel movement and thorough drying of the perineum after each urination (BIII). Females should always wipe the perineum from front to back after using the toilet to prevent fecal contamination of the urethra and urinary tract infections (AIII). Moreover, to prevent vaginal irritation, menstruating immunocompromised HSCT recipients should not use tampons (DIII) to avoid the risk for cervical and vaginal abrasions. Additionally, the use of rectal thermometers, enemas, suppositories, and rectal exams are contraindicated among HSCT recipients to avoid skin or mucosal breakdown (DIII).
All HSCT candidates and their caregivers should be educated regarding the importance of maintaining good oral and dental hygiene for at least the first year after HSCT to reduce the risk for oral and dental infections (AIII). For example, HSCT candidates should be informed that establishment of the best possible periodontal health before HSCT is a substantial step in avoiding short-and long-term oral infections and that maintenance of safe oral hygiene after HSCT can minimize the severity of infections and facilitate healing of mucositis, particularly before engraftment (BIII).
All HSCT candidates should receive a dental evaluation and relevant treatment before conditioning therapy begins (270,271 ) (AIII). Likely sources of dental infection should be vigorously eliminated (271 ) (AIII). For example, teeth with moderate to severe caries should be restored; ill-fitting dental prostheses should be repaired; and teeth compromised by moderate to severe periodontal disease should be extracted. Ideally, 10-14 days should elapse between the completion of tissue-invasive oral procedures and onset of conditioning therapy to allow for adequate healing and monitoring for postsurgical complications (AIII).
HSCT recipients with mucositis and HSCT candidates undergoing conditioning therapy should maintain safe oral hygiene by performing oral rinses 4-6 times/day with sterile water, normal saline, or sodium bicarbonate solutions (270 ) (AIII). HSCT recipients and candidates should brush their teeth ≈2 times/day with a soft regular toothbrush (270 ) (BIII). If the recipient cannot tolerate these brushings, use of an ultrasoft toothbrush or toothette (i.e., foam swab on a stick), can be used (CIII), but physicians should be aware that using the latter products are less desirable than using soft regular or ultrasoft toothbrushes because the toothettes remove less dental debris [bib_ref] Oral complications, Schubert [/bib_ref]. Using toothpaste is optional, depending on the recipient's tolerance (270 ) (CIII). HSCT recipients and candidates undergoing conditioning therapy who are skilled at dental flossing should floss daily if this can be done without trauma (BIII). Routine dental supervision is advised to monitor and guide the patient's maintenance of oral and dental hygiene (BIII). To decrease the risk for mechanical trauma and infection of oral mucosa, fixed orthodontic appliances and space maintainers should not be worn from the start of conditioning therapy until preengraftment mucositis resolves, and these devices should not be worn during any subsequent periods of mucositis (270 ) (DIII). Dental and transplant teams and the patient's community dentist should coordinate removal of these appliances and long-term rehabilitation of any oral lesions (BIII). However, patients who normally wear removable dental prostheses might be able to wear them during conditioning therapy before HSCT and during mucositis after HSCT, depending on the degree of tissue integrity at the denture-bearing sites and the ability of the patient to maintain denture hygiene on a daily basis (CIII).
## Preventing bacterial intravascular catheter-related infections
HSCT center personnel are advised to implement published guidelines for preventing intravascular device-related infections (33 ) (AIII). Contact with tap water at the central venous catheter site should be avoided (BIII). For long-term central venous access among children, HSCT physicians can use a totally implantable device among children aged <4 years if the anticipated duration of vascular access is >30 days (CII). However, such a device among children aged <4 years is not generally used as the actual HSCT infusion site because a) problems with skin fragility contraindicate repeated punctures over the port site and b) the port device might have an insufficient number of lumens for optimal patient management immediately after HSCT.
To prevent bloodstream infections associated with needleless intravenous access devices, HSCT recipients should a) cover and protect the catheter tip or end cap during bathing or showering to protect it from tap water contamination, b) change the device in accordance with manufacturers' recommendations, if available, and c) have a caregiver perform intravenous infusions whenever possible [bib_ref] Bloodstream infections (BSI) associated with needleless device use, bathing practices and home..., Toscano [/bib_ref] [bib_ref] Bloodstream infection associated with needleless device use and the importance of infection-control..., Do [/bib_ref] (BII). Also, HSCT recipients and their caregivers should be educated regarding proper care of needleless intravenous access devices (272 ) (BII). No recommendation regarding the use of antibiotic impregnated central venous catheters among HSCT recipients can be made because of lack of data.
## Control of specific nosocomial infections
## Recommendations regarding legionella species
HSCT physicians should always include Legionnaires' disease (LD) in the differential diagnosis of pneumonia among HSCT recipients (140 ) (AIII). Appropriate tests to confirm LD include a) culturing sputum, BAL, and tissue specimens; b) testing BAL specimens for Legionellae by direct fluorescent antibody; and c) testing for Legionella pneumophila serogroup 1 antigen in urine. The incubation period for LD is usually 2-10 days; thus, laboratory-confirmed legionellosis that occurs in a patient who has been hospitalized continuously for ≈10 days before the onset of illness is regarded as a definite case of nosocomial LD, and a laboratory-confirmed infection that occurs 2-9 days after hospital admission is a possible case of nosocomial LD. When a case of laboratory confirmed nosocomial LD [bib_ref] More than 10 years of unrecognized nosocomial transmission of Legionnaires' disease among..., Kool [/bib_ref] is identified in a person who was in the inpatient HSCT center during all or part of the 2-10 days before illness onset, or if two or more cases of laboratory-confirmed LD occur among patients who had visited an outpatient HSCT center, hospital personnel should
- report the case(s) to the local or state health department if the disease is reportable in that state or if assistance is needed (140 ) (AIII); and
- in consultation with the hospital infection control team, conduct a thorough epidemiologic and environmental investigation to determine the likely environmental source(s) of Legionella species (e.g., showers, tap water faucets, cooling towers, and hot water tanks) [bib_ref] More than 10 years of unrecognized nosocomial transmission of Legionnaires' disease among..., Kool [/bib_ref] [bib_ref] Recurrent outbreak of nosocomial Legionnaires' disease detected by urinary antigen testing: evidence..., Lepine [/bib_ref] (AI). The source of Legionella infection should be identified and decontaminated or removed (AIII). Extensive hospital investigations of an isolated case of possible nosocomial LD might not be indicated if the patient has had limited contact with the inpatient center during most of the incubation period (CIII). Because HSCT recipients are at much higher risk for disease and death from legionellosis compared with other hospitalized persons [bib_ref] More than 10 years of unrecognized nosocomial transmission of Legionnaires' disease among..., Kool [/bib_ref] , periodic routine culturing for Legionellae in water samples from the center's potable water supply could be regarded as part of an overall strategy for preventing LD in HSCT centers (CIII). However, the optimal methodology (i.e., frequency or number of sites) for environmental surveillance cultures in HSCT centers has not been determined, and the cost-effectiveness of this strategy has not been evaluated. Because HSCT recipients are at high risk for LD and no data were found to determine a safe concentration of Legionellae organisms in potable water, the goal, if environmental surveillance for Legionellae is undertaken, should be to maintain water systems with no detectable organisms (AIII). Physicians should suspect legionellosis among HSCT recipients with nosocomial pneumonia even when environmental surveillance cultures do not yield Legionellae (AIII). If Legionella species are detected in the water supplying an HSCT center, the following should be done until Legionella species are no longer detected by culture:
- The water supply should be decontaminated(AII).
- HSCT recipients should be given sponge baths with water that is not contami-nated with Legionella species (e.g., not with the HSCT center's Legionella speciescontaminated potable water system) (BIII).
- Patients should not take showers in LD-contaminated water (DIII).
- Water from faucets containing LD-contaminated water should not be used in patient rooms or the HSCT center and outpatient clinic to avoid creating infectious aerosols (CIII).
- HSCT recipients should be given sterile water instead of tap water for drinking, brushing teeth, or flushing nasogastric tubes during Legionellosis outbreaks (BIII).
HSCT center personnel should use only sterile water (i.e., not distilled unsterile water) for rinsing nebulization devices and other semicritical respiratory-care equipment after cleaning or disinfecting and for filling reservoirs of nebulization devices (140 ) (BII). HSCT centers should not use large-volume room air humidifiers that create aerosols (e.g., by Venturi principle, ultrasound, or spinning disk) and, thus, are actually nebulizers (140 ) (DI) unless these humidifier or nebulizers are sterilized or subjected to daily high-level disinfection and filled with sterile water only (140 ) (CIII). When a new hospital with an HSCT center is constructed, the cooling towers should be placed so that the tower drift is directed away from the hospital's air-intake system, and the cooling towers should be designed so that the volume of aerosol drift is minimized (140 )
## Recommendations regarding methicillin-resistant
Sta. aureus HSCT center HCWs should follow basic infection control practices (e.g., hand washing between patients and use of barrier precautions, including wearing gloves whenever entering the methicillin-resistant Sta. aureus [MRSA] infected or colonized patient's room); these practices are essential for MRSA control (62 ) (AII). If MRSA is a substantial problem in the HSCT center and evidence exists of ongoing MRSA transmission, MRSA infected or colonized patients should be treated as a cohort (e.g., cared for exclusively by a limited number of HCWs) (BIII). HSCT transplant recipients with recurrent Sta. aureus infections should undergo extensive evaluation for persistent colonization, including cultures of nares, groin, axilla, and ostomy sites (e.g., tracheostomy or gastrointestinal tube) (BIII). For patients with recurrent MRSA infection, elimination of the carrier state should be attempted by applying a 2% mupirocin calcium ointment to the nares (BIII), although this strategy has been only marginally effective in certain institutions (278 ) (Appendix). High-level mupirocin-resistant MRSA has been reported in Europe, the Middle East, and South America [bib_ref] Outbreak of mupirocin-resistant Staphylococci in a hospital in Warsaw, Poland, due to..., Leski [/bib_ref] [bib_ref] Prevalence of lowand high-level mupirocin resistance in Staphylococci from 19 European hospitals, Schmitz [/bib_ref] [bib_ref] Control of an outbreak of an epidemic methicillin-resistant Staphylococcus aureus also resistant..., Irish [/bib_ref] [bib_ref] Molecular fingerprinting of mupirocin-resistant methicillin-resistant Staphylococcus aureus from a burn unit, Udo [/bib_ref] [bib_ref] Giambiagi-deMarval M. Molecular characterization and transfer among Staphylococcus strains of a plasmid..., Bastos [/bib_ref] but is uncommon in the United States. As with any antibiotic, incorrect or overuse of mupirocin can result in mupirocin-resistant Staphylococci ; therefore, mupirocin use should be reserved for infection control strate-gies only [bib_ref] Outbreak of mupirocin-resistant Staphylococci in a hospital in Warsaw, Poland, due to..., Leski [/bib_ref] [bib_ref] Prevalence of lowand high-level mupirocin resistance in Staphylococci from 19 European hospitals, Schmitz [/bib_ref]. For patients who fail mupirocin, physicians have used bacitracin, TMP-SMZ, or rifampin administered with another antibiotic, but no standardized protocol using these drugs for this indication has been evaluated and no recommendations can be made because of lack of data. Selection of a systemic antibiotic should be guided by susceptibility patterns.
Intravascular cannulas or other implantable devices that are infected or colonized with MRSA should be removed (AIII). Patients with MRSA should be placed under contact precautions until all antibiotics are discontinued and until three consecutive cultures, taken ≈1 weeks apart, are negative (62 ) (BIII). Screening cultures for MRSA include the anterior nares, any body site previously positive for MRSA, and any wounds or surgical sites.
## Recommendations regarding staphylococcus species with reduced susceptibility to vancomycin
All HSCT centers should have sufficient laboratory capability to identify all Staphylococci isolates and their susceptibility patterns to antibiotics, including vancomycinAvoiding overuse and misuse of antibiotics will decrease the emergence of Staphylococcus species with reduced susceptibility to vancomycin [bib_ref] Emergence of vancomycin resistance in Staphylococcus aureus, Smith [/bib_ref]. There-fore, medical and ancillary staff members who are responsible for monitoring antimicrobial use patterns in the facility should routinely review vancomycin-use patterns
## Recommendations regarding vre
Use of intravenous vancomycin is associated with VRE emergence. Vancomycin and all other antibiotics, particularly antianaerobic agents (e.g., metronidazole and third-generation cephalosporins) must be used judiciously [bib_ref] Bloodstream infections with vancomycin-resistant Enterococci, Montecalvo [/bib_ref] [bib_ref] Outbreak of vancomycin-dependent Enterococcus faecium in a bone marrow transplant unit, Kirkpatrick [/bib_ref] - Wash hands with antibacterial soap before entering and after leaving HSCT recipients' rooms, particularly those who have VRE colonization or infection; alternatively, wash hands with a waterless antiseptic agent (e.g., an alcohol-based rinse or gel) (250 ).
- Whenever possible, treat as a cohort patients who are known to be colonized or infected with VRE (290 ).
- Disinfect patient rooms and equipment [bib_ref] Disinfection of hospital rooms contaminated with vancomycinresistant Enterococcus faecium, Byers [/bib_ref] , including surfaces of the hospital ward environment (e.g., floors, walls, bed frames, doors, bathroom surfaces) with an FDA-or EPA-registered disinfectant [bib_ref] APIC guideline for selection and use of disinfectants, Rutala [/bib_ref]
## Recommendations regarding cl. difficile
HSCT physicians should follow published recommendations for preventing and controlling Cl. difficile disease, including minimizing the duration of antibiotic therapy and number of antibiotics used for any indication (295,296 ) (AIII). All patients with Cl. difficile disease should be placed under contact precautions for the duration of illness (62 ) (AII). All HCWs who anticipate contact with a Cl. difficile -infected patient or the patient's environment or possessions should put on gloves before entering the patient's room [bib_ref] Hospital Infection Control Practices Advisory Committee, Garner [/bib_ref] [bib_ref] Clostridium difficile-associated diarrhea and colitis, Gerding [/bib_ref] [bib_ref] Clostridium difficile-associated diarrhea, Johnson [/bib_ref] [bib_ref] Nosocomial acquisition of Clostridium difficile infection, Mcfarland [/bib_ref] [bib_ref] Prospective, controlled study of vinyl glove use to interrupt Clostridium difficile nosocomial..., Johnson [/bib_ref] and before handling the patient's secretions and excretions (AI). During Cl. difficile outbreaks, HSCT center personnel should restrict use of antibiotics (e.g., clindamycin) (299 ) (BII). To prevent transmission of Cl. difficile to patients during nosocomial Cl. difficile outbreaks, HSCT center HCWs should a) use disposable rectal thermometers or tympanic thermometers; b) disinfect gastrointestinal endoscopes with 2% glutaraldehyde immersion for 10 minutes or use an equivalent disinfectant strategy [bib_ref] Disinfection of endoscopes: review of new chemical sterilants used for high-level disinfection, Rutala [/bib_ref] ; and c) perform surface sterilization of the hospital ward environment (e.g., floors, walls, bed frames, doors, bathroom surfaces) with an FDA-or EPA-registered sterilant (e.g., phosphate-buffered sodium hypochlorite solution [1,660 ppm available chloride]; unbuffered hypochlorite solution [500 ppm available chloride]; 0.04% formaldehyde and 0.03% glutaraldehyde [bib_ref] Clostridium difficile-associated diarrhea and colitis, Gerding [/bib_ref] [bib_ref] Acquisition of Clostridium difficile from the hospital environment, Kaatz [/bib_ref] ; or ethylene oxide [bib_ref] Clostridium difficile-associated diarrhea, Johnson [/bib_ref] (BII). Additionally, physicians should treat patients with Cl. difficile disease with antibiotics as recommended in published reports (62,295 ) (BII).
Certain researchers also recommend antibiotic treatment of Cl. difficile carriers. However, other researchers have reported that treatment of asymptomatic Cl. difficile carriers with metronidazole is not effective and that treatment with vancomycin is only effective temporarily (i.e., <2 months after treatment) [bib_ref] Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole, Johnson [/bib_ref]. Consequently, no recommendation regarding treatment of asymptomatic Cl. difficile carriers can be made. Similarly, although symptomatic Cl. difficile disease recurrence or relapse occurs among 7%-20% of patients [bib_ref] Clostridium difficile-associated diarrhea and colitis, Gerding [/bib_ref] , data are insufficient to make a recommendation for preventing multiple Cl. difficile relapses.
The following practices are not recommended for Cl. difficile control:
- routine stool surveillance cultures for Cl. difficile for asymptomatic patients or HCWs, even during outbreaks (DIII);
- culturing HCWs' hands for Cl. difficile (DIII); or
- treating patients presumptively for Cl. difficile disease pending toxin results (DIII), unless the patient is very sick with a compatible syndrome or the hospital has a high prevalence of Cl. difficile (CIII).
Prophylactic use of lyophilized Saccharomyces boulardii to reduce diarrhea among antibiotic recipients is not recommended because this therapy is not associated with a substantial reduction in diarrhea associated with Cl. difficile disease [bib_ref] Prevention of antibiotic associated diarrhea by Saccharomyces boulardii: a prospective study, Surawicz [/bib_ref] and has been associated with Saccharomyces boulardii fungemia (304 ) (DII).
## Recommendations regarding crv infections
Physicians should institute appropriate precautions and infection control measures for preventing nosocomial pneumonia among hospitalized HSCT recipients and candidates undergoing conditioning therapy, particularly during community or nosocomial CRV outbreaks (140 ) (AIII). Patients with URI or LRI symptoms should be placed under a) contact precautions for most viral respiratory infections including varicella; b) droplet precautions for influenza or adenovirus; or c) airborne precautions for measles or varicella to avoid transmitting infection to other HSCT candidates and recipients as well as to HCWs and visitors (BIII). Identifying HSCT recipients with RSV infection and placing them under contact precautions immediately (AIII) to prevent nosocomial transmission is critical. When suctioning the respiratory tract of patients with URI or LRI symptoms, HCWs should wear gowns, surgical masks, and eye protection to avoid contamination from the patient's respiratory secretions. All protective clothing (e.g., gown, gloves, surgical mask, and eye protection) should be put on when entering a patient's room and discarded in the same room before exiting; protective clothing should always be changed between patient rooms (140 ) (AIII). When caring for an HSCT recipient or candidate undergoing conditioning therapy with URI or LRI, HCWs and visitors should change gloves and wash hands a) after contact with a patient; b) after handling respiratory secretions or objects contaminated with secretions from one patient and before contact with another patient, object, or environmental surface; and c) between contacts with a contaminated body site and the respiratory tract of or respiratory device used on the same patient (140 ) (AII). This practice is critical because most respiratory infections are usually transmitted by contact, particularly by hand to nose and eye. Therefore just wearing a mask, without appropriate hand washing, glove-wearing, or use of eye protection is insufficient to prevent transmission of CRV infections.
Researchers have proposed that HSCT recipients or candidates undergoing conditioning therapy be placed under contact precautions during nosocomial outbreaks (131 ) (CIII). Even when no nosocomial or community outbreak of CRV infections exists, all persons who enter the HSCT center should be screened daily for URI symptoms, including visitors and HCWs (BIII). Researchers also describe systems where HCWs provide daily verification (e.g., using sign-in sheets) that they are free of URI symptoms before being allowed to provide HSCT patient care. HCWs and visitors with URI symptoms should be restricted from contact with HSCT recipients and candidates undergoing conditioning therapy to minimize the risk for CRV transmission (131 ) (AIII). All HCWs with URI symptoms should be restricted from patient contact and reassigned to nonpatient care duties until the HCW's symptoms resolve (BIII). Visitors with URI symptoms should be asked to defer their visit to the HSCT center (131 ) until their URI symptoms resolve (BIII).
Respiratory secretions of any hospitalized HSCT candidate or recipient with signs or symptoms of CRV infection should be tested promptly by viral culture and rapid diagnostic tests for CRV (BIII). Appropriate samples include nasopharyngeal washes, swabs, aspirates, throat swabs, and BAL fluid. This practice is critical because preemptive treatment of certain CRVs (e.g., influenza and RSV) (133 ) might prevent severe disease and death among HSCT recipients. Viral shedding among HSCT recipients with CRV infection has been reported to last £4 months for influenza [bib_ref] Prevention and treatment of influenza in immunocompromised patients, Hayden [/bib_ref] , £2 years for adenovirus [bib_ref] Virus watch program: a continuing surveillance of viral infections in metropolitan New..., Fox [/bib_ref] [bib_ref] Adenovirus infection in West Bengal. I: persistence of viruses in infants and..., Hillis [/bib_ref] , and £22 days for RSV [bib_ref] Outbreak of respiratory syncytial virus in a bone marrow transplant center, Harrington [/bib_ref] ; however, RSV viral shedding has been reported to last 112 days in a child with severe combined immunodeficiency [bib_ref] Respiratory syncytial virus infection in children with compromised immune function, Hall [/bib_ref]. Therefore, to prevent nosocomial transmission of CRV [bib_ref] Outbreak of respiratory syncytial virus in a bone marrow transplant center, Harrington [/bib_ref] , HSCT center HCWs should recognize that prolonged CRV shedding can occur when determining the duration of appropriate precautions for CRV-infected HSCT recipients or candidates undergoing conditioning therapy (CIII). HSCT centers should use serial testing by using cultures from nasopharyngeal swabs, throat swabs or aspirates, or rapid antigen tests to help determine whether patients have stopped shedding influenza virus (BIII). Researchers have proposed that HSCT physicians conduct routine CRV surveillance among HSCT recipients to detect outbreaks and implement infection control measures as early as possible (CIII). During RSV season, HSCT recipients and candidates with signs or symptoms should be tested for RSV infection (i.e., the presence of RSV antigen in respiratory secretions tested by enzyme-linked immunosorbent assay and viral culture) starting with admission to the HSCT center. All patients who are RSV-antigen positive should be treated as a cohort during nosocomial RSV outbreaks because this practice reduces nosocomial RSV transmission (130,131 ) (BII). Symptomatic HCWs should be excluded from patient contact until symptoms resolve. HCWs and visitors with infectious conjunctivitis should be restricted from direct patient contact until the drainage resolves (i.e., usually, 5-7 days for adenovirus) and the ophthalmology consultant concurs that the infection and inflammation have resolved (268 ) (AII) to avoid possible transmission of adenovirus to HSCT recipients.
Preventing CRV exposure among HSCT recipients after hospital discharge is more challenging because of high CRV prevalence. Preventive measures should be individualized in accordance with the immunologic status and tolerance of the patient. In outpatient waiting rooms, patients with CRV infections should be separated to the extent possible from other patients (BIII).
## Recommendations regarding tb
HSCT candidates should be screened for TB by careful medical history and chart review to ascertain any history of prior TB exposure (AIII) because immunocompromised persons have higher risk for progression from latent TB infection to active disease. Also, physicians can administer a tuberculin skin test (TST) using the Mantoux method with five tuberculin units of purified protein derivative (CIII); but because of a patient's immunocompromise, this test might not be reliable. If a TST is administered, either the Tubersol ® or Aplisol ® formulation of purified protein derivative can be used [bib_ref] Comparable specificity of 2 commercial tuberculin reagents in persons at low risk..., Villarino [/bib_ref]. Persons with a recently positive TST or a history of a positive TST and no prior preventive therapy should be administered a chest radiograph and evaluated for active TB (309 ) (AI). For immunocompromised persons, a positive TST is defined as ≈5 mm of indurationbecause of their decreased ability to mount a delayed hypersensitivity response (CIII). Because immunosuppressive therapy decreases the sensitivity of the TST, HSCT physicians should not rely solely on the TST to determine whether latent TB infection is present and whether preventive therapy should be administered to HSCT recipients or candidates (DIII). Instead, a full 9-month course of isonicotinic acid hydrazide preventive therapy should be administered to immunocompromised HSCT recipients or candidates who have been substantially exposed to someone with active, infectious (i.e., sputum-smear positive) pulmonary or laryngeal TB, regardless of the HSCT recipient's or candidate's TST status (309 ) (BIII). A full 9-month course of isonicotinic acid hydrazide preventive therapy should also be administered to HSCT recipients or candidates with a positive TST who were not previously treated and have no evidence of active TB disease (309 ) (AIII) (Appendix). Routine anergy screening might not be reliable among HSCT recipients and candidates undergoing conditioning therapy and, therefore, is not recommended (DIII). An HSCT should not be canceled or delayed because of a positive TST (DIII).
Use of a 2-month course of a daily pyrazinamide/rifampin (PZA/RIF) regimen has been recommended as an alternate preventive therapy for persons with TB (309 ). However, limited data were found regarding safety and efficacy of this regimen among non-HIV-infected persons. Furthermore, rifampin has substantial drug interactions with certain medications, including cyclosporine, tacrolimus (FK506), corticosteroids, fluconazole, and pain medications. Therefore, routine use of the 2-month PZA/RIF prophylactic regimen among HSCT recipients is not recommended (DIII). However, this regimen can be used for HSCT candidates who are not at risk for serious rifampin drug interactions and whose HSCT is not scheduled until ≈2 weeks after completion of the 2-month PZA/RIF course (CIII). This delay will diminish the possibility of adverse effects of rifampin on drugs used for routine HSCT OI prophylaxis (e.g., fluconazole) (311 ). An HSCT candidate or recipient who has been exposed to an active case of extrapulmonary, and therefore, noninfectious TB does not require preventive therapy (DIII).
HSCT center personnel should follow guidelines regarding the control of TB in health-care facilities, including instituting airborne precautions and negative pressure rooms for patients with suspected or confirmed pulmonary or laryngeal TB (62,244 ) (AII). HCWs should wear N95 respirators, even in isolation rooms, to protect themselves from possible TB transmission from patients with active pulmonary or laryngeal TB, particularly during cough-inducing procedures (62,244,245,312 ) (AIII). To be maximally effective, respirators (e.g., N95) must be fit-tested, and all respirator users must be trained to use them correctly (243 ) (AIII). Unless they become soiled or damaged, changing N95 respirators between patient rooms is not necessary (DIII). Bacillus of Calmette and Guérin vaccination is contraindicated among HSCT candidates and recipients because it might cause disseminated or fatal disease among immunocompromised persons (313,314 ) (EII). No role has been identified for chronic suppressive therapy or follow-up surveillance cultures among HSCT recipients who have a history of successfully treated TB (DIII).
## Infection control surveillance
HSCT center personnel are advised to follow standard guidelines for surveillance of antimicrobial use and nosocomial pathogens and their susceptibility patterns (315 ) (BIII). HSCT center personnel should not perform routine fungal or bacterial cultures of asymptomatic HSCT recipients [bib_ref] Surveillance cultures in bone marrow transplant recipients: worthwhile or wasteful?, Riley [/bib_ref] [bib_ref] Role of surveillance cultures in prevention and treatment of fungal infections, Walsh [/bib_ref] (DII). In the absence of epidemiologic clusters of infections, HSCT center personnel should not perform routine periodic bacterial surveillance cultures of the HSCT center environment or of equipment or devices used for respiratory therapy, pulmonary-function testing, or delivery of inhalation anesthesia (140 ) (DIII). Researchers recommend that hospitals perform routine sampling of air, ceiling tiles, ventilation ducts, and filters to test for molds, particularly when construction or renovation occurs near or around the rooms of immunocompromised patients [bib_ref] Role of surveillance cultures in prevention and treatment of fungal infections, Walsh [/bib_ref] [bib_ref] Nosocomial aspergillosis: environmental microbiology, hospital epidemiology, diagnosis and treatment, Walsh [/bib_ref] or when clinical surveillance demonstrates a possible increase in mold (i.e., aspergillosis) cases (CIII). Strategies that might decrease fungal spores in the ventilation system include eliminating access of birds (i.e., primarily pigeons) to air-intake systems, removing bird droppings from the air-intake ducts, and eliminating moss from the hospital roof [bib_ref] Nosocomial aspergillosis: environmental microbiology, hospital epidemiology, diagnosis and treatment, Walsh [/bib_ref]. Furthermore, in the absence of a nosocomial fungal outbreak, HSCT centers need not perform routine fungal cultures of devices and dust in the rooms of HSCT recipients and candidates undergoing conditioning therapy (DIII). HSCT center personnel should routinely perform surveillance for the number of aspergillosis cases occurring among HSCT recipients, particularly during hospital construction or renovation (BIII). A two-fold or greater increase in the attack rate of aspergillosis during any 6-month period indicates that the HSCT center environment should be evaluated for breaks in infection control techniques and procedures and that the ventilation system should be investigated carefully (174 ) (BIII).
## Strategies for safe living after hsct -preventing exposure and disease
## Avoiding environmental exposures
HSCT recipients and candidates undergoing conditioning therapy, particularly allogeneic recipients, and parents of pediatric HSCT recipients and candidates should be educated regarding strategies to avoid environmental exposures to opportunistic pathogens (AIII).
## Preventing infections transmitted by direct contact
HSCT recipients and candidates should wash their hands thoroughly (i.e., with soap and water) and often. For example, hands should be washed - before eating or preparing food;
- after changing diapers;
- after gardening or touching plants or dirt;
- after touching pets or animals;
- after touching secretions or excretions or items that might have had contact with human or animal stool (e.g., clothing, bedding, toilets, or bedpans);
- after going outdoors; and
- before and after touching wounds (249 ) (AIII).
Conscientious hand washing is critical during the first 6 months after HSCT and during other periods of substantial immunosuppression (e.g., GVHD, systemic steroid use, or relapse of the underlying disease for which the transplant was performed) (AIII). Pediatric HSCT recipients and candidates should be supervised by adults during hand washing to ensure thorough cleaning (316 ) (BIII). Hand washing should be performed with an antimicrobial soap and water (AIII); alternatively, use of hygienic hand rubs is an acceptable means of maintaining hand hygiene [bib_ref] APIC guideline for handwashing and hand antisepsis in health care settings, Larson [/bib_ref]. HSCT recipients who visit or live on farms should follow published recommendations for preventing cryptosporidiosis (5,316,317-319 ) (BIII).
## Preventing respiratory infections
To prevent respiratory infections after hospital discharge, HSCT recipients should observe the following precautions:
- Frequent and thorough hand washing is critical (BIII), but HSCT recipients should also avoid touching their mucus membranes, unless they have washed their hands first, to avoid inoculating themselves with CRV.
- HSCT recipients should avoid close contact with persons with respiratory illnesses (BIII). When close contact is unavoidable, those persons with respiratory illnesses should be encouraged to wash their hands frequently and to wear surgical masks or, at a minimum, smother their sneezes and coughs in disposable tissues. Alternatively, the HSCT recipient can wear a surgical mask (CIII).
- HSCT recipients should avoid crowded areas (e.g., shopping malls or public elevators) where close contact with persons with respiratory illnesses is likely (BIII).
- HSCT candidates or recipients should be advised that certain activities and occupations (e.g., work in healthcare settings, prisons, jails, or homeless shelters) can increase their risk for TB exposure (BIII). In deciding whether a patient should continue activities in these settings, physicians should evaluate the patient's specific duties, the precautions used to prevent TB exposure in the workplace, and the prevalence of TB in the community. The decision to continue or terminate such activities should be made jointly between patient and physician (BIII). HSCT recipients should avoid exposure to persons with active tuberculosis, particularly during the first 6 months after HSCT and during other periods of substantial immunosuppression (e.g., GVHD, systemic steroid use, or relapse of the underlying disease for which the transplant was performed) (BIII). Researchers report that allogeneic recipients should avoid construction or excavation sites or other dust-laden environments for the first 6 months after HSCT and during other periods of substantial immunosuppression (e.g., GVHD, systemic steroid use, or relapse of the underlying disease for which the transplant was performed) to avoid exposures to molds (CIII). Researchers also report that outpatient HSCT recipients should be advised of travel routes to the HSCT center that will avoid or minimize exposure to construction sites (CIII).
Coccidioidomycosis is uncommon after allogeneic HSCT; however, researchers report that HSCT recipients traveling to or residing in coccidioidomycosis-endemic areas (e.g., the American southwest, Mexico, and Central and South America) should avoid or minimize exposure to disturbed soil, including construction or excavation sites, areas with recent earthquakes, farms, or other rural areas (CIII). Histoplasmosis (Histoplasma capsulatum ) after allogeneic HSCT is also rare; however, researchers report that HSCT recipients in histoplasmosis-endemic areas should avoid exposure to chicken coops and other bird-roosting sites and caves for the first 6 months after HSCT and during periods of substantial immunosuppression (e.g., GVHD, systemic steroid use, or relapse of the underlying disease for which the transplant was performed) (CIII).
Smoking tobacco and exposure to environmental tobacco smoke are risk factors for bacterial and CRV infections among healthy adults and children [bib_ref] Morbidity and mortality in children associated with the use of tobacco products..., Difranza [/bib_ref] [bib_ref] Smoking, alcohol consumption, and susceptibility to the common cold, Cohen [/bib_ref] [bib_ref] Tobacco smoke as a risk factor for meningococcal disease, Fischer [/bib_ref] [bib_ref] Risk factors for acquiring pneumococcal infections, Lipsky [/bib_ref] [bib_ref] Long-term prospective study in children after respiratory syncytial virus infection, Hall [/bib_ref] [bib_ref] Cigarette smoking and invasive pneumococcal disease, Nuorti [/bib_ref] ; consequently, logic dictates that physicians advise HSCT recipients not to smoke and to avoid exposure to environmental tobacco smoke (CIII). However, no data were found that specifically assess whether smoking or environmental smoke exposure are risk factors for OIs among HSCT recipients. Researchers have reported that marijuana smoking might be associated with generation of invasive pulmonary aspergillosis among immunocompromised persons, including HSCT recipients [bib_ref] Successfully treated invasive pulmonary aspergillosis associated with smoking marijuana in a renal..., Marks [/bib_ref] [bib_ref] Letter: pulmonary aspergillosis, inhalation of contaminated marijuana smoke, chronic granulomatous disease, Chusid [/bib_ref] [bib_ref] Fatal aspergillosis associated with smoking contaminated marijuana in a marrow transplant recipient, Hamadeh [/bib_ref]. Therefore, HSCT recipients should refrain from smoking marijuana to avoid Aspergillus species exposure (326,330-334 ) (BIII).
## Preventing infections transmitted through direct contact and respiratory transmission
Researchers have proposed that immunocompromised HSCT recipients and candidates who are undergoing conditioning therapy avoid gardening or direct contact with soil, plants, or their aerosols to reduce exposure to potential pathogens (e.g., To. gondii, Hi. capsulatum, Cryptococcus neoformans, Nocardia species, and Aspergillus species) (CIII). HSCT recipients, particularly allogeneic recipients, could wear gloves while gardening or touching plants or soil (335 ) (CIII), and they should avoid creating plant or soil aerosols (BIII). Additionally, they should always wash their hands afterwards [bib_ref] Caring for pets of immunocompromised persons, Angulo [/bib_ref] and care for skin abrasions or cuts sustained during soil or plant contact (AIII).
Persons whose occupations involve animal contact (e.g., veterinarians, pet store employees, farmers, or slaughterhouse workers) could be at increased risk for toxoplasmosis and other zoonotic diseases. Although data are insufficient to justify a general recommendation against HSCT recipients working in such settings, these exposures should be avoided during the first 6 months after HSCT and during other periods of substantial immunosuppression (e.g., GVHD, systemic steroid use, or relapse of the underlying disease for which the transplant was performed) (BIII).
## Safe sex
Sexually active HSCT recipients should avoid sexual practices that could result in oral exposure to feces (5,316 ) (AIII). Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to CMV, HSV, HIV, hepatitis B and C, and other sexually transmitted pathogens (AII). However, even long-time monogamous partners can be discordant for these infections. Therefore, during periods of immunocompromise, sexually active HSCT recipients in such relationships should consider using latex condoms during sexual contact to reduce the risk for exposure to these sexually transmitted infections (CIII).
## Pet safety
## Preventing pet-transmitted zoonotic infections
HSCT physicians should advise recipients and candidates undergoing conditioning therapy of the potential infection risks posed by pet ownership; however, they should not routinely advise HSCT recipients to part with their pets, with limited exceptions. Generally, immunocompromised HSCT recipients and candidates undergoing conditioning therapy should minimize direct contact with animals [bib_ref] Pet-associated illness, Elliott [/bib_ref] [bib_ref] Animal-associated opportunistic infections among persons infected with the human immunodeficiency virus, Glaser [/bib_ref] , particularly those animals that are ill (e.g., with diarrhea) (335 ) (BIII). Immunocompromised persons who choose to own pets should be more vigilant regarding maintenance of their pet's health than immunocompetent pet owners (BIII). This recommendation means seeking veterinary care for their pet early in the pet's illness to minimize the possible transmission of the pet's illness to the owner (335 ) (BIII). Feeding pets only high-quality commercial pet foods reduces the possibility of illness caused by spoiled or contaminated foods, thus reducing the possibility of transmitting illness from the pet to the HSCT recipient. If eggs, poultry, or meat products are given to the pet as supplements, they should be well-cooked. Any dairy products given to pets should be pasteurized (335 ) (BIII). Pets should be prevented from drinking toilet bowl water and from having access to garbage; pets should not scavenge, hunt, or eat other animals' feces (335 ) (BIII).
If HSCT recipients have contact with pets or animals, they should wash their hands after handling them (particularly before eating) and after cleaning cages; HSCT recipients should avoid contact with animal feces to reduce the risk for toxoplasmosis, cryptosporidiosis, salmonellosis, and campylobacteriosis (335 ) (BIII). Adults should supervise hand washing of pediatric HSCT recipients (BIII). Immunocompromised HSCT recipients and candidates should not clean pet litter boxes or cages or dispose of animal waste (DIII). If this cannot be avoided, patients should wear disposable gloves during such activities and wash their hands thoroughly afterwards (BIII). Immunocompromised HSCT recipients and candidates should avoid adopting ill or juvenile pets (e.g., aged <6 months for cats) [bib_ref] Caring for pets of immunocompromised persons, Angulo [/bib_ref] and any stray animals (5,316 ) (BIII). Any pet that experiences diarrhea should be checked by a veterinarian for infection with Cryptosporidium, Giardia species (335 ), Salmonella , and Campylobacter (5,335,337 ) (BIII).
Immunocompromised HSCT recipients and candidates should not have contact with reptiles (e.g., snakes, lizards, turtles, or iguanas) (DII) to reduce their risk for acquiring salmonellosis [bib_ref] Caring for pets of immunocompromised persons, Angulo [/bib_ref] [bib_ref] Animals in schools: a zoonosis threat?, Adams [/bib_ref] [bib_ref] Iguana-associated salmonellosis in children, Dalton [/bib_ref] [bib_ref] Reptile-associated salmonellosis-selected states, 1996-1998, Cdc [/bib_ref]. Additionally, patients should be informed that salmonellosis can occur from fomite contact alone [bib_ref] Iguanas and Salmonella marina infection in children: a reflection of the increasing..., Mermin [/bib_ref]. Therefore, HSCT recipients and candidates should avoid contact with a reptile, its food, or anything that it has touched, and if such contact occurs, recipients and candidates should wash their hands thoroughly afterwards (AIII). Immunocompromised HSCT recipients and candidates should avoid contact with ducklings and chicks because of the risk for acquiring Salmonella or Campylobacter species infections (338,343 ) (BIII). Immunocompromised HSCT recipients and candidates should avoid contact with exotic pets (e.g., nonhuman primates) (BIII). Bird cage linings should be cleaned regularly (e.g., daily) [bib_ref] Animal-associated opportunistic infections among persons infected with the human immunodeficiency virus, Glaser [/bib_ref]. All persons, but particularly immunocompromised HSCT candidates and recipients, should wear gloves whenever handling items contaminated with bird droppings (337 ) (BIII) because droppings can be a source of Cryptococcus neoformans, Mycobacterium avium, or Hi. capsulatum. However, routine screening of healthy birds for these diseases is not recommended (335 ) (DIII). To minimize potential exposure to Mycobacterium marinum, immunocompromised HSCT recipients and candidates should not clean fish tanks (DIII). If this task cannot be avoided, patients should wear disposable gloves during such activities and wash their hands thoroughly afterwards (335,337 ) (BIII).
## Preventing toxoplasmosis
The majority of toxoplasmosis cases in the United States is acquired through eating undercooked meat [bib_ref] Caring for pets of immunocompromised persons, Angulo [/bib_ref] [bib_ref] Animal-associated opportunistic infections among persons infected with the human immunodeficiency virus, Glaser [/bib_ref]. However, all HSCT recipients and candidates, particularly those who are To. gondii seronegative, should be informed of the risks for contracting toxoplasmosis from cat feces (BIII), but need not be advised to give away their cats (DII). For households with cats, litter boxes should not be placed in kitchens, dining rooms, or other areas where food preparation and eating occur [bib_ref] Caring for pets of immunocompromised persons, Angulo [/bib_ref]. Additionally, litter boxes should be cleaned daily by someone other than the HSCT recipient during the first 6 months after HSCT and during periods of substantial immunosuppression (e.g., GVHD, steroid use, or relapse of the underlying disease for which the transplant was performed) to reduce the risk for transmitting toxoplasmosis to the HSCT recipient (BIII). Daily litter box changes will minimize the risk for fecal transmission of To. gondii oocysts, because fecal oocysts require ≈2 days of incubation to become infectious. If HSCT recipients perform this task during the first 6 months after HSCT and during subsequent periods of substantial immunocompromise (e.g., during GVHD, systemic steroid use, or relapse of the underlying neoplastic disease for which the transplant was performed), they should wear disposable gloves [bib_ref] Caring for pets of immunocompromised persons, Angulo [/bib_ref]. Gloves should be discarded after a single use (BIII). Soiled, dried litter should be disposed of carefully to prevent aerosolizing the To. gondii oocysts (BIII). Cat feces (but not litter) can be flushed down the toilet (BIII). Also, persons who clean cat litter, particularly HSCT recipients, should wash their hands thoroughly with soap and water afterwards to reduce their risk for acquiring toxoplasmosis (BIII).
HSCT recipients and candidates with cats should keep their cats inside (BIII) and should not adopt or handle stray cats (DIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats, to eliminate the possibility of causing an illness that could be transmitted from the cat to the HSCT recipient (BIII). Pet cats of HSCT recipients do not need to be tested for toxoplasmosis (EII). Playground sandboxes should be kept covered when not in use to prevent cats from soiling them (BIII). HSCT recipients and candidates undergoing conditioning therapy should avoid drink -ing raw goat's milk to decrease the risk for acquiring toxoplasmosis (BIII).
## Water and other beverage safety
Although limited data were found regarding the risks for and epidemiology of Cryptosporidium disease among HSCT recipients, HSCT recipients are prudent to avoid possible exposures to Cryptosporidium (BIII) because it has been reported to cause severe, chronic diarrhea, malnutrition, and death among other immunocompromised persons. HSCT recipients should avoid walking, wading, swimming, or playing in recreational water (e.g., ponds or lakes) that is likely to be contaminated with Cryptosporidium, Es. coli O157:H7 [bib_ref] First reported outbreak in the United States of cryptosporidiosis associated with a..., Kramer [/bib_ref] , sewage, or animal or human waste (BII). HSCT recipients should also avoid swallowing such water (e.g., while swimming) [bib_ref] First reported outbreak in the United States of cryptosporidiosis associated with a..., Kramer [/bib_ref] as well as any water taken directly from rivers and lakes (5,316 ) (AIII).
HSCT recipients should not use well water from private wells or from public wells in communities with limited populations (DIII) because tests for microbial contamination are performed too infrequently (e.g., in certain locations, tests are performed £1 times/month) to detect sporadic bacterial contamination. However, drinking well water from municipal wells serving highly populated areas is regarded as safe from bacterial contamination because the water is tested ≈2 times/day for bacterial contamination. If HSCT recipients consume tap water, they should routinely monitor mass media (e.g., radio, television, or newspapers) in their area to immediately implement any boil-water advisories that might be issued for immunocompromised persons by state or local governments (BIII). A boil-water advisory means that all tap water should be boiled for ≈1 minutes before it is consumed. Tap water might not be completely free of Cryptosporidium. To eliminate the risk for Cryptosporidium exposure from tap water, HSCT recipients can boil tap water for ≈1 minutes before consuming it (e.g., drinking or brushing teeth) (5 ) (CIII). Alternately, they can use certain types of water filters (316 ) or a home distiller (317 ) to reduce their risk for Cryptosporidium (5 ) and other waterborne pathogens (CIII). If a home water filter* is used, it should be capable of removing particles ≈1 µm in diameter, or filter by reverse osmosis. However, the majority of these filters are not capable of removing smaller microbes (e.g., bacteria or viruses), and therefore, should only be used on properly treated municipal water. Further, the majority of these devices would not be appropriate for use on an unchlorinated private well to control viral or bacterial pathogens. Bottled water can be consumed if it has been processed to remove Cryptosporidium by one of three processes -reverse osmosis, distillation, or 1-µm particulate absolute filtration. To confirm that a specific bottled water has undergone one of these processes, HSCT recipients should contact the bottler directly. † Patients can take other precautions in the absence of boilwater advisories to further reduce their risk for cryptosporidiosis. These extra precautions include avoiding fountain beverages and ice made from tap water at restaurants, bars, and theaters (5 ), fruit drinks made from frozen concentrate mixed with tap water, and iced tea or coffee made with tap water (317 ). Drinks that are likely to be Cryptosporidium safe for HSCT recipients include nationally distributed brands of bottled or canned carbonated soft drinks and beers (5 ); commercially packaged noncarbonated drinks that contain fruit juice; fruit juices that do not require refrigeration until after opening (e.g., those that are stored unrefrigerated on grocery shelves) (5 ); canned or bottled soda, seltzer or fruit drinks; steaming hot (≈175 F) tea or coffee (317 ); juices labeled as pasteurized; and nationally distributed brands of frozen fruit juice concentrate that are reconstituted with water from a safe source . HSCT recipients should not drink unpasteurized milk or fruit or vegetable juices (e.g., apple cider or orange juice) to avoid infection with Brucella species, Es. coli O157:H7, Salmonella species, Cryptosporidium, and others (319,347-351 ) (DII).
## Food safety
HSCT candidates and household or family members who prepare food for them after HSCT should review food safety practices that are appropriate for all persons (352 ) (AIII), and food preparers should be educated regarding additional food safety practices appropriate for HSCT recipients. This review and education should be done before the conditioning regimen (i.e., chemotherapy and radiation) begins (BIII). Adherence to these guidelines will decrease the risk for foodborne disease among HSCT recipients.
## Food safety practices appropriate for all persons
Raw poultry, meats, fish, and seafood should be handled on separate surfaces (e.g., cutting board or counter top) from other food items. Food preparers should always use separate cutting boards (i.e., one for poultry and other meats and one for vegetables and remaining cutting or carving tasks) (AIII), or the board(s) should be washed with warm water and soap between cutting different food items (AIII). To prevent foodborne illnesses caused by Campylobacter jejuni and Salmonella enteritidis, which can cause severe and invasive infections among immunocompromised persons, uncooked meats should not come in contact with other foods (BIII).
After preparing raw poultry, meats, fish, and seafood and before preparing other foods, food handlers should wash their hands thoroughly in warm, soapy water. Any cutting boards, counters, knives, and other utensils used should be washed thoroughly in warm, soapy water also (AIII). Food preparers should keep shelves, counter tops, refrigerators, freezers, utensils, sponges, towels, and other kitchen items clean (AIII). All fresh produce should be washed thoroughly under running water before serving (355 ) (AIII). Persons preparing food should follow published U.S. Department of Agriculture recommendations regarding safe food thawing (356 ) (BIII).
Persons cooking food for HSCT recipients should follow established guidelines for monitoring internal cooking temperatures for meats (357 ) (AII). The only method for determining whether the meat has been adequately cooked is to measure its internal temperature with a thermometer because the color of the meat after cooking does not reliably reflect the internal temperature. Different kinds of meat should be cooked to varying internal temperatures, all ≈150 F (AII). Specifically, the U.S. Department of Agriculture recommends that poultry be cooked to an internal temperature of 180 F; other meats and egg-containing casseroles and souffles should be cooked to an internal temperature of ≈160 F. Cold foods should be stored at <40 F; hot foods should be kept at >140 F (BIII). Food preparers should - wash their hands before and after handling leftovers (AIII);
- use clean utensils and food-preparation surfaces (AIII);
- divide leftovers into small units and store in shallow containers for quick cooling (AII);
- refrigerate leftovers within 2 hours of cooking (AII).
- discard leftovers that were kept at room temperature for >2 hours (AIII);
- reheat leftovers or heat partially cooked foods to ≈165 F throughout before serving (AII);
- bring leftover soups, sauces, and gravies to a rolling boil before serving (AIII); and
- follow published guidelines for cold storage of food (352 ) (AII).
## Additional food safety practices appropriate for hsct recipients
HSCT recipients' diets should be restricted to decrease the risk for exposure to foodborne infections from bacteria, yeasts, molds, viruses, and parasites (BIII). Currently, a low microbial diet is recommended for HSCT recipients [bib_ref] Chapter 80: nutritional support of patients with hematologic malignancies, Aker [/bib_ref] (BIII). This diet should be continued for 3 months after HSCT for autologous recipients. Allogeneic recipients should remain on the diet until all immunosuppressive drugs (e.g., cyclosporine, steroids, and tacrolimus) are discontinued. However, the HSCT physician should have final responsibility for determining when the diet can be discontinued safely. Only one study has reported that dietary changes (e.g., consuming yogurt) have decreased the risk for mycotic infections (e.g., candidal vaginitis) (360 ) [fig_ref] TABLE 3: DT should be used whenever a contraindication exists to pertussis vaccination [/fig_ref]. HSCT recipients should not eat any raw or undercooked meat, including beef, poultry, pork, lamb, venison or other wild game, or combination dishes containing raw or undercooked meats or sweetbreads from these animals (e.g., sausages or casseroles) (AII). Also, HSCT recipients should not consume raw or undercooked eggs or foods that might contain them (e.g., certain preparations of hollandaise sauce, Caesar and other salad dressings, homemade mayonnaise, and homemade eggnog) because of the risk for infection with Salmonella enteritidis (354 ) (AII). HSCT recipients should not consume raw or undercooked seafood (e.g., oysters or clams) to prevent exposure to Vibrio species, viral gastroenteritis, and Cryptosporidium parvum (361-364 ) (AII).
HSCT recipients and candidates should only consume meat that is well-done when they or their caretakers do not have direct control over food preparation (e.g., when eating in a restaurant) (AI). To date, no evidence exists in the United States that eating food at a fast food restaurant is riskier than eating at a conventional sit-down restaurant. Generally, HSCT candidates undergoing conditioning therapy and HSCT recipients with neutropenia (i.e., ANC < 1,000/ml 3 ), GVHD, or immunosuppression should avoid exposures to naturopathic medicines that might contain molds (365 ) (DIII). HSCT recipients wishing to take naturopathic medications are advised to use them only as prescribed by a licensed naturopathic physician working in consultation with the recipient's transplant and infectious disease physicians (CIII).
## Travel safety
Travel to developing countries can pose substantial risks for exposure to opportunistic pathogens for HSCT recipients, particularly allogeneic recipients chronically immunosuppressed. HSCT recipients should not plan travel to developing countries without consulting their physicians (AIII), and travel should not occur until the period of severe immunosuppression has resolved. Generally, allogeneic recipients should not plan travel to developing countries for 6-12 months after HSCT, particularly if GVHD has occurred. Autologous recipients can travel to developing countries 3-6 months after HSCT if their physicians agree.
HSCT recipients should be informed regarding strategies to minimize the risk for acquiring foodborne and waterborne infections while traveling. They should obtain updated, detailed health information for international travelers from health organizations (366,367 ) (AIII). Generally, while traveling in developing countries, HSCT recipients should avoid consuming the following (BIII):
- raw fruits and vegetables,
- tap water or any potentially untreated or contaminated water,
- ice made from tap water or any potentially contaminated water,
- unpasteurized milk or any unpasteurized dairy products,
- fresh fruit juices,
- food and drinks from street vendors, and
- raw or undercooked eggs.
Steaming hot foods, fruits peeled by oneself, bottled and canned processed drinks, and hot coffee or tea are probably safe. Travelers should plan for treating their drinking water while in developing countries. If bottled water is not available, boiling is the best method of making water safe. However, if boiling water is not feasible, the traveler should carry supplies for disinfecting water (e.g., commercially available iodine disinfection tablets or a portable water filter). Antimicrobial prophylaxis for traveler's diarrhea is not recommended routinely for HSCT recipients traveling to developing countries (DIII) because traveler's diarrhea is not known to be more frequent or more severe among immunocompromised hosts. However, HSCT physicians who wish to provide prophylaxis to HSCT recipients who are traveling can prescribe a fluoroquinolone (e.g., ciprofloxacin hydrochloride) or TMP-SMZ (CIII), although resistance to TMP-SMZ is now common and resistance to fluoroquinolones is increasing in tropical areas (Appendix). Researchers recommend using bismuth subsalicylate to prevent traveler's diarrhea among adults. However, no data were found regarding safety and efficacy among HSCT recipients, and salicylates are not recommended for use among persons aged <18 years because salicylates are associated with Reye's syndrome [bib_ref] Reye's syndrome in the United States from 1981 through 1997, Belay [/bib_ref].
HSCT recipients' immunization status should be assessed and their vaccinations updated as needed before travel. Influenza chemoprophylaxis with rimantadine or amantadine can be used for immunocompromised HSCT recipients who are traveling outside the continental United States and who could be exposed to influenza A (CIII).
## Hsct recipient vaccinations
Antibody titers to vaccine-preventable diseases (e.g., tetanus, polio, measles, mumps, rubella, and encapsulated organisms) decline during the 1-4 years after allogeneic or autologous HSCT [bib_ref] Polysaccharide conjugate vaccine responses in bone marrow transplant patients, Guinan [/bib_ref] [bib_ref] Immunity to poliovirus and immunization with inactivated poliovirus vaccine after autologous bone..., Pauksen [/bib_ref] [bib_ref] Immunity to and immunization against measles, rubella and mumps in patients after..., Pauksen [/bib_ref] [bib_ref] Responses to tetanus toxoid immunization after allogeneic bone marrow transplantation, Ljungman [/bib_ref] [bib_ref] Efficacy and safety of vaccination of marrow transplant recipients with a live..., Ljungman [/bib_ref] if the recipient is not revaccinated. Clinical relevance of decreased antibodies to vaccine-preventable diseases among HSCT recipients is not immediately apparent because a limited number of cases of vaccine preventable diseases are reported among U.S. recipients. However, vaccine-preventable diseases still pose risks to the U.S. population. Additionally, evidence exists that certain vaccinepreventable diseases (e.g., encapsulated organisms) can pose increased risk for HSCT recipients [bib_ref] Polysaccharide conjugate vaccine responses in bone marrow transplant patients, Guinan [/bib_ref] ; therefore, HSCT recipients should be routinely revaccinated after HSCT so that they can experience immunity to the same vaccine-preventable diseases as others [fig_ref] TABLE 4: HSCT as indicated [/fig_ref].
HSCT center personnel have developed vaccination schedules for HSCT recipients [bib_ref] National survey of immunization practices following allogeneic bone marrow transplantation, Henning [/bib_ref]. One study determined that HSCT center personnel used 3-11 different vaccination schedules per vaccine [bib_ref] National survey of immunization practices following allogeneic bone marrow transplantation, Henning [/bib_ref] ; consequently, the study authors requested national guidelines for doses and timing of vaccines after HSCT to eliminate confusion among HSCT center personnel regarding how to vaccinate their patients. To address this need, an interim vaccination schedule for HSCT recipients was drafted in collaboration with partner organizations, including CDC's Advisory Committee on Immunization Practices. The purpose of the vaccination schedule in these guidelines is to provide guidance for HSCT centers [fig_ref] TABLE 4: HSCT as indicated [/fig_ref]. Although limited data were found regarding safety and immunogenicity (e.g., serologic studies of antibody titers after vaccination) among HSCT recipients, no data were found regarding vaccine efficacy among HSCT recipients (e.g., which determine whether vaccinated HSCT recipients have decreased attack rates of disease compared with unvaccinated HSCT recipients). Because certain HSCT recipients have faster immune system recovery after HSCT than others, researchers have proposed that different vaccination schedules be recommended for recipients of different types of HSCT. However, to date, data are too limited to do so. Therefore, the same vaccination schedule is recommended for all HSCT recipients (e.g., allogeneic, autologous, and bone marrow, peripheral, or UCB grafts) until additional data are published. In the tables, vaccines have only been recommended for use among HSCT recipients if evidence exists of safety and immunogenicity for those recipients. Vaccination of family *Broviac dolls are used to demonstrate medical procedures (e.g., insertion of catheters) to children to lessen their fears.
members, household contacts, and HCWs are also recommended to minimize exposure of vaccine-preventable diseases among HSCT recipients [fig_ref] TABLE 5: Vaccinations for family, close contacts, and health-care workers [/fig_ref].
## Hematopoietic stem cell safety
With allogeneic HSCT, the life of the recipient might depend on the timely selection of an acceptable HLA-matched donor. Only a limited number of HLA-matched donors might be identified; hence, the transplant physician often has to accept a higher risk for transmission of an infectious agent through HSCT than would be permitted for routine blood transfusion. This section provides strategies for the HSCT physician to minimize transmission of infectious diseases, whenever possible, from donors to recipients.* † Whether to select a donor who is at risk for or who has an infectious disease transmissible by HSCT, should be determined on a case-by-case basis (AIII) and is the final responsibility of the HSCT physician (AIII). If the only possible donor is at risk for or known to be infected with a bloodborne pathogen and the patient is likely to succumb rapidly from his or her disease if an HSCT is not received, the physician must carefully weigh the risks and benefits of using potentially infected donor cells. No person should be denied a potentially life-saving HSCT procedure solely on the basis of the risk for an infectious disease. However, HSCT physicians should avoid transplanting any infected or infectious donor hematopoietic stem cell product unless no other stem cell product can be obtained and the risk for death from not undergoing transplantation is deemed to be greater than the risk for morbidity or death from the infection that could potentially be transmitted (DII). If such a product is selected for use, it should be done on a case-by-case basis [bib_ref] Bacterial contamination rates following processing of bone marrow and peripheral blood progenitor..., Padley [/bib_ref] and the following should be noted in the recipient's chart:
- knowledge and authorization of the recipient's HSCT physician regarding the potential for transmission of an infectious agent during HSCT, and
- advance informed consent from the recipient or recipient's legal guardian acknowledging the possible transmission of an infectious agent during the transplantation (AIII).
Subsequently, the HSCT physician should include the infectious agent in the differential diagnosis of any illness that the HSCT recipient experiences so that the infection, if transmitted, can be diagnosed early and treated preemptively, if possible. Infectious products (except those in which CMV seropositivity is the only evidence of infectiousness) should be labeled as being a biohazard or as untested for biohazards, as applicable. Tissue intended for autologous use should be labeled "For Autologous Use Only -Use Only for (Patient's Name)."
## Preventing transmission of infections from hsct donors to recipients
All prospective HSCT donors should be evaluated through a physical history and examination to determine their general state of health and whether they pose a risk for transmitting infectious diseases to the recipient. To detect transmissible infections, all HSCT donor collection site personnel should follow up-todate published guidelines and standards for donor screening (e.g., medical history), physical exam, and serologic testing [bib_ref] Suitability determination for donors of human cellular and tissue-based products, Food [/bib_ref] (AIII). Initial donor screening and physical exam should be performed £8 weeks before the planned donation (BIII). Donor serologic testing should be done £30 days before donation to detect potentially transmissible infections (BII); additionally, researchers recommend that donors be retested £7 days before collection. If testing is done >7 days before donation, donor screening should be repeated to ensure that no new risk behaviors have occurred during the interval between the original screening and the time of donation (BIII). This practice is critical because if new behavioral risk factors have occurred, the potential donor might need to be deferred. Screening and testing should be done on all allogeneic or syngeneic donors (AIII). Screening and testing of autologous donors is recommended to ensure the safety of laboratory personnel and to prevent cross contamination (BIII). If autologous donors are not tested, their autologous units should be specially labeled and handled as if potentially infected (BIII). For donors screened in the United States, FDA-licensed or -approved tests should be used in accordance with the manufacturers' instructions (AIII), and the donor samples should be tested in laboratories certified by the Clinical Laboratory Improvement Amendments of 1988 (AIII).
All HSCT donors should be in good general health (376 ) (BIII). Acute or chronic illness in the prospective donor should be investigated to determine the etiology. Generally, persons who are ill should not be HSCT donors (DIII). A flu-like illness in a prospective donor at the time of evaluation or between the time of evaluation and donation should prompt evaluation of and serologic testing for infections that might pose a risk to the recipient (e.g., EBV, CMV, To. gondii ) (BIII). Persons with a positive serum EBV-viral capsid antigen IgM but negative serum EBV-viral capsid antigen IgG should not serve as donors for allogeneic Tcell-depleted HSCT, particularly for unrelated or mismatched transplants, until their serum EBV-viral capsid antigen IgG becomes positive (DIII). Persons with acute toxoplasmosis should not donate until the acute illness has resolved (DII); however, physicians should be aware that persons who are asymptomatically seropositive for To. gondii might transmit this infection through HSCT [bib_ref] Toxoplasma gondii infection in marrow transplant recipients: a 20 year experience, Slavin [/bib_ref].
Prospective donors with symptoms of active TB should be evaluated for that disease (383 ) (BIII). Prospective donors with active TB should not donate (EIII) until the TB is well-controlled (e.g., no longer contagious as determined by the donor's primary physician) after appropriate medical therapy. However, no known risk exists from transplanting marrow from an untreated, tuberculin-positive donor who has no evidence of active disease. Screening potential donors for TB with Mantoux skin tests (DIII) is not necessary. Prospective HSCT donors who reside in or have traveled to areas endemic for rickettsia or other tickborne pathogens and who are suspected of having an acute tickborne infection should be temporarily deferred as donors until infection with these pathogens is excluded (DIII). Relevant pathogens include Rickettsia rickettsii, Babesia microti and other Babesia species, Coxiella burnetii, and the Colorado tick fever virus, which are the etiologic agents of Rocky Mountain spotted fever, babesiosis, Q fever, and Colorado tick fever, respectively; these pathogens have been reported to be transmitted by blood transfusion [bib_ref] Rocky Mountain spotted fever caused by blood transfusion, Wells [/bib_ref] [bib_ref] Transfusiontransmitted babesiosis in Washington State: first reported case caused by a WA1-type..., Herwaldt [/bib_ref] [bib_ref] Cluster of transfusionassociated babesiosis cases traced to a single asymptomatic donor, Dobroszycki [/bib_ref]. Researchers recommend deferral for a past history of Q fever or babesiosis because these infections can be chronic and the babesiosis parasite might persist despite appropriate therapy (389 ) (CIII). Additionally, researchers have recommended deferring persons with acute human ehrlichiosis (e.g., human active human granulocytic ehrlichiosis [bib_ref] Primary bone marrow progenitors of both granulocytic and monocytic lineages are susceptible..., Klein [/bib_ref] , human monocytic ehrlichiosis, as well as any infections from Ehrlichia ewingii ) from HSCT donation (CIII).
The medical history of the prospective HSCT donor should include the following:
- History of vaccinations (377 ) during the 4 weeks before donation (AII). If the potential donor is unsure of vaccinations received, his or her records should be reviewed. HSCT donation should be deferred for 4 weeks after the donor receives any live-attenuated vaccine (e.g., rubeola [measles], mumps, rubella [German measles], oral polio, varicella, yellow fever, and oral typhoid vaccines) (EIII). This deferral will avoid the possibility of infusing a live infectious agent into an HSCT recipient. HSCT donation need not be deferred for persons who have recently received toxoid or killed (i.e., inactivated), recombinant viral, bacterial, or rickettsial vaccines as long as the donor is asymptomatic and afebrile (389 ) (BIII). Such vaccines include tetanus toxoid, diphtheria toxoid, hepatitis A and B, cholera, influenza (i.e., killed intramuscular vaccine), meningococcal, paratyphoid, pertussis, plague, polio (i.e., inactivated polio vaccine), rabies, typhoid (i.e., inactivated intramuscular vaccine), or typhus vaccines (389 ).
- Travel history (BIII) to determine whether the donor has ever resided in or traveled to countries with endemic diseases that might be transmitted through HSCT (e.g., malaria). Permanent residents of nonendemic countries who have traveled to an area that CDC regards as endemic for malaria can be accepted as HSCT donors if 1 year has elapsed since the donor's departure from the endemic area and if the donor has been free of malaria symptoms, regardless of whether he or she received antimalarial chemoprophylaxis. Because cases ofHSCT-transmitted malaria have been reported [bib_ref] Transmission of malaria by bone marrow transplantation, Dharmasena [/bib_ref] [bib_ref] Plasmodium falciparum infection following allogeneic bone-marrow transplantation, Villeneuve [/bib_ref] , persons who have had malaria and received appropriate treatment should be deferred from HSCT donation for 3 years after becoming asymptomatic. Immigrants, refugees, citizens, or residents for ≈5 years of endemic countries can be accepted as HSCT donors if 3 years have elapsed since they departed the malarious area and if they have been free of malaria symptoms.
- History of Chagas' disease and leishmaniasis. Persons with active Chagas' disease or leishmaniasis should not serve as HSCT donors (DIII) because these diseases can be transmitted by transfusion [bib_ref] Trypanosoma cruzi in a low-to moderate-risk blood donor population: seroprevalence and possible..., Leiby [/bib_ref] [bib_ref] Strategies for prevention of transfusion-associated Chagas' disease, Moraes-Souza [/bib_ref] [bib_ref] Chagas' disease after bone marrow transplantation, Altclas [/bib_ref] [bib_ref] Prospective evaluation of a patient with Trypanosoma cruzi infection transmitted by transfusion, Leiby [/bib_ref] [bib_ref] Seroepidemiology of Trypanosoma cruzi , etiologic agent of Chagas' disease, in US..., Leiby [/bib_ref]. Researchers also recommend deferral of HSCT donation if a past history exists of either of these diseases because the parasite can persist despite therapy [bib_ref] Trypanosoma cruzi in a low-to moderate-risk blood donor population: seroprevalence and possible..., Leiby [/bib_ref] [bib_ref] Recipients and donors of bone marrow transplants suffering from Chagas' disease: management..., Dictar [/bib_ref] [bib_ref] Strategies for prevention of transfusion-associated Chagas' disease, Moraes-Souza [/bib_ref] [bib_ref] Chagas' disease after bone marrow transplantation, Altclas [/bib_ref] [bib_ref] Prospective evaluation of a patient with Trypanosoma cruzi infection transmitted by transfusion, Leiby [/bib_ref] [bib_ref] Seroepidemiology of Trypanosoma cruzi , etiologic agent of Chagas' disease, in US..., Leiby [/bib_ref] (CIII).
- History of any deferral from plasma or blood donation.
The reason for such a deferraland whether it was based on a reported infectious disease or behavioral or other risk factor should be investigated (BIII).
- History of viral hepatitis. A person with a history of viral hepatitis after his or her eleventh birthday should be excluded from HSCT donation (BIII).
- History of blood product transfusion, solid organ transplantation, or transplantation of tissue within the last 12 months (BIII). Such persons should be excluded from HSCT donation (DIII). Xenotransplant product recipients and their close contacts should be indefinitely deferred from donating any blood products, including hematopoietic stem cells, whole blood, or other blood components including plasma, leukocytes, and tissues (396 ) (AIII). Close contacts to be deferred from donations include persons who have engaged repeatedly in activities that could result in an intimate exchange of body fluids with a xenotransplantation product recipient. Such close contacts could include sexual partners, household members who share razors or toothbrushes, and HCWs or laboratory personnel with repeated percutaneous, mucosal, or other direct exposures.
- History of risk factors for classic Creutzfeldt-Jakob disease (CJD), including any blood relative with Creutzfeldt-Jakob disease, receipt of a human pituitary-derived growth hormone or receipt of a corneal or dura mater graft (383,397-399 ) (BIII). Potential HSCT donors should also be screened for new variant Creutzfeldt-Jakob Disease (nvCJD) risk factors, including a history of cumulative travel or residence in the United Kingdom for ≈6 months during 1980-1996 or receipt of injectable bovine insulin since 1980, unless the product was not manufactured since 1980 from cattle in the United Kingdom (398 ) (BIII). The clinical latency period for iatrogenic, classic CJD can be >30 years, and transmission of classic CJD by blood products is highly unlikely. Although no classic or nvCJD has ever been reported among HSCT recipients, persons with a history of classic or nvCJD risk factors should be excluded from donation for unrelated HSCT (DIII) if a choice exists between two otherwise equally suitable donors. The risk for transmitting classic or nvCJD from an HSCT donor to a recipient is unknown, but researchers believe that persons with nvCJD risk factors could be at higher risk for transmitting nvCJD to HSCT recipients than persons with classic CJD risk factors.
- Past medical history that indicates the donor has clinical evidence of or is at high risk for acquiring a bloodborne infection (e.g. Persons reporting any of these past medical histories should be excluded from donation (DIII).
The following serologic tests should be performed for each prospective donor:
- HIV-1 antigen, anti-HIV-1 and -2, anti-HTLV-I and -II, hepatitis B surface antigen, total antihepatitis B core antigen, antihepatitis C, anti-CMV, and a serologic test for syphilis [bib_ref] Suitability determination for donors of human cellular and tissue-based products, Food [/bib_ref] (AIII). Potential donors who have repeatedly reactive screening tests for HIV-1 antigen, anti-HIV-1 or -2, anti-HTLV-I or -II, antihepatitis C, hepatitis B surface antigen, or antihepatitis B core antigen should be excluded as HSCT donors (381 ) (EII). Persons who refuse infectious disease testing should also be excluded as HSCT donors (381 ) (EIII).
- Investigational nucleic acid tests to detect hepatitis C virus RNA and HIV RNA are currently being used in the United States to screen blood donors and could be used for screening HSCT donors. If nucleic acid tests are approved by FDA, these tests should be incorporated into routine screening regimens for HSCT donors. When nucleic acid testing is done for HIV and hepatitis C investigationally, a positive result should exclude the potential donor.
All infectious disease testing and results should be reported to the HSCT physician before the candidate's conditioning regimen begins (381 ) (AIII). Bone marrow should be collected using sterile technique in a medically acceptable setting and according to standard operating procedures (AIII). HSCT transplant center personnel should keep accurate records of all HSCT received and the disposition of each sample obtained. These tracking records must be separate from patients' medical records (e.g., in a log book) so that this information is easily obtainable. Recorded information should include the donor identification number, name of procurement of distribution center supplying the HSCT, recipient-identifying information, name of recipient's physician, and dates of a) receipt by the HSCT center and b) either transplantation to the recipient or further distribution (381 ) (AIII). All centers for donation, transplantation, or collection of hematopoietic stem cells should keep records of donor screening and testing, and HSCT harvesting, processing, testing, cryopreservation, storage, and infusion or disposal of each aliquot of donated hematopoietic progenitor cells for ≈10 years after the date of implantation, transplantation, infusion, or transfer of the product (378 ) (AIII). However, if that date is not known, records should be retained ≈10 years after the product's distribution, disposition, or expiration, whichever is latest.
## Pediatric donors
Children aged >18 months who are born to mothers with or at risk for HIV infection, who have not been breast-fed during the past 12 months, and whose HIV antibody tests, physical examination, and medical records do not indicate evidence of HIV infection can be accepted as donors (381 ) (BIII). Children aged <18 months who are born to mothers with or at risk for HIV infection and who have not been breast-fed by an HIV-infected woman during the past 12 months can be accepted as donors only if HIV infection has been excluded according to established criteria (402 ) (BIII). Children who have been breast-fed by an HIVinfected woman during the past 12 months should be excluded as stem cell donors regardless of HIV infection status (AIII). The mother and, if possible, the father of all pediatric stem-cell donors who are at risk for perinatal transmission of HIV and other bloodborne infections, should be interviewed by a health-care professional competent to elicit information regarding risk factors for possible bloodborne infection in the potential pediatric donor (AIII). Children who meet any of the adult donor exclusion criteria should not become HSCT donors (381 ) (EIII).
## Preventing infection from extraneous contamination of donated units
Personnel of donation, collection, or transplantation centers, cell-processing laboratories, and courier services should follow current standards for detecting and preventing extrinsic bacterial and fungal contamination of collected stem cell units at the collection site, during processing and transportation, and at the transplant center (376 ) (AIII). Quality improvement programs and procedure manuals of collection centers, cell-processing laboratories, and transplant programs should include strategies for preventing transplant-associated infections. For example, collection centers should use aseptic techniques when collecting marrow, peripheral blood, and UCB hematopoietic stem cells (376,378 ) (AIII). Whenever possible, closed systems should be used for pooling hematopoietic stem cells during a collection procedure (BIII) because higher rates of microbial contamination seen in marrow harvests versus blood stem cell collections can be caused by use of open collecting systems [bib_ref] Bacterial contamination rates following processing of bone marrow and peripheral blood progenitor..., Padley [/bib_ref] [bib_ref] Microbial contamination of peripheral blood stem cell collections, Attarian [/bib_ref] [bib_ref] Bacterial contamination of bone marrow grafts intended for autologous and allogeneic bone..., Rowley [/bib_ref]. The highest risk for extraneous microbial contamination of hematopoietic stem cells occurs during extensive manipulation and processing in the laboratory [bib_ref] Bacterial contamination of bone marrow grafts intended for autologous and allogeneic bone..., Rowley [/bib_ref] [bib_ref] Sources and sequelae of bacterial contamination of hematopoietic cell components: implications for..., Webb [/bib_ref]. Po-tential sources include unprotected hands and laboratory equipment and freezers [bib_ref] Parenterally transmitted hepatitis A associated with platelet transfusions: epidemiologic study of an..., Meyers [/bib_ref] , particularly the liquid phases of liquid nitrogen freezers [bib_ref] Liquid nitrogen freezers: a potential source of microbial contamination of hematopoietic stem..., Fountain [/bib_ref]. Therefore, stem cell processing should be performed according to current standards (378 ) using approved manufacturing practices (AIII). Hematopoietic stem cell units thawed in a water bath should be enclosed in a second bag (i.e., double-bagged technique) to prevent contamination of the ports or caps from unsterile bath water (407 ) (BIII). Additionally, water baths should be cleaned routinely (BIII) and certain researchers have proposed that the bath contain sterile water (407 ) (CIII). Researchers also report sterilizing liquid nitrogen freezers before initial use for hematopoietic stem cell storage [bib_ref] Liquid nitrogen freezers: a potential source of microbial contamination of hematopoietic stem..., Fountain [/bib_ref] until fungal and bacterial cultures are negative (CIII).
Cell-processing laboratory personnel should implement programs to detect extrinsic bacterial or fungal contamination of collected stem cell units, ideally before transplantation (AIII). Although repeated cultures are costly [bib_ref] Routine cultures of bone marrow and peripheral stem cell harvests: clinical impact,..., Nasser [/bib_ref] , donated hematopoietic stem cells should be cultured for aerobic bacteria and fungi ≈1 times during initial processing and freezing (BIII). Researchers also have proposed adding anaerobic bacterial cultures and culturing twice, once at the end of processing, and once after thawing just before use (407 ) (CIII). If bacterial culture results are positive, antibiotic-susceptibility tests should be performed . Results of cultures and antibiotic-susceptibility tests should be provided to the transplant physician before release of a cryopreserved marrow or blood stem cell unit, and as soon as feasible for transplants infused before completion of culture incubation (BIII).
Collection center, cell-processing laboratory, and transplant program personnel should maintain active surveillance of infections among persons who have received hematopoietic stem cells from those facilities to collect data regarding the number of infections after HSCT that might have been caused by exogenous contamination of donor stem cells (BIII) because this type of infection has been reported [bib_ref] Sources and sequelae of bacterial contamination of hematopoietic cell components: implications for..., Webb [/bib_ref].
## In utero or fetal hsct
No national standards exist for in utero or fetal HSCT, and the overall risks for transmitting infections to a fetus through HSCT [bib_ref] Treatment of x-linked severe combined immunodeficiency by in utero transplantation of paternal..., Flake [/bib_ref] [bib_ref] In utero hematopoietic stem cell transplantation: a status report, Flake [/bib_ref] have not been determined. However, in addition to precautions appropriate for adult recipients, physicians performing in utero or fetal HSCT are advised to evaluate potential donors for evidence of active infectious diseases that could cause serious congenital infections (e.g., rubella, varicella, CMV, syphilis, or To. gondii ) in the fetus (CIII). Routine vaccination is recommended for persons at increased risk for hepatitis A or its adverse consequences (e.g., persons with chronic liver disease or persons traveling to hepatitis Aendemic countries) and for children aged ⊕24 months living in areas with consistently elevated hepatitis A incidence. † Household contacts -Vaccination is strongly recommended during each influenza season (i.e., October-May) beginning in the season before the transplant and continuing to ⊕24 months after HSCT. All household contacts of immunocompromised HSCT recipients should be vaccinated annually as long as these conditions persist. HCWs and home caregivers -Annual vaccination is strongly recommended during each influenza season.
Vaccination is not routinely recommended for adults but should be administered when polio vaccination is indicated according to published Advisory Committee on Immunization Practices guidelines; when polio vaccine is administered, inactivated polio vaccine should be used.
Vaccination is recommended for all persons who are aged ⊕12 months and who are not pregnant or immunocompromised.
Contraindicated because intussusception has been reported among infants during the first 1-2 weeks after rotavirus vaccination with substantially increased frequency.
Vaccination should be administered to all susceptible HCWs, household contacts, and family members who are aged ⊕12 months and who are not pregnant or immunocompromised. When varicella vaccination is administered to persons aged ⊕13 years, 2 doses are required, administered 4-8 weeks apart. Postexposure vaccination should be administered with or without tetanus immunoglobulin as indicated for tetanus exposure § § that occurs anytime after HSCT.
Ideally, should be administered to HSCT recipients ≤96 hours after close contact with a person with varicella or shingles if the HSCT recipient is at a) <24 months after HSCT or b) ⊕24 months after HSCT and still immunocompromised. Administration can extend the varicella incubation period from 10-21 days to 10-28 days. If the HSCT recipient experiences a varicella-zoster virus-like rash after contact with or exposure to a person with varicella or herpes zoster, antiviral drug therapy should be administered until ⊕2 days after all lesions have crusted.*** Should be administered to hepatitis A-susceptible HSCT recipients who anticipate hepatitis A exposure, (e.g., during travel to endemic areas) and for postexposure prophylaxis as indicated. † † † Should also be administered after measles exposure among HSCT recipients who were not vaccinated against measles after HSCT. § § § Can be administered to HSCT recipients with severe hypogammaglobulinemia (immunoglobulin G < 400 mg/ dl) ≤100 days after HSCT to prevent bacterial infections**** (Appendix). . Notes: RSV intravenous immunoglobulin is contraindicated among patients with immunoglobulin A deficiency or who might have allergic reactions or anaphylaxis when receiving blood products containing immunoglobulin A (DIII). RSV monoclonal antibody is under investigational use among HSCT recipients for treatment with ribavirin but not for prophylaxis. [bib_ref] Recovery of antibody production in human allogeneic marrow graft recipients: influence of..., Witherspoon [/bib_ref] [bib_ref] Detection of specific antibody formation to recall antigens after human bone marrow..., Lum [/bib_ref] [bib_ref] Kinetics of immune reconstitution after human marrow transplantation, Lum [/bib_ref] [bib_ref] Chronic graft-versushost syndrome in man: a long-term clinicopathologic study of 20 Seattle..., Shulman [/bib_ref] [bib_ref] Disordered salivary immunoglobulin secretion and sodium transport in human chronic graft-versus-host disease, Izutsu [/bib_ref] [bib_ref] Long lasting IgG subclass and antibacterial polysaccharide antibody deficiency after allogeneic bone..., Aucouturier [/bib_ref] [bib_ref] Randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients..., Pizzo [/bib_ref] [bib_ref] Fluoroquinolone prophylaxis for the prevention of bacterial infections in patients with cancer-is..., Murphy [/bib_ref] [bib_ref] Escherichia coli resistant to fluoroquinolones in patients with cancer and neutropenia, Cometta [/bib_ref]. Researchers also propose checking serum immunoglobulin G levels every 2 weeks for patients receiving intravenous immunoglobulin replacement therapy.
## Pathogen: bacterial infections, general prophylaxis
[fig] *: For additional information regarding the epidemiology of Chagas' disease, contact CDC/National Center for Infectious Diseases/Division of Parasitic Diseases, (770) 488-7760. [/fig]
[table] TABLE 1: Evidence-based rating system used to determine strength of recommendations [/table]
[table] TABLE 2: Evidence-based rating system used to determine quality of evidence supporting recommendation [/table]
[table] TABLE 3: DT should be used whenever a contraindication exists to pertussis vaccination. § HSCT recipients should be revaccinated with tetanus-diphtheria toxoids every 10 years, as routinely recommended for all adolescents and adults (Sources: Hib conjugate vaccine is recommended for HSCT recipients of any age(Sources: CDC. Recommendations for use of Haemophilus b conjugate vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1993;42[No. RR-13]:1-15; and CDC. Use of vaccines and immunoglobulin in persons with altered immunocompetence: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1993;42[No. RR-4]:1-18). ** Hepatitis B vaccination is recommended for all susceptible persons aged ≤18 years and for adults who have risk factors for hepatitis B virus infection (Sources: CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination; No data were found regarding immunogenicity, safety, and efficacy of hepatitis A vaccine among HSCT recipients. Researchers report that hepatitis A vaccination can be used for investigational use among HSCT recipients aged ⊕24 months at ⊕12 months after HSCT and who are at increased Children aged <9 years receiving influenza vaccination for the first time require two doses. Children aged ≤12 years should receive only split-virus influenza Administration of meningococcal vaccine should be evaluated for HSCT recipients who live in endemic areas or areas experiencing outbreaks (Source: CDC. [/table]
[table] TABLE 4: HSCT as indicated. Existing ACIP and American Academy of Pediatrics guidelines for postexposure human rabies immunoglobulin and vaccine administration should be followed, which include administering 5 doses of rabies vaccine administered on days 0, 3, 7, 14, and 28 postexposure (Sources: American Academy of Pediatrics.Rabies. In: Pickering LK, ed. 2000 red book: report of the Committee on Infectious Diseases. 25 th ed. Elk Grove Village, IL: American Academy of Pediatrics;2000:475-82; and CDC. Human rabies prevention-United States, 1999: recommendations of the Advisory Committee on Immunization Practices [ACIP] MMWR 1999;48[No. RR-1]:1-21; published erratum, MMWR 1999;48[1]:16). ¶ ¶ ¶ The first dose of measles-mumps-rubella vaccine should be administered ⊕24 months after HSCT if the HSCT recipient is presumed immunocompetent. The second measles-mumps-rubella dose is recommended 6-12 months later (BIII); however, the benefit of a second dose among HSCT recipients has not been evaluated. During outbreaks, the second dose can be administered 4 weeks after the first dose (Source: CDC. Use of vaccines and immunoglobulin in persons with altered immunocompetence: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1993;42[No. RR-4]:1-18). **** The half-life of intravenous immunoglobulin is decreased among HSCT recipients, but its effect on vaccine immunogenicity has not been evaluated. ACIP's and the American Academy of Pediatrics' recommendations regarding intervals between administration of immunoglobulin preparations for various indications and vaccines containing live measles virus should be used (Sources: American Academy of Pediatrics. Measles. In: Pickering LK, ed. 2000 red book: report of the Committee on Infectious Diseases. 25 th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2000:385-96; CDC. Measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1998;47[No. RR-8]:1-48; and CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1994;43[No. RR-1]:1-38). † † † † Use of live vaccines (e.g., measles-mumps-rubella) is indicated only among immunocompetent persons and is contraindicated for recipients after HSCT who are not presumed immunocompetent (Sources: CDC. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1996;45[No. RR-11]:1-36; and CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1994;43[No. RR-1]:1-38). Further research is needed to determine the safety, immunogenicity, and efficacy of varicella vaccine among HSCT recipients. § § § § To protect HSCT recipients from varicella exposure, all varicella-susceptible health-care workers, family members, and close contacts of the recipient should be vaccinated against varicella (Source: American Academy of Pediatrics. Varicella-zoster infections. In: Pickering LK, ed. 2000 red book: report of the committee on Infectious diseases. 25 th ed. Elk Grove Village, IL: American Academy of Pediatrics;2000:624-38). ¶ ¶ ¶ ¶ Source: CDC. Withdrawal of rotavirus vaccine recommendation. MMWR 1999;48[43]:1007. Additional Notes: All indicated nonlive vaccines should be administered to HSCT recipients regardless of HSCT type or presence of GVHD. Live-attenuated vaccines, (e.g., measles-mumps-rubella, varicella, Bacillus Calmette-Guérin, yellow fever, and oral typhoid vaccines) should not be administered to any HSCT recipient with active GVHD or immunosuppression(Source: CDC. Role of BCG [Bacillus of Calmette and Guérin] vaccine in the prevention and control of tuberculosis in the United States: a joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR 1996;45[No. RR-4]:1-18). To date, no adverse events have been reported (e.g., exacerbation of GVHD) among vaccinated HSCT recipients. However, data regarding immunization among HSCT recipients are limited and further studies are needed to evaluate safety, efficacy, and immunogenicity of the proposed HSCT immunization schedule. Use of combination vaccines is encouraged (Source: CDC. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices [ACIP], the American Academy of Pediatrics [AAP], and the American Academy of Family Physicians [AAFP]. MMWR 1999;48[No. RR-5]:1-15). No contraindications to simultaneous administration of any vaccines exist, except cholera and yellow fever. Adverse events after vaccination should be reported promptly to the Vaccine Adverse Event Reporting System (VAERS), P.O. Box 1100, Rockville, MD 20849-1100. Forms and information can be obtained from VAERS ([800] 822-7967).If the HSCT recipient has lapsed immunizations after HSCT (i.e., has missed one or more vaccine doses), the immunization schedule does not have to be restarted. Instead, the missing vaccine dose should be administered as soon as possible or during the next scheduled clinic appointment. [/table]
[table] TABLE 5: Vaccinations for family, close contacts, and health-care workers (HCWs) of hematopoietic stem cell transplantation (HSCT) recipients* * This vaccination schedule refers only to vaccine-preventable diseases that are spread person-to-person. † Source: CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(No. RR-12):1-37. § Children aged <9 years receiving influenza vaccination for the first time require 2 doses. Children aged ≤12 years should receive only split-virus influenza vaccine. Persons aged >12 years can receive whole-or splitvirus vaccine (Sources: CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2000;49[No. RR-3]:1-38; and CDC. Immunization of health care workers: recommendations of the Advisory Committee on Immunization Practices [ACIP] and the Hospital Infection Control Practices Advisory Committee. MMWR 1997;46[No. RR-18]:1-42). ¶ If HCWs, family members, or other close contacts of HSCT recipients receive influenza vaccination during an influenza A outbreak, they should also receive amantadine or rimantadine chemoprophylaxis for 2 weeks after the influenza vaccination (BI) while the vaccinee develops an immunologic response to the vaccine. However, if a nosocomial outbreak occurs with an influenza A strain that is not contained in the available influenza vaccine, HCWs, family members, and other close contacts of HSCT recipients and candidates should be administered influenza A chemoprophylaxis with amantadine or rimantadine until the end of the outbreak (Source: CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2000;49[No. RR-3]:1-38) (BIII). HCWs, family members, or other close contacts can be offered a neuroaminidase inhibitor (e.g., zanamivir or oseltamivir) using the same strategies outlined previously, if one or more of the following exists: a) rimantadine or amantadine cannot be tolerated; b) the outbreak strain of influenza A is amantadine-or rimantadine-resistant; or c) the outbreak strain is influenza B (Sources: Monto AS, Robinson DP, Herlocher ML, Hinson JM Jr, Elliott MJ, Crisp A. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA 1999;282[1]:31-5; Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. New Engl J Med 1999;341[18]:1336-43; Hayden FG, Gubareva L, Klein T, et al. Inhaled zanamivir for preventing transmission of influenza in families [Abstract LB-2]. In: Final program, abstracts and exhibits addendum, 38 th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology, 1991:1; and CDC. Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR 1999;48[No. RR-14]:1-10) (BI). Zanamivir can be administered to persons aged ⊕12 years, and oseltamivir can be administered to persons aged ⊕18 years. ** Caution: Vaccine-strain polio virus in oral polio vaccine can be transmitted person-to-person; therefore, oral polio vaccine administration is contraindicated among household contacts of immunocompromised persons. If oral polio vaccine is inadvertently administered to a household contact of an HSCT recipient, ACIP's and the American Academy of Pediatrics' recommendations should be followed to minimize close contact with the immunocompromised person for 4-6 weeks after vaccination (Sources: American Academy of Pediatrics. Poliovirus infections. In: Pickering LK, ed. 2000 red book: report of the Committee on Infectious Diseases. 25 th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2000:465-70; CDC. Immunization of health care workers: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Hospital Infection Control Practices Advisory Committee. MMWR 1997;46[No. RR-18]:1-42; and CDC. Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine; recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1997;46[No. RR-3]:1-25). Although vaccine-associated paralytic poliomyelitis has not been reported among HSCT recipients after exposure to household contacts inadvertently vaccinated with oral polio vaccine, inactivated polio vaccine should be used among family members, close contacts, and HCWs to avoid person-to-person transmission of vaccine-strain polio virus (Source: CDC. Poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine; recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1997;46[No. RR-3]:1-25). † † No evidence exists that live-attenuated vaccine-strain viruses in measles-mumps-rubella vaccine have ever been transmitted from person-to-person, except rubella vaccine virus from a nursing mother to her infant (Source: CDC. Measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1998;47[No. RR-8]:1-48). ** HCWs, family members, close contacts and visitors who do not have a documented history of varicella-zoster infection or who are seronegative should receive this vaccination before being allowed to visit or have direct contact with an HSCT recipient (AIII). Ideally, varicella-zoster-susceptible HCWs, family members, household contacts, and potential visitors of immunocompromised HSCT recipients should be vaccinated as soon as the decision to perform an HSCT is made. The vaccination dose or doses should be completed ⊕4 weeks before the conditioning regimen begins or ⊕6 weeks (42 days) before contact with the HSCT recipient is planned (BIII). If a varicella vaccinee develops a postvaccination rash within 42 days of vaccination, the vaccinee should avoid contact with HSCT recipients until all rash lesions are crusted or the rash has resolved (Sources: CDC. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 1996;45[No. RR-11]:1-36; and CDC. Immunization of health care workers: recommendations of the Advisory Committee on Immunization Practices [ACIP] and the Hospital Infection Control Practices Advisory Committee. MMWR 1997;46[No. RR-18]:1-42). [/table]
[table] TABLE 6: Vaccinations for hematopoietic stem cell transplant (HSCT) recipients traveling to areas endemic for selected vaccine-preventable diseases VaccineRecommendations for use Rating* Source: CDC. Role of BCG [Bacillus of Calmette and Guérin] vaccine in the prevention and control of tuberculosis in the United States: a joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR 1996;45(No. RR-4):1-18.† Source: CDC. Recommendations of the Immunization Practices Advisory Committee: cholera vaccine. MMWR 1988;37(40):617-8; 623-4. § Source: CDC. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999;48(No. RR-12):1-37. ¶ Source: CDC. Inactivated Japanese encephalitis virus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1993;42(No. RR-1):1-15. ** Source: CDC. Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks. MMWR 1997;46(No. RR-5):1-Not recommended for prophylaxis among HSCT recipients because of its lack of efficacy.* Immunocompromised persons who have percutaneous or permucosal exposure to hepatitis B virus should receive 2 doses administered 1 month apart. For immunocompetent persons, the need for postexposure prophylaxis depends on the vaccination history and antibody to hepatitis B surface antigen response status of the exposed person. † Should be administered with rabies vaccine at anytime after HSCT as indicated for postexposure rabies prophylaxis. Existing Advisory Committee on Immunization Practices guidelines for postexposure should be followed, with 5 doses of rabies vaccine administered on days 0, 3, 7, 14, and 28 postexposure. §Because of high rates of case fatality from respiratory syncytial virus pneumonia among HSCT recipients, HSCT physicians can administer HSCT recipients with upper or lower respiratory infection preemptive therapy with a high titer of neutralizing antibodies to prevent severe disease and death until controlled trials can be performed.** Physicians can use respiratory syncytial virus monoclonal antibody † † investigationally as preemptive therapy (Appendix). [/table]
[table] TABLE 7: Use of passive immunization for hematopoietic stem cell transplant (HSCT) recipients exposed to vaccine-preventable diseasesSource: Boeckh M, Bowden R. Cytomegalovirus infection in marrow transplantation. In: Buckner CD, ed. Technical and biological components of marrow transplantation. Boston, MA: Kluwer Academic Publishers, 1995:97-136. † Source: CDC. Immunization of health care workers: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Hospital Infection Control Practices Advisory Committee. MMWR 1997;46(No. RR-18):1-42. § Sources: American Academy of Pediatrics. Rabies. In: Pickering LK, ed. 2000 red book: report of the Committee on Infectious Diseases. 25 th ed. Elk Grove Village, IL: American Academy of Pediatrics;2000:475-82; and CDC. Human rabies prevention-United States, 1999: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR 1999;48(No. RR-1):1-21; published erratum, MMWR 1999;48(1):16. [/table]
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Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference
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Controversies in acute kidney injury: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference
[bib_ref] The effects of alternative resuscitation strategies on acute kidney injury in patients..., Kellum [/bib_ref] [bib_ref] Prophylactic hydration to protect renal function from intravascular iodinated contrast material in..., Nijssen [/bib_ref] [bib_ref] Balanced crystalloids versus saline in noncritically ill adults, Self [/bib_ref] [bib_ref] Balanced crystalloids versus saline in critically ill adults, Semler [/bib_ref] [bib_ref] Effect of early vs delayed initiation of renal replacement therapy on mortality..., Zarbock [/bib_ref] [bib_ref] Initiation strategies for renal-replacement therapy in the intensive care unit, Gaudry [/bib_ref] [bib_ref] Timing of renal-replacement therapy in patients with acute kidney injury and sepsis, Barbar [/bib_ref] [bib_ref] Clinical decision support for in-hospital AKI, Dealmeida [/bib_ref] [bib_ref] An organizational-level program of intervention for AKI: a pragmatic stepped wedge cluster..., Selby [/bib_ref] [bib_ref] An organizational-level program of intervention for AKI: a pragmatic stepped wedge cluster..., Selby [/bib_ref] [bib_ref] Improved management of acute kidney injury in primary care using e-alerts and..., Tollitt [/bib_ref] [bib_ref] Automated, electronic alerts for acute kidney injury: a single-blind, parallel-group, randomised controlled..., Wilson [/bib_ref] [bib_ref] Impact of compliance with a care bundle on acute kidney injury outcomes:..., Kolhe [/bib_ref] [bib_ref] A sustained quality improvement program reduces nephrotoxic medication-associated acute kidney injury, Goldstein [/bib_ref] [bib_ref] Discovery and validation of cell cycle arrest biomarkers in human acute kidney..., Kashani [/bib_ref] [bib_ref] Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication, Bihorac [/bib_ref] [bib_ref] Clinical use of [TIMP-2]*[IGFBP7] biomarker testing to assess risk of acute kidney..., Guzzi [/bib_ref] [bib_ref] Disparate outcomes observed within Kidney Disease: Improving Global Outcomes (KDIGO) acute kidney..., Sparrow [/bib_ref] [bib_ref] Acute kidney injury: a problem of definition, Barasch [/bib_ref]
## Nomenclature and diagnostic criteria aki-related definitions
AKI and chronic kidney disease (CKD) are increasingly recognized as related entities representing a continuum of disease. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) 2002 guideline and the 2012 KDIGO AKI guideline defined CKD as measured or estimated glomerular filtration rate (GFR) <60 ml/min per 1.73 m 2 , or the presence of markers of kidney damage (e.g., albuminuria) for >90 days.The 2012 KDIGO guideline defined AKI as an abrupt decrease in kidney function occurring over 7 days or fewer .To complete the continuum, the 2012 guideline proposed the term acute kidney diseases and disorders (AKD) to define conditions of impaired kidney function not meeting the criteria for either AKI or CKD but having adverse outcomes and requiring clinical care. However, consensus on the exact criteria and indicators of severity is urgently needed.
Because the diagnosis of AKI should be tied to management decisions, and because changing disease definitions may have major implications for disease epidemiology, the case for revising the 2012 KDIGO definition of AKI should be strong before changes are proposed. Furthermore, in the context of an AKI guideline revision, several classification systems in addition to the stages of AKI should be rigorously defined. These relate to the distinctions among persistent, transient, relapsing, and recovered AKI; various etiologies of AKI; and community-onset versus hospital-onset AKI. In addition, there is emerging evidence that markers of structural kidney damage may be associated with clinically relevant outcomes and therefore identify potentially actionable entities. For an AKI guideline revision, the evidence base should be reviewed to determine whether markers of kidney damage constitute risk factors for AKI, define a new entity (such as subclinical or preclinical AKI), or should be incorporated into the AKI definition. Finally, the future guideline should use nomenclature that is precise and patient-centered.
The clinical importance of AKD needs to be further assessed. Retrospective cohort data based only on changes in serum creatinine values and with limited clinical context suggest a relevance for AKD: the population of patients who meet laboratory criteria for AKD but not CKD or AKI is relatively large, and these individuals have increased risks of incident and progressive CKD, kidney failure (formally referred to as "end-stage kidney disease"), and death, [bib_ref] Incidence and prognosis of acute kidney diseases and disorders using an integrated..., James [/bib_ref] confirming the need to better define and classify AKD. Furthermore, a revised definition and classification of AKD could be better harmonized with both the definitions and classifications of AKI and CKD and tie to clinical management. As in adults, the AKI/AKD/CKD spectrum should be unified in children, and definitions should be the same for children and adults. A special consideration in children, as well as in adults with low muscle mass, is a reduced serum creatinine concentration, which may impact AKI diagnosis.
The assessment of renal recovery is still controversial, and its definition is essential given the implications for patients and clinicians. Issues related to assessment of recovery include changes in creatinine generation due to reduction in muscle mass, among others.
## Advances in diagnosis of aki
Serum creatinine and urine output continue to be the foundational measures for AKI diagnosis even though their limitations are well known. In the future, kidney damage biomarkers, biopsy, and imaging may be useful for staging AKI, classification of cause, prognosis, and treatment. However, currently there is insufficient information about any of these measures to warrant addition to the AKI definition. Given that the global availability of novel biomarkers is limited, incorporating them into definitions will be challenging. Measurements of real-time or kinetic GFR are research tools at present, and more evidence is needed regarding their clinical applicability .
Both urine output and serum creatinine level should continue to be used 29 ; ideally, the new AKI guideline would provide further clarification as to the role of these measurements. If possible, both should be ascertained. However, if serum creatinine measurements are not immediately available, urine output criteria should be used.
It remains unclear how to best determine baseline kidney function. What constitutes a baseline serum creatinine level is controversial and inconsistently defined. It would be ideal to have prior serum creatinine or GFR measurements widely available through electronic medical records, but this is not current practice in many parts of the world. Prior serum creatinine or GFR measures may also further elucidate the risk of AKI in patients considered at high risk on the basis of either comorbidity or an intervention. There is controversy about whether an acute decrease in serum creatinine level indicates AKI that has already occurred, and more research is needed in this area. For example, small declines in serum creatinine level need to be interpreted with caution because they may be the result of acute changes in creatinine production or volume of distribution. After a timed insult (e.g., coronary angiography, elective surgery, nephrotoxic drug exposure), serum creatinine level should be measured at an appropriate time, allowing for AKI to manifest. After AKI onset, serum creatinine level should be measured during follow-up as necessary for clinical management and care transitions (e.g., transfer to and from intensive care) and for determining changes in AKI staging and classification (AKI vs. AKD), including onset of CKD at 90 days.
How urine output should be evaluated is also an area that needs further investigation to avoid variability in reporting of AKI incidence (i.e., use of actual or ideal body weight, strict time period vs. time-averaged values). [bib_ref] Definition of hourly urine output influences reported incidence and staging of acute..., Allen [/bib_ref] Future guidelines should address how differences in body composition (overweight, fluid overload) affect the interpretation of urine output, and whether these differences need to be considered in regard to the thresholds for AKI. Similarly, fluid status should be considered when evaluating for AKI. Fluid overload is associated with increased mortality and AKI, and it may impact the diagnosis of AKI through its impact on the volume of distribution of serum creatinine. Although there are research methods to define fluid overload, these are not routinely used in clinical practice, and it is unclear whether there is sufficient evidence to define a clinical threshold for fluid overload. In the next AKI guideline, fluid overload should be defined operationally through a rigorous literature review.
## Aki risk stratification and assessment
## Risk stratification
In community and hospital settings, risk stratification of patients using a combination of baseline risks and acute exposures is important. [bib_ref] Quality improvement goals for acute kidney injury, Kashani [/bib_ref] In the future, risk stratification could incorporate various clinical contexts: geographic region, onset in community or hospital settings, and location within hospitals. Although the 2012 guideline discussed risk models and clinical scores, these were limited to models for cardiothoracic surgery, contrast exposure, and aminoglycoside administration. Many other clinical scenarios and contexts, such as sepsis and cardiac failure, require guidance for risk assessment. In clinical practice, risk models may be tailored for location and context. Multicenter studies are needed for externally validating models as well as standardization and correlation with outcomes. Furthermore, since 2012, biomarkers for AKI risk stratification have been approved by the US Food and Drug Administration (https://www.accessdata.fda.gov/cdrh_docs/reviews/ DEN130031.pdf) and integrated in recent guideline recommendations for cardiac surgery. 32
## Determining cause and prognosis
Determining the etiology of AKI is essential for management; however, this can be difficult, especially in the presence of multifactorial mechanisms. Newer developments related to monitoring and evaluating risk progression include e-alert systems, machine-learning algorithms and artificial intelligence for AKI recognition and monitoring, 20,33-36 as well as models based upon the renal angina index, 37,38 furosemide stress test (FST), [bib_ref] Furosemide stress test and biomarkers for the prediction of AKI severity, Koyner [/bib_ref] or biomarkers. [bib_ref] Developing risk prediction models for kidney injury and assessing incremental value for..., Kerr [/bib_ref] [bib_ref] Urinary biomarkers predict advanced acute kidney injury after cardiovascular surgery, Wang [/bib_ref] [bib_ref] Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney..., Basu [/bib_ref] [bib_ref] A prediction model for severe AKI in critically ill adults that incorporates..., Bhatraju [/bib_ref] In revisiting the guideline for AKI, severity of AKI should be based not only upon serum creatinine elevation and urine output, but also upon duration, possibly with the inclusion of biomarkers. The need to increase attention for persistent (>48 hours) AKI should also be considered. [bib_ref] Acute kidney disease and renal recovery consensus report of the Acute Disease..., Chawla [/bib_ref] The 2012 KDIGO guideline suggests performing a kidney biopsy when the cause of AKI is unclear. Potential benefits for biopsy in AKI are controversial and further research is needed. [bib_ref] Expanding the role for kidney biopsies in acute kidney injury, Waikar [/bib_ref] Since the 2012 guideline, which recommended ultrasound for assessing kidney size and the presence of an obstruction, new imaging techniques have become available, such as contrast-enhanced ultrasound, doppler ultrasound, and blood oxygenation leveldependent functional magnetic resonance imaging. [bib_ref] New ultrasound techniques promise further advances in AKI and CKD, Hull [/bib_ref] [bib_ref] Ultrasound in acute kidney disease, Meola [/bib_ref] [bib_ref] Functional magnetic resonance imaging in acute kidney injury: present status, Zhou [/bib_ref] The role of these techniques in changing outcomes of AKI is yet to be determined.
The 2012 KDIGO guideline recommended urine sediment analysis for differential diagnosis in patients with AKI, especially when glomerular disease is expected. Meeting participants noted that urine sediment analysis is not routinely performed in many centers despite its potential role in the workup of AKI. [bib_ref] Traditional urinary biomarkers in the assessment of hospital-acquired AKI, Perazella [/bib_ref] [bib_ref] A prospective evaluation of urine microscopy in septic and non-septic acute kidney..., Bagshaw [/bib_ref] Additionally, the value of urine biochemistry analysis has been challenged, especially in sepsis. [bib_ref] Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational..., Bagshaw [/bib_ref] The FST may be useful for identifying patients with AKI who are likely to have progressive disease and need dialysis. [bib_ref] Development and standardization of a furosemide stress test to predict the severity..., Chawla [/bib_ref] There is also evidence that the FST is useful in predicting delayed graft function following deceased donor kidney transplantation. [bib_ref] The prognostic value of the furosemide stress test in predicting delayed graft..., Mcmahon [/bib_ref] This test was not included in the 2012 guideline but should now be considered. Importantly, unregulated diagnostics tests such as FST or urine sediment analysis require careful standardization and quality control. Their introduction into clinical practice should include local evaluation for correct performance and interpretation.
The traditional approach to classifying AKI as pre-renal, renal, and post-renal is still found in many medical text-books. A different framework is needed, because these terms are considered unhelpful, especially the term pre-renal, which is often misinterpreted as "hypovolemic" and may encourage indiscriminate fluid administration. For classifying AKI, it may be more beneficial to distinguish between conditions that reduce glomerular function, conditions that result in injury of tubules and/or glomeruli, and conditions that do both.
Endpoints for clinical trials and quality improvement initiatives for AKI include mortality, new onset or progression of CKD, and dialysis dependency. Additional endpoints are needed for both clinical management and research, and these might include recovery of function, maximum changes in creatinine concentration, stage of AKI/AKD, impact on renal reserve, and patient experience. Additionally, there is a need to better define renal recovery and its functional (filtration, tubular, endocrine) and anatomic/structural dimensions.
## Follow-up
Increased risks for mortality, cardiovascular events, and progression of kidney disease are well-documented outcomes of AKI. 28,54-56 However, not everyone with AKI has a poor outcome, and predictors of poor outcomes have been identified. [bib_ref] Derivation and external validation of prediction models for advanced chronic kidney disease..., James [/bib_ref] Follow-up recommendations [bib_ref] Quality improvement goals for acute kidney injury, Kashani [/bib_ref] have been proposed that could be integrated into a KDIGO guideline revision. Although it has been suggested that patients be screened at hospital discharge or seen within 1 month of AKI diagnosis, [bib_ref] Care of the acute kidney injury survivor, Wald [/bib_ref] there is no consensus on the optimal strategy and duration of follow-up to improve short-and long-term outcomes.
## Fluid management and hemodynamic support
## Timing of fluid administration
Ensuring adequate hydration and volume status is essential in preventing and treating AKI. Oral or i.v. fluid may be administered depending on the local environment and clinical context. The administration of i.v. fluids should be guided by hemodynamic assessment for specific indications and contraindications. When deciding on fluid therapy, consideration for the clinical context and history, including timing of the insult, is critical. lists clinical contexts in which indications for fluid administration should be balanced against potential coexisting conditions that require a more cautious approach. Because both the physiological response to fluids and the underlying condition related to AKI are dynamic over time, fluid administration should be based on repeated assessment of overall fluid and hemodynamic status and dynamic tests of fluid responsiveness. [bib_ref] Assessment of fluid responsiveness: recent advances, Monnet [/bib_ref] [bib_ref] Fluid administration for acute circulatory dysfunction using basic monitoring: narrative review and..., Cecconi [/bib_ref] There continues to be concern about excessive fluid administration for hypotension, and earlier use of vasoactive medications may be appropriate for some patients. [bib_ref] Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory..., Silversides [/bib_ref] [bib_ref] Liberal versus restrictive intravenous fluid therapy for early septic shock: rationale for..., Self [/bib_ref] The effect of these strategies on kidney function is not clearly defined and likely to be context specific. [bib_ref] Restrictive versus liberal fluid therapy for major abdominal surgery, Myles [/bib_ref] Ongoing major multicenter RCTs examining kidney endpoints are evaluating fluid administration and vasoactive medications, and their results are likely to impact AKI treatment recommendations.
## Methods of fluid administration
Significant new evidence from several large multicenter RCTs regarding use of protocolized goal-directed fluid therapy in early septic shock has suggested lack of benefits for survival and kidney outcome. [bib_ref] A randomized trial of protocol-based care for early septic shock, Pro [/bib_ref] [bib_ref] Trial of early, goal-directed resuscitation for septic shock, Mouncey [/bib_ref] However, there is some evidence to suggest that goal-directed protocols have benefits in perioperative patients. [bib_ref] Does goal-directed haemodynamic and fluid therapy improve peri-operative outcomes?: A systematic review..., Chong [/bib_ref] [bib_ref] Perioperative fluid management strategies in major surgery: a stratified meta-analysis, Corcoran [/bib_ref] Therefore, recommendations regarding goal-directed fluid therapy for preventing or treating AKI may emerge to become more context specific. Additionally, clinical fluid therapy targets have evolved to include more dynamic indices, including the passive leg-raising test, pulse/stroke volume variation, and parameters derived from ultrasound. However, there is limited evidence that specific physiological targets for fluid therapy improve kidney outcomes.
## Composition of i.v. fluid preparations
Crystalloids.-Evidence of biochemical abnormalities and adverse clinical outcomes associated with 0.9% saline compared with more physiological crystalloids (e.g., lactated Ringer's) has continued to accumulate since 2012. [bib_ref] Balanced crystalloids versus saline in noncritically ill adults, Self [/bib_ref] [bib_ref] Balanced crystalloids versus saline in critically ill adults, Semler [/bib_ref] Results from two large ongoing multicenter RCTs (NCT02875873, NCT02721654) are awaited. This evidence will require careful evaluation to provide the community with a new consensus regarding the magnitude of risks associated with 0.9% saline in acute illness and surgery, including considerations for resource-limited settings in which alternatives may be limited.
Synthetic colloids.-In recent years, consensus has emerged that due to the increased incidence of kidney dysfunction and mortality, synthetic colloids are harmful in critically ill patients, especially those with sepsis. [bib_ref] Hydroxyethyl starch or saline for fluid resuscitation in intensive care, Myburgh [/bib_ref] [bib_ref] Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis, Perner [/bib_ref] However, whether these risks also apply to perioperative patients remains controversial, and this question is being examined in ongoing trials.
Albumin.-In RCTs, the use of albumin (including hyper-oncotic solutions) has not been shown to be harmful to kidney or other outcomes. [bib_ref] Albumin replacement in patients with severe sepsis or septic shock, Caironi [/bib_ref] [bib_ref] Small volume resuscitation with 20% albumin in intensive care: physiological effects :..., Martensson [/bib_ref] However, clear evidence of benefit is also lacking, and any benefits may be limited to specific patient populations. [bib_ref] Association between albumin administration and survival in cardiac surgery: a retrospective cohort..., Kingeter [/bib_ref] [bib_ref] Management of ascites and hepatorenal syndrome, Piano [/bib_ref] [bib_ref] A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic..., Martin [/bib_ref]
## Fluid removal
Physiological and epidemiologic evidence indicates that volume overload and venous congestion have adverse effects on kidney function and outcomes in both acute and chronic illness. [bib_ref] Fluid overload in the ICU: evaluation and management, Granado [/bib_ref] [bib_ref] Controversies in acute kidney injury: effects of fluid overload on outcome, Mehta [/bib_ref] [bib_ref] Increased fluid administration after early acute kidney injury is associated with less..., Raimundo [/bib_ref] In children, there is evidence that >10%-15% fluid overload by body weight is associated with adverse outcomes. [bib_ref] Fluid overload and mortality in children receiving continuous renal replacement therapy: the..., Sutherland [/bib_ref] [bib_ref] Fluid overload is associated with impaired oxygenation and morbidity in critically ill..., Arikan [/bib_ref] However, the method for determining fluid overload and the threshold for clinically significant fluid overload in adults are not well defined, nor is the precise role of timing of fluid removal on kidney function and other outcomes. Therefore, there is a need to develop a consensus around methods and thresholds for fluid overload evaluation in adults and to establish recommendations for its management .
## Nephrotoxic agents and drugs that affect kidney function
The use of drugs associated with kidney injury or dysfunction is common both in the hospital setting and in the community for patients with chronic illnesses such as hypertension, congestive heart failure, diabetes mellitus, cancer, and CKD. These drugs are often referred to as "nephrotoxic," although many of them lead to kidney dysfunction without direct glomerular or tubular cell damage. Furthermore, some drugs that may cause a rise in serum creatinine are actually reno-protective and associated with improved outcomes (i.e., angiotensin-converting enzyme inhibitors or sodium-glucose co-transporter-2 inhibitors 81 in diabetic nephropathy). Although it would be ideal to propose a simple yet inclusive term to encompass the various mechanisms by which drugs interface with the kidney, meeting participants were unable to identify one. Thus, here the term "nephrotoxic drugs" is retained for consistency with the literature. A new classification should also encompass drugs that are not directly harmful to kidney function but are eliminated by the renal route, and where there is concern about harm from accumulation of parent drug or metabolites in the setting of AKI and AKD. Similarly, failure to increase drug doses and intervals in renal recovery or with enhanced elimination via extracorporeal clearance may lead to therapeutic failure. [bib_ref] Drug management in acute kidney disease-Report of the Acute Disease Quality Initiative..., Ostermann [/bib_ref] In the past 10 years, significant progress has been made regarding susceptibility, management, and preventive strategies to avoid or ameliorate drug-and drug combinationassociated kidney injury and dysfunction more broadly.
Overarching nephrotoxic medication management considerations are as follows:
## -
Patients should receive potentially nephrotoxic medications only if needed and only for as long as needed.
## -
Potentially nephrotoxic agents should not be withheld in life-threatening conditions, owing to concern for AKI, including i.v. contrast.
- Kidney function must be monitored in patients who are exposed to agents that are associated with kidney injury or dysfunction, to limit the risk and progression of AKI and AKD.
- Patients and clinicians need appropriate and effective education as to the potential for kidney injury and dysfunction from nephrotoxic agents.
## Classifying drugs that affect kidney function and/or are nephrotoxic
There are multiple mechanisms by which drugs affect the kidney. They are summarized in 2 major categories: systemic or renal/glomerular hemodynamic effects (i.e., kidney dysfunction); and tubular or structural damage (i.e., kidney injury). Kidney dysfunction can result from drugs that lead to systemic hypotension (e.g., systemic arterial vasodilation) and/or altered intraglomerular hemodynamics (e.g., afferent arteriole constriction, efferent arteriole dilation). As a result, renal perfusion pressure is decreased, and if the decrease is sustained or severe, it can lead to ischemic injury. In comparison, drug-associated kidney injury is characterized by glomerular or tubular cell injury triggered by filtered toxins, tubular obstruction, endothelial dysfunction, or an allergic reaction. [bib_ref] Paradigms of acute kidney injury in the intensive care setting, Kellum [/bib_ref] [bib_ref] Drug-induced glomerular disease: attention required!, Radhakrishnan [/bib_ref] [bib_ref] Drug use and nephrotoxicity in the intensive care unit, Perazella [/bib_ref] Important to note is that a given drug may lead to both dysfunction and injury.
A useful framework for classifying the mechanisms of drug-induced kidney injury or dysfunction is depicted in a 2x2 table to classify functional, structural, and combined functional/structural AKI 86. Drugs can affect the kidney by each of these mechanisms, and the figure depicts susceptibilities for AKI, as well as accelerants to develop dysfunction or injury and transition to dysfunction and injury. An important aspect of the framework is consideration of risk-mitigation strategies. Currently, there is sufficient evidence to classify drugs that affect kidney function or are nephrotoxic, in a clinically useful way. [bib_ref] Acute kidney injury and 'nephrotoxins': mind your language, Jones [/bib_ref] [bib_ref] Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies, Wu [/bib_ref] Preventing and mitigating drug-associated AKI A number of strategies have emerged for preventing or mitigating drug-associated kidney injury or dysfunction. The most important of these is drug stewardship, 21,89,90 with a primary goal of balancing the changing risks and benefits of drug utilization and dosing in AKI/AKD . [bib_ref] Drug management in acute kidney disease-Report of the Acute Disease Quality Initiative..., Ostermann [/bib_ref] Specifically, it is critical to balance the risk of toxicity caused by excessive doses or drug/metabolite accumulation in AKI/AKD versus the risk of therapeutic failure caused by either overly conservative drug avoidance or under-dosing, or the risk of failing to adapt to renal recovery or use of renal replacement therapy (RRT).
Recent literature has demonstrated that certain drug combinations and overall drug burden are associated with AKI. [bib_ref] Drug class combination-associated acute kidney injury, Rivosecchi [/bib_ref] These include the "triple whammy" of renin-angiotensin system inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs, and an increased AKI risk when patients receive 3 or more nephrotoxic drugs daily. [bib_ref] Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers..., Lapi [/bib_ref] A single center has utilized electronic health records to identify children exposed to 3 or more nephrotoxic drugs, and the approach has led to a sustained decrease in incidence of AKI. 21
## Preventing and managing contrast-associated aki
The only nephrotoxic agent addressed in any detail by the 2012 KDIGO AKI guideline was iodinated radiocontrast media.The 2012 guideline included several recommendations to prevent contrast-induced AKI, including use of volume expansion with sodium bicarbonate solutions and oral N-acetylcysteine. Results of the Prevention of Serious Adverse Events Following Angiography (PRESERVE) and POSEIDON trials demonstrated lack of efficacy of these interventions (and instead found improvement using a personalized approach targeting cardiac filling pressures in POSEIDON). [bib_ref] Outcomes after angiography with sodium bicarbonate and acetylcysteine, Weisbord [/bib_ref] [bib_ref] Haemodynamic-guided fluid administration for the prevention of contrast-induced acute kidney injury: the..., Brar [/bib_ref] Furthermore, recent evidence suggests that the risks associated with i.v. contrast are far fewer with modern agents and practice patterns, and significant kidney injury is unusual in patients with normal or mildly reduced baseline kidney function. [bib_ref] Post-contrast acute kidney injury in intensive care unit patients: a propensity score-adjusted..., Mcdonald [/bib_ref] I.v. contrast should not be withheld owing to concern for AKI in life-threatening conditions in which the information gained from the contrast study could have important therapeutic implications.
## Renal replacement therapy rrt terminology and initiation
In recent years, the suggestion has been made that the English term "renal" should be replaced by "kidney," because the latter is more familiar to most English speakers. Additionally, the term "replacement" may not be sufficient, and terms such as "support" or "partial replacement" may be more accurate. The implications of changes in nomenclature are not insignificant. Additionally, the distinction between kidney versus renal does not apply in all languages. Accordingly, KDIGO has convened a separate Nomenclature Consensus Conference for the purpose of recommending nomenclature consistent with guidelines for acute and chronic kidney disease.Above all, patients should be the focus of all communication and care. Whenever possible, all decisions about treatment should be shared with patients, their families and/or next of kin, and if required, all members of the end-of-life care multidisciplinary team. All communication with patients and their supporting families/friends should be provided in simple lay language at regular intervals, with the awareness that patients may be traumatized. "Life support," "kidney machine," or similar words are preferred to the term RRT. If RRT becomes permanent, and the patient enters the chronic dialysis pathway, all relevant medical or nursing personnel should change their language to specify the type of RRT (transplant, hemodialysis, or peritoneal dialysis).
The 2012 KDIGO AKI guideline suggested initiating RRT emergently in the presence of life-threatening changes in fluid, electrolyte, and acid-base balance. Since 2012, data from several RCTs and observational studies have become available. [bib_ref] Effect of early vs delayed initiation of renal replacement therapy on mortality..., Zarbock [/bib_ref] [bib_ref] Initiation strategies for renal-replacement therapy in the intensive care unit, Gaudry [/bib_ref] [bib_ref] Timing of renal-replacement therapy in patients with acute kidney injury and sepsis, Barbar [/bib_ref] [bib_ref] Comparison of standard and accelerated initiation of renal replacement therapy in acute..., Wald [/bib_ref] [bib_ref] A comparison of early versus late initiation of renal replacement therapy in..., Karvellas [/bib_ref] [bib_ref] The impact of "early" versus "late" initiation of renal replacement therapy in..., Wierstra [/bib_ref] [bib_ref] Timing of RRT based on the presence of conventional indications, Vaara [/bib_ref] [bib_ref] Late initiation of renal replacement therapy is associated with worse outcomes in..., Shiao [/bib_ref] [bib_ref] Impact of timing of renal replacement therapy initiation on outcome of septic..., Chou [/bib_ref] [bib_ref] Timing of renal replacement therapy and patient outcomes in the randomized evaluation..., Jun [/bib_ref] [bib_ref] Selection and receipt of kidney replacement in critically ill older patients with..., Bagshaw [/bib_ref] However, the optimal timing for acute RRT remains unknown. It has been proposed that initiation of RRT should be considered when metabolic and fluid demands exceed the kidney's capacity to meet them. [bib_ref] When should renal replacement therapy be initiated for acute kidney injury?, Macedo [/bib_ref] [bib_ref] Patient selection and timing of continuous renal replacement therapy, Ostermann [/bib_ref] [bib_ref] Dialysis versus nondialysis in patients with AKI: a propensity-matched cohort study, Wilson [/bib_ref] This concept acknowledges the dynamic nature of acute illness and stresses the importance of regular evaluation of the demand and renal capacity relationship. However, the exact methods for determining demand and capacity are unknown. Existing evidence does not support using biomarkers when deciding whether to initiate RRT. [bib_ref] Effect of early vs delayed initiation of renal replacement therapy on mortality..., Zarbock [/bib_ref] [bib_ref] Comparison of standard and accelerated initiation of renal replacement therapy in acute..., Wald [/bib_ref] [bib_ref] Biomarkers for prediction of renal replacement therapy in acute kidney injury: a..., Klein [/bib_ref] Use of a standardized FST can be considered in AKI, to further quantify the likelihood of AKI progression, and integrated into the spectrum of clinical information available when planning for and deciding to initiate RRT. [bib_ref] Furosemide stress test and biomarkers for the prediction of AKI severity, Koyner [/bib_ref] [bib_ref] Development and standardization of a furosemide stress test to predict the severity..., Chawla [/bib_ref] [bib_ref] The furosemide stress test for prediction of worsening acute kidney injury in..., Rewa [/bib_ref] [bib_ref] Early versus standard initiation of renal replacement therapy in furosemide stress test..., Lumlertgul [/bib_ref] In determining whether or not to start RRT, risk of complications, global prognosis, potential for recovery, and patient preferences should be considered [fig_ref] Figure 3: Schematic diagram of renal replacement therapy [/fig_ref]. Although some regions of the globe have challenges and constraints in providing universal access to RRT, [bib_ref] The challenge of providing renal replacement therapy in developing countries: the Latin..., Obrador [/bib_ref] we recommend a similar approach be undertaken for considering for whom and when to start RRT in all regions. [bib_ref] Peritoneal dialysis in acute kidney injury: trends in the outcome across time..., Ponce [/bib_ref] [bib_ref] Comparing continuous venovenous hemodiafiltration and peritoneal dialysis in critically ill patients with..., George [/bib_ref] [bib_ref] Peritoneal dialysis for children with acute kidney injury in Lagos, Nigeria: experience..., Esezobor [/bib_ref] Additionally, a similar approach should be undertaken in both intensive care unit and nonintensive care unit settings.
## Providing rrt
Although the timing of RRT initiation is controversial, the provision of RRT itself has become fairly well established. Patients with AKI requiring RRT have an evolving clinical status and should be supported by the appropriate and available modality. Modality choice should also be tailored to patient clinical status. As suggested in the 2012 KDIGO guideline, in hemodynamically unstable patients, continuous RRT, rather than intermittent hemodialysis, is more physiologically appropriate, but RCTs have not demonstrated better outcomes with continuous RRT.Both continuous and intermittent RRT can lead to changes in intracranial pressure, but the risk is higher with intermittent RRT. Selection of modalities should be considered in the context of available resources and expertise of personnel.
An uncuffed non-tunnelled dialysis catheter of appropriate length and gauge should be used to initiate RRT in AKI patients. In patients with expected prolonged indication for RRT, a cuffed catheter can be considered. [bib_ref] Vascular access for renal replacement therapy in acute kidney injury: are nontunneled..., Kelly [/bib_ref] The first choice for site is the right jugular vein or femoral vein, although the femoral site is inferior in patients with increased body mass. The next choices would be left jugular vein followed by subclavian vein. Anticoagulation type should be selected based on local resources and expertise of personnel. The recommendation from 2012 to use regional citrate anticoagulation for continuous RRT in patients who do not have a contraindication remains supported by existing data. [bib_ref] A randomized controlled trial of regional citrate versus regional heparin anticoagulation for..., Gattas [/bib_ref] [bib_ref] Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically..., Liu [/bib_ref] [bib_ref] Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis..., Bai [/bib_ref] Delivery of RRT must reach the goals of electrolyte, acid-base, solute, and fluid balance for each specific patient. [bib_ref] Precision continuous renal replacement therapy and solute control, Bagshaw [/bib_ref] When using intermittent or extended RRT, a Kt/V of at least 1.2 per treatment 3 times a week should be delivered. [bib_ref] Dosing of renal replacement therapy in acute kidney injury: lessons learned from..., Bouchard [/bib_ref] For peritoneal dialysis, future studies should focus on dosing in AKI, although currently we suggest a dose of 0.3 Kt/V per session. An effluent volume of 20-25 ml/kg per h should be delivered when continuous RRT is used. This will sometimes require a higher prescription of effluent volume. [bib_ref] Effluent volume in continuous renal replacement therapy overestimates the delivered dose of..., Granado [/bib_ref] [bib_ref] Solute clearance in CRRT: prescribed dose versus actual delivered dose, Lyndon [/bib_ref] The rate of fluid removal for a given patient with fluid overload is controversial, [bib_ref] Net ultrafiltration intensity and mortality in critically ill patients with fluid overload, Murugan [/bib_ref] [bib_ref] Association of net ultrafiltration rate with mortality among critically ill adults with..., Murugan [/bib_ref] and more research is needed. Methods to better assess fluid management goals during RRT would also be valuable. Finally, RRT should be discontinued when kidney function has recovered or when RRT becomes inconsistent with shared care goals. Modality transition from continuous RRT to intermittent hemodialysis in intensive care unit patients should be considered when vasopressor support has been stopped, intracranial hypertension has resolved, and positive fluid balance can be controlled by intermittent hemodialysis.
## Rrt in the context of multi-organ support
The 2012 KDIGO AKI guideline did not address utilization of extracorporeal life support (ECLS) such as extracorporeal membrane oxygenation (ECMO), extracorporeal carbon dioxide removal (ECCO2R), and left or right ventricular assist device. Several issues remain unresolved: the optimal approach to patient selection, techniques, and timing/indications; circuit integration; and monitoring for ECLS and concomitant blood-purification techniques. Several observational studies on this theme warrant analysis and interpretation. [bib_ref] Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically..., Chen [/bib_ref] [bib_ref] Safety and efficacy of combined extracorporeal CO2 removal and renal replacement therapy..., Allardet-Servent [/bib_ref] [bib_ref] Low flow extracorporeal CO2 removal in ARDS patients: a prospective short-term crossover..., Peperstraete [/bib_ref] [bib_ref] A safe procedure for connecting a continuous renal replacement therapy device into..., Suga [/bib_ref] [bib_ref] Renal replacement therapy in critically ill patients receiving extracorporeal membrane oxygenation, Askenazi [/bib_ref] [bib_ref] A multicenter international survey of renal supportive therapy during ECMO: the Kidney..., Fleming [/bib_ref] [bib_ref] Low-flow CO(2) removal integrated into a renal-replacement circuit can reduce acidosis and..., Forster [/bib_ref] Decisions regarding how to combine RRT with ECLS devices will depend on local expertise, technology, and human resources. Such combined treatment should be based on a multidisciplinary approach to patient care and shared decision-making. More studies are needed to define the best strategy for training and practice.
Although different RRT modalities can be used to support patients during ECLS, and comparative studies are not available, because of hemodynamic status, continuous RRT is more appropriate in this setting. It would be useful to develop a registry focused on patients receiving ECLS-RRT, to understand the epidemiology, technology, indications, and complications associated with current practice.
There is no clear evidence that usual RRT indications should vary according to the presence or absence of an ECMO/ECCO2R circuit. Nonetheless, patients for whom ECMO or ECCO2R is required are very sensitive to fluid overload. Therefore, in patients with versus without ECMO/ECCO2R, earlier RRT may be required for preventing and managing fluid overload. A registry of patients combining ECMO/ECCO2R and RRT could improve understanding of current practice for initiating RRT in patients (adults and children) with ECMO/ECCO2R and fluid management. Respiratory dialysis (ECCO2R and ECMO) with modified dialysis solutions is currently limited to in vitro and experimental studies, [bib_ref] Extracorporeal CO2 removal by hemodialysis: in vitro model and feasibility, May [/bib_ref] [bib_ref] Extracorporeal CO2 removal may improve renal function of patients with acute respiratory..., Fanelli [/bib_ref] and research focused on this technical aspect is needed.
The anticoagulation of RRT circuits when ECMO/ECCO2R is already running is not standardized. The administration of heparin may depend on patient factors (e.g., risk of bleeding), circuit set-up (e.g., connection to patient or to ECMO), and institutional protocols. [bib_ref] A safe procedure for connecting a continuous renal replacement therapy device into..., Suga [/bib_ref] [bib_ref] A multicenter international survey of renal supportive therapy during ECMO: the Kidney..., Fleming [/bib_ref] [bib_ref] Continuous renal replacement therapy during extracorporeal membrane oxygenation: why, when and how?, Ostermann [/bib_ref] [bib_ref] Continuous renal replacement therapy during extracorporeal membrane oxygenation in patients treated in..., Seczynska [/bib_ref] [bib_ref] A new approach combining venoarterial extracorporeal membrane oxygenation and CRRT for adults:..., Zhou [/bib_ref] [bib_ref] CRRT connected to ECMO: managing high pressures, De Tymowski [/bib_ref] [bib_ref] The use of regional citrate anticoagulation continuous venovenous hemofiltration in extracorporeal membrane..., Shum [/bib_ref] [bib_ref] Extracorporeal organ support (ECOS) in critical illness and acute kidney injury: from..., Husain-Syed [/bib_ref] [bib_ref] Choice of renal replacement therapy modality and dialysis dependence after acute kidney..., Schneider [/bib_ref] It is possible to have RRT circuits without dedicated heparin in this setting, unless excessively frequent clotting is observed. Studies are needed to compare different anticoagulation strategies in this setting. Citrate anticoagulation during RRT added to ECMO/ECCO2R is possible. [bib_ref] The use of regional citrate anticoagulation continuous venovenous hemofiltration in extracorporeal membrane..., Shum [/bib_ref] [bib_ref] Extracorporeal organ support (ECOS) in critical illness and acute kidney injury: from..., Husain-Syed [/bib_ref] Its feasibility and performance compared with other forms of anticoagulation remain untested, and thus comparative studies of citrate anticoagulation are recommended.
## Rrt long-term outcomes and follow-up
Choice of RRT modality and impact on recovery.-The selection of RRT modality does not appear to have a major impact on recovery of kidney function. [bib_ref] Choice of renal replacement therapy modality and dialysis dependence after acute kidney..., Schneider [/bib_ref] [bib_ref] Continuous renal replacement therapy versus intermittent hemodialysis in intensive care patients: impact..., Truche [/bib_ref] [bib_ref] Modality of RRT and recovery of kidney function after AKI in patients..., Liang [/bib_ref] Selection of modality of RRT should therefore be based on shared decision-making, local expertise, logistic factors, and patient characteristics. Estimated GFR in conjunction with major adverse kidney events has been used for medium-and long-term assessment but has several limitations. There is uncertainty about the best way to measure renal recovery after RRT in both the short-and medium-term. However, proteinuria is associated with worse long-term outcomes and is easy to measure.
Assessment of kidney function for renal recovery.-In addition to the development of CKD, patient-centered outcomes (quality of life, functional recovery), along with patient experience after AKI, should be a priority and need to be assessed. Post-AKI proteinuria is associated with future loss of kidney function and is regarded as a valuable risk-stratification tool in the post-AKI period. [bib_ref] Dipstick albuminuria and acute kidney injury recovery in critically ill septic patients, Neyra [/bib_ref] [bib_ref] The significance of tubular and glomerular proteinuria in critically ill patients with..., Lim [/bib_ref] Optimal follow-up for AKI patients following RRT Shared decision-making and communication among caregivers, the patient, and family members is crucial to patient recovery. Patients recovering from critical illness and AKI are often discharged to rehabilitation/skilled nursing facilities and need close monitoring to ensure adequate overall recovery to a baseline state of health and well-being. Such patients should receive multidisciplinary, recovery-focused care. Patients with AKI who continue to require RRT at hospital discharge often receive hemodialysis in outpatient dialysis facilities. Patients with congestive heart failure are less likely to recover kidney function. [bib_ref] Acute kidney injury (AKI) and risk of readmissions in patients with heart..., Thakar [/bib_ref] Higher ultrafiltration rates and more intradialytic hypotensive episodes are associated with higher risk of non-recovery of kidney function. [bib_ref] Renal replacement therapy intensity for acute kidney injury and recovery to dialysis..., Wang [/bib_ref] [bib_ref] Long-term outcome in ICU patients with acute kidney injury treated with renal..., De Corte [/bib_ref] To assess for renal recovery, hemodynamic status, intravascular volume, and urine output during dialysis should be carefully monitored.
## Quality indicators for acute rrt
The importance of measuring and monitoring the quality of acute RRT provided to critically ill patients with AKI, including the optimal "benchmarking" for acute RRT programs, is receiving great attention. [bib_ref] Precision continuous renal replacement therapy and solute control, Bagshaw [/bib_ref] [bib_ref] Process based quality improvement using a continuous renal replacement therapy dashboard, Mottes [/bib_ref] Quality of acute RRT should be monitored to ensure the effective and safe delivery of care. [bib_ref] Quality of care and safety measures of acute renal replacement therapy: workgroup..., Rewa [/bib_ref] At a minimum, institutions and programs providing RRT should integrate, monitor, and report quality and outcome indicators across all forms of acute RRT therapies. [bib_ref] Quality improvement goals for acute kidney injury, Kashani [/bib_ref] These outcome measures should comprise a variety of metrics that incorporate patient survival, patient-centered acute RRT outcomes, safety, AKI survivorrelated outcomes, and patient experience. Quality indicators should include shared goals that are patient-and clinically centered.
# Conclusions
Although much of the 2012 KDIGO AKI guideline remains state of the art, advances over the past decade have improved our understanding of best practices. Many of these advances are widely accepted (e.g., nephrotoxic medication stewardship, shared decision making for RRT), but others are more controversial . Although some centers and specific programs have embraced new technologies and ways of thinking, others have taken a more conservative, or "wait-and-see" approach. Even among conference participants, there was lack of unanimity for various perspectives, and obvious practice variation continues to exist, even among experts. Perhaps more than any new trial or discovery, this fact provides ample rationale for revisiting the AKI guideline in the near future.
We thank Jennifer King, PhD, for assistance with manuscript preparation. The figure displays a potential paradigm for the care of patients who experience AKI/ AKD. The degree of nephrology-based follow-up increases as the duration and severity of AKI/AKD increases. The timing and nature of follow-up are suggestions, as there are limited data to inform this process. Future research efforts should work to clarify the timing of AKI/AKD follow-up and which specific healthcare providers should provide it. The items in each bucket follow the "OR" rule; therefore, each patient should follow the most-severe bucket even if they meet only 1 criterion in that bucket. For example, a patient with CKD G4, regardless of severity of AKI, should be followed by a nephrologist in 1 week. AKI stage 3D, AKI stage 3 treated by dialysis; CKD, chronic kidney disease; CV, cardiovascular; dx, diagnosis; KAMPS, kidney function-advocacy-medications-pressure-sick day protocol; SCr, serum creatinine; UA, urine analysis; WATCH-ME, weight assessment-accessteaching-clearance-hypotension-medications. Reproduced with permission under a Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0) from Acute Dialysis Quality Initiative. Quality improvement goals for acute kidney injury; ADQI XXII. Available at: https://www.adqi.org/Images_Charts-Call.htm. Accessed June 14, 2020. 31 Iterative classification of agents that have potential to cause kidney dysfunction or kidney injury or both. Functional and injury biomarkers have a role in distinguishing among the different pathophysiological processes. Examples of deleterious risk modifiers are duration of therapy, drug burden, hypotension, and pharmacokinetic/pharmacodynamic interactions. Examples of interventions to mitigate risk are daily dynamic prescribing, kidney monitoring, and patient and provider education. Susceptibility factors include those listed in the 2012 Kidney Disease: Improving Global Outcomes Acute Kidney Injury guideline: dehydration or volume depletion; advanced age; female gender; black race; chronic kidney disease; chronic diseases of the heart, lung, or liver; diabetes mellitus; cancer; and anemia.Any final impact depends on underlying susceptibility, associated risk factors, clinical context, drug management, and modifying factors. Examples of drugs that correspond to the relevant categories above include trimethoprim, cimetidine (neither dysfunction nor injury); angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers (dysfunction without injury); aminoglycoside, acyclovir, vascular endothelial growth factor antagonists (injury without dysfunction); and nonsteroidal anti-inflammatory drugs (dysfunction and injury).
[fig] Figure 1 |: Schematic for acute kidney injury/acute kidney diseases and disorders (AKI/AKD) follow-up. [/fig]
[fig] Figure 2 |: Classifying drugs that potentially cause acute kidney injury. [/fig]
[fig] Figure 3: Schematic diagram of renal replacement therapy (RRT) decisions in acute kidney injury (AKI). [/fig]
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deecebe28e4b568fc833d6a91079605040872b29
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pubmed
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Prioritizing surgery during the COVID-19 pandemic: the Quebec guidelines
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Prioritizing surgery during the COVID-19 pandemic: the Quebec guidelines
## Process
A literature review served as the basis for discussion. The criteria of the prioritization system were identified by consensus. Those involved in the process were surgeons (n = 5), radiation oncologists (n = 1), oncologists (n = 1), the national director of a cancer program, patients (n = 6), intensivists (n = 1), ethicists (n = 3), and research professionals (n = 2). These 20 people were divided into 3 groups, including a working group that developed a first draft of the system (n = 9), a review group that revised and enhanced the system to a final version (n = 5) and a patient group (n = 6) that also reviewed and commented on the draft. Several iterations were necessary before achieving consensus among all groups. In many countries, health care institutions have ramped down nonemergent activities in order to free up hospital and critical care beds in anticipation of a wave of patients with coronavirus disease 2019 (COVID-19). Medical activities were reduced to a minimum, leaving operating rooms to run semiurgent and urgent surgeries only. The status quo of systematically prioritizing resources away from surgical care to patients with COVID-19 may lead to unintended long-term outcomes. We propose a 4-step prioritization system based on resource availability and clinical criteria, as well as supplemental triage criteria for instances where multiple patients have equal claims to priority. The algorithm aims to guide clinicians and decision-makers toward allocating resources to surgical patients while still optimizing pandemicspecific benefits to the population.
## The prioritization system
The system aims to support the orientation of each patient. Its ethical principles are benefit maximization, proportionality, nonmaleficence, equity, reciprocity, agility and protection of stakeholders and the public. Continuous communication between the surgeon and the patient transcends this system. Continuous follow-up is required and provides an opportunity to reassure and respond to the questions and concerns of patients and family members.The system contains 4 sequential steps based on resource availability, clinical criteria and supplemental triage criteria when needed as tie-breakers.
Step 1: maximize the daily capacity of the OR Institutions determine their daily OR capacity. They negotiate an equitable distribution of resources, aiming to maximize benefits, proportional to current demand, across patient populations. Once agreement is reached on the distribution of resources, the OR capacity is finalized .
## Step 2: pretriage by specialty
Individual surgeons within each specialty pretriage all their patients. The goal of pretriage is to identify patients for whom the surgery is essential and for whom alternative care is not an acceptable equivalent .
## Step 3: overall prioritization
Final prioritization of surgical cases across specialties is a dynamic and continuous process that adapts to various changes in OR capacity and patient condition. First, a list is produced by each surgeon within each specialty. Second, a single list combines all the p a t i e n t s ( r e g a r d l e s s o f s u r g e o n ) w i t h i n e a c h specialty.
Decisions are then made by a local committee that applies the proposed prioritization criteria across specialties [fig_ref] Figure 3: Step 3 [/fig_ref]. This algorithm proposes more stringent clinical criteria as capacity decreases, but demands frequent reassessment as resources become available again, until the backlog is empty. If 2 or more patients have equal claims to priority, 2 supplemental criteria are proposed to choose fairly. The "fair innings" criterion favours intergenerational equity and therefore gives priority to the person who is at an earlier stage of life. [bib_ref] Scarce resource allocation during disasters. a mixed-method community engagement study, Biddison [/bib_ref] If this criterion is not applicable, randomization will be carried out to best respect equality of opportunity between patients. [bib_ref] Identifying prioritization criteria to supplement critical care triage protocols for the allocation..., Winsor [/bib_ref] Step 4: determining the OR schedule
The operating schedule is constructed by combining the daily OR capacity (step 1) and the prioritized lists of patients (result of step 2 and 3) [fig_ref] Figure 4: Step 4 [/fig_ref].
## Recommendations
This prioritization system can only be justified on the basis of equity if it is applied in the larger context of prioritizing the care needs of the entire population. To that Priority list of patients for all specialties (with resources required for each patient) 30% to 50% of the operating room capacity Prioritize patient according to: Those whose survival is most at risk Those nearest to or beyond the maximum surgery date Those requiring the least amount of operating time and resources possible (considering the cases most at risk and requiring more operating time.) Those most likely to recover quickly (low ASA classification)
## From
Step 2
Ensure that the patient list considers the capacity of other clinical services e.g., radiotherapy, rehabilitation
Step 3: overall prioritization of patients awaiting surgery The prioritization is done in two stages using the same decision-making process:
- By specialty - All specialties combined end, 3 recommendations emerge for maximizing population benefit during the COVID-19 pandemic. First, a system for prioritizing access to surgery during a pandemic should be applied immediately to identify patients across specialties who should have access to surgery, even when resources are limited. Otherwise, people suffering from life-threatening clinical conditions other than COVID-19 may be disproportionately disadvantaged, resulting in indirect morbidity and deaths from the pandemic beyond those caused by COVID-19 directly. Second, implementation of this protocol should be uniform across jurisdictions so that the entire population can have equitable access to scarce resources. Finally, many patients will not be selected and will continue to wait for their surgery, most likely with increasing anxiety and stress over time. Maintenance of the therapeutic relationship between patients and surgeons is important to assess the clinical and emotional consequences of delays.
# Conclusion
Our group advocates for the regionalization of resource allocation. This can be achieved with standardized surgical triage criteria based on clinical relevance. We submit that such a system will minimize the harm of the COVID-19 pandemic to the countless patients on surgical waiting lists. Step 4: determine a surgical program and the follow-up Step 1
## From
Step 3
Choice of rooms and patients
Evaluation of the consequences of the delay in surgery
[fig] Figure 3: Step 3: overall prioritization of patients awaiting surgery. ASA = American Society of Anesthesiologists. [/fig]
[fig] Figure 4: Step 4: determining the operating room schedule.Daily surgical capacity by specialty [/fig]
[table] , 4: Fig. 1.Step 1: determine the capacity of the operating room. Step 2: pretriage of patients, by specialty. Alternative treatment refers to a treatment that may not be the best curative option, but an alternative to the standard of care. Intermediate care refers to care units for patients who are more stable than those in intensive care, but who require specialized care that is not available in acute care medical and surgical units. Palliative care refers to care focused on the patient's quality of life, without the objective of curing the patient. COVID-19 = coronavirus disease 19.Do not perform the surgery and assess whether alternative care is required. Assess whether the patient should remain on the waiting list. [/table]
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Summary In many countries, health care institutions have ramped down nonemergent activities in order to free up hospital and critical care beds in anticipation of a wave of patients with coronavirus disease 2019 (COVID-19). Medical activities were reduced to a minimum, leaving operating rooms to run semiurgent and urgent surgeries only. The status quo of systematically prioritizing resources away from surgical care to patients with COVID-19 may lead to unintended long-term outcomes. We propose a 4-step prioritization system based on resource availability and clinical criteria, as well as supplemental triage criteria for instances where multiple patients have equal claims to priority. The algorithm aims to guide clinicians and decision-makers toward allocating resources to surgical patients while still optimizing pandemic-specific benefits to the population.
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Revised Guidelines for Coronavirus Disease 19 Management in Hematopoietic Cell Transplantation and Cellular Therapy Recipients (August 2022)
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Revised Guidelines for Coronavirus Disease 19 Management in Hematopoietic Cell Transplantation and Cellular Therapy Recipients (August 2022)
## Preface to the update
Since the declaration of the Coronavirus disease 2019 (COVID-19) pandemic more than 2 years ago, there have been significant therapeutic and preventative advances in the use of vaccines, antivirals, and monoclonal antibodies (mAbs) for prophylaxis and treatment. There has also been a dramatic decrease in COVID-19-related complications and mortality. COVID-19 testing has become widely available and incorporated in institutional guidelines. Prompt diagnosis of COVID-19 is instrumental for early treatment and isolation of patients to prevent spread in the community. Prevention of COVID-19 through vaccination is the most well-supported strategy to reduce COVID-19 incidence and/or severity, even in patients who may not be able to mount an adequate humoral response. For patients who are unlikely to have protective immunity or who cannot receive COVID-19 vaccines, a combination of mAbs (tixagevimab and cilgavimab is currently recommended, as long as it maintains neutralizing activity against circulating variants.
Treatment of COVID-19 has shifted from the inpatient to the outpatient setting with the availability of oral antiviral agents and mAbs. For hospitalized patients, detailed guidelines have been developed by the National Institutes of Health (NIH) and Infectious Diseases Society of America (IDSA). As acute mortality from COVID-19 has declined, persistent COVID-19, characterized by relapsing or progressing respiratory symptoms and persistent viral RNA positivity, has emerged as a challenge . There has been a transformation in healthcare delivery with the incorporation of telehealth into our practice, and masking, handwashing, and social distancing have been woven into the social framework for the foreseeable future.
# Introduction/scope
This document is intended as a guide for diagnosis and management of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, in adult and pediatric hematopoietic cell transplant (HCT) and cellular therapy recipients. The document was prepared using available data and with expert opinion provided by members of the American Society of Transplantation and Cellular Therapy (ASTCT) Infectious Diseases Special Interest Group (ID-SIG) and is an update of a previous publication [bib_ref] Guidelines for COVID-19 management in hematopoietic cell transplantation and cellular therapy recipients, Waghmare [/bib_ref]. Specific practices may vary depending on local epidemiology and state and federal guidelines. Since our original publication in 2020, the NIH and IDSA have published extensive guidelines for management of COVID-19 that are readily accessible (NIH Guidelines, IDSA Guidelines). This update focuses primarily on issues pertaining specifically to HCT/cellular therapy recipients. The information provided in this article may change as new information becomes available.
## Covid-19 prevention vaccines
COVID-19 vaccines remain the cornerstone for prevention of severe illness, hospitalization, and death from SARS-CoV-2 infection. Our understanding of vaccine responses in immunocompromised patients has improved, leading to revised schedules and changes in the number of doses needed (Centers for Disease Control and Prevention Vaccination in Immunocompromised). The ASTCT, National Marrow Donor Program (NMDP), and American Society of Hematology (ASH) have continued to engage with the CDC to better understand and communicate changes in vaccination schedules and types reflecting our better understanding of vaccine responses in immunocompromised patients (https://www.hematology.org/ covid-19/ash-astct-covid-19-vaccination-for-hct-and-car-tcell-recipients).
Responses to COVID-19 vaccines are more likely to be blunted in HCT or cell therapy recipients compared with healthy individuals [bib_ref] Impaired humoral and cellular response to primary COVID-19 vaccination in patients less..., Murray [/bib_ref]. However, despite the scarcity of data, the high level of protection afforded to those vaccinated in the clinical trials, and the overall safety of the vaccine in clinical trials and post-emergency use authorization (EUA) experience, the ASTCT and ASH strongly support vaccination of this vulnerable patient population along with their caregivers, family members, and household contacts.
## Passive immunization
For patients who are unlikely to mount protective immunity or cannot receive COVID-19 vaccines, the combination of monoclonal antibodies (mAb) tixagevimab and cilgavimab (Evusheld) is presently recommended as long as it retains activity against circulating variants [bib_ref] Intramuscular AZD7442 (tixage-vimabÀcilgavimab) for prevention of Covid-19, Levin [/bib_ref] (see Section IV, B.3) (FDA PrEP).
## Diagnostic considerations key updates
Timely diagnosis of COVID-19 is essential to ensure rapid treatment and limit transmission. Polymerase chain reaction (PCR) assays, either single-target or multiplex and with or without other respiratory viruses, are more sensitive than antigen-based testing and may be used on nasal, nasopharyngeal (NP), and lower respiratory specimens. Serologic tests are available for SARS-CoV-2 nucleoprotein (Np) and spike protein (Sp) IgG. HCT/cell therapy recipients may not mount IgG to natural infection or vaccination. The immunologic correlates of protective immunity to vaccination have not been established.
With ongoing community prevalence and transmission of COVID-19, any patient with exposure to a known case of COVID-19 or with symptoms compatible with COVID-19 should be tested for SARS-CoV-2. Patients with a known exposure who are asymptomatic at initial testing should be retested between 3 and 7 days after the exposure (CDC Postexposure Testing).
PCR tests are available with SARS-CoV2 as a single target or multiplexed with other respiratory pathogens. Antigen testing has overall lower sensitivity compared with PCR, especially with emerging variants, and the yield is highest at 4 days after symptom onset or on consecutive tests [bib_ref] Rapid antigen assays for SARS-CoV-2: promise and peril, Truong [/bib_ref] [bib_ref] Comparison of home antigen testing with RT-PCR and viral culture during the..., Chu [/bib_ref]. For patients with COVID-19-like illness, a PCR test on an upper respiratory sample should be sought even if an antigen test is negative. The diagnostic yield for other sample types, including oropharyngeal, anterior nasal, mid-turbinate nasal, and saliva, may be comparable or lower [bib_ref] SARS-CoV-2 viral load in upper respiratory specimens of infected patients, Zou [/bib_ref] [bib_ref] Diagnostic performance of different sampling approaches for SARS-CoV-2 RT-PCR testing: a systematic..., Tsang [/bib_ref]. Patients with a hematologic malignancy and those undergoing HCT or cellular therapy may not be able to mount effective humoral immunity in response to natural infection and/or SAR-CoV-2 vaccines [22À24]. Protective titers, waning of antibody response, and durability of immunity remain unknown. The IDSA and NIH do not recommend relying solely on serologic testing for diagnosis of SARS-CoV-2 infection.
Routine postvaccination serologic testing should not be used to guide decisions regarding primary and secondary preventive strategies (eg, mAb use). At present, the immunologic correlates of protection, such as antibody titer threshold, are not well defined.
## Pretransplantation hct and cellular therapy candidates and donor considerations key points
Test-based or time-based approaches have been used for clearing COVID-19-recovered HCT and cellular therapy candidates and donors. The optimal approach must be individualized, taking into consideration the urgency of transplantation/cellular therapy as well as clinical and other considerations, such as severity of illness, therapeutics, and circulating variants. The long-term outcomes of COVID-19-recovered HCT recipients are yet to be determined.
As of January 2022, CDC guidelines recommend extending isolation to 20 or more days for immunocompromised patients and using a test-based strategy requiring 2 consecutive negative results. Given the known prolonged viral shedding in this population, we suggest an alternative approach for ending isolation that relies on significant clinical improvement and at least 14 to 20 days from a positive test. Decisions related to proceeding with HCT or cellular therapy should be individualized on a case-by-case basis while weighing the risks and benefits of delaying therapy and consequently risking underlying disease relapse and/or progression.
Based on our prior experience with other respiratory viruses, such transplantation-related characteristics as conditioning regimen type, donor and graft type, graft manipulation, and graft-versus-host disease (GVHD) prophylaxis can impact host immune responses and recovery from SARS-CoV-2 infection. There are no specific recommendations favoring one type of conditioning or GVHD prophylaxis strategy over the other. Multiple studies have shown that age and a shorter time from transplantation to COVID-19 infection are associated with poor outcomes [bib_ref] Clinical presentation and outcomes of COVID-19 following hematopoietic cell transplantation and cellular..., Camargo [/bib_ref] [bib_ref] Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an..., Sharma [/bib_ref] [bib_ref] Impact of the SARS-CoV-2 pandemic on hematopoietic cell transplantation and cellular therapies..., Passweg [/bib_ref]. For other respiratory viruses, the presence of LRTI and myeloablative conditioning are associated with an increased risk of post-HCT complications [bib_ref] Respiratory viruses in hematopoietic cell transplant candidates: impact of preexisting lower tract..., Kim [/bib_ref]. In a recent systematic review, a higher performance status was associated with decreased mortality in HCT recipients acquiring COVID-19 at all stages following transplantation (hazard ratio, .83; 95% confidence interval [CI], .74 to .93; P = .001) [bib_ref] A portrait of SARS-CoV-2 infection in patients undergoing hematopoietic cell transplantation: a..., Bailey [/bib_ref]. Based on our expert opinion and clinical experience in managing COVID-19 in this population, we provide a summary of recommendations on evaluating HCT and cellular therapy candidates in [fig_ref] Table 1: Summary of Recommendations for Pre-Transplantation Evaluation of HCT and Cellular Therapy Recipients... [/fig_ref].
SARSÀCoVÀ2 Screening of Asymptomatic HCT and Cellular Therapy Candidates 1. Given the negative consequences of COVID-19 on posttransplantation or post-cellular therapy outcomes and the unpredictable virulence of the circulating SARS-CoV-2 strains [bib_ref] Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an..., Sharma [/bib_ref] [bib_ref] Impact of the SARS-CoV-2 pandemic on hematopoietic cell transplantation and cellular therapies..., Passweg [/bib_ref] [bib_ref] Poor outcome of patients with COVID-19 after CAR T-cell therapy for B-cell..., Spanjaart [/bib_ref] , it is currently encouraged to screen candidates for SARS-CoV-2 within 72 hours before receipt of conditioning or lymphodepleting regimens. The optimal test timing depends on the level of SARS-CoV-2 community transmission and testing turnaround time, which can vary by center. Positive SARS-CoV-2 assay If asymptomatic: defer for 5-7 days, then proceed. If symptomatic: defer until clinical improvement (no fever for 24 hours) and at least 7 days from a positive test, whichever is longer. y
Local institutional polices vary in their screening procedures based on COVID-19 community levels and urgency of transplantation. * Close contact to COVID-19 occurs when an individual is within 6 feet or less of someone with COVID-19 symptoms for at least 15 minutes regardless of mask wearing.
y Duration can be shortened for those who require immediate transplantation, weighing risks and benefits. z For those with prolonged shedding and in need of immediate transplantation, can proceed with transplantation on a case-by-case basis.
x Donors should adhere to good practice measures (masks wearing, hand hygiene, social distancing) during the 14 days period prior to donation 2. HCT and cellular therapy candidates and their caregivers should practice good hygiene, social distancing, and protective masking in public and should avoid nonessential travel, crowds, and large group gatherings. 3. In HCT and cellular therapy candidates meeting the CDC's definition of SARS-CoV-2 exposure, procedures including peripheral blood stem cell mobilization, bone marrow (BM) harvest, T cell collection, and conditioning/lymphodepletion should be deferred for 14 days from the day of last contact. Exposed patients should be closely monitored for the development of symptoms and can be retested with SARS-CoV-2 PCR at 5 to 7 days. If the test is negative and the patient remains asymptomatic, transplantation can proceed. A shorter duration can be pursued on a case-by-case basis in patients needing immediate transplantation. No currently available antiviral or mAb is approved for postexposure prophylaxis; however, if authorized, mAb prophylaxis should be provided. 4. In those patients who remain asymptomatic but SARS-CoV-2 PCR-positive, the recommendation is to defer HCT or cellular therapy for 14 days. However, if early infusion is desired, retesting at 5 to 7 days and then proceeding if the test is negative is an option as long as the patient remains symptom-free.
HCT and Cellular Therapy Candidates with Active Respiratory Symptoms 1. HCT and cellular therapy candidates with symptoms of an acute respiratory tract infection should be tested for respiratory viruses, preferably by multiplex respiratory viral PCR, including SARS-CoV-2. Short-interval retesting is recommended for patients with initial negative PCR results. 2. If SARS-CoV-2 is detected, early treatment with antivirals or variant-specific mAb should be given in accordance with the latest Food and Drug Administration (FDA) recommendations. Deferral of HCT or cellular therapy is recommended for at least 14 days and until clinical improvement is evident [fig_ref] Table 1: Summary of Recommendations for Pre-Transplantation Evaluation of HCT and Cellular Therapy Recipients... [/fig_ref]. Procedures including peripheral blood stem cell mobilization, BM harvest, T cell collection, and conditioning/lymphodepletion should be deferred for at least 14 days from a positive test and until the patient is clinically improved or asymptomatic.
## Prolonged viral shedding is a known phenomenon of sars-
CoV-2 in both the general population and the immunocompromised population. RNA detection by PCR can outlast the presence of replication-competent virus, and thus the requirement for PCR clearance prior to treatment should be balanced with the urgency of proceeding with transplantation in clinically recovered individuals [bib_ref] Shedding of viable SARS-CoV-2 after immunosuppressive therapy for cancer, Aydillo [/bib_ref]. A negative SARS-CoV-2 PCR is not a pre-HCT/cellular therapy prerequisite in those who have fully recovered form COVID-19 unless clinically indicated. In a large multicenter study of both autologous and allogeneic HCT recipients, the median time to viral clearance was 24 days, and the longest was 210 days [bib_ref] COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter..., Ljungman [/bib_ref]. Transplantation candidates who are clinically recovered without evidence of lower airway involvement at the time of HCT or cellular therapy and are at least 14 to 20 days from diagnosis can pursue transplantation procedures at designated areas according to transplantation center practices/polices. 4. Persistent dry cough, fatigue, and loss of smell and taste may last for weeks or months after clinical recovery. Institutional isolation policies should be followed for clinically recovered patients with persistent SARS-CoV2 RNA positivity. 5. In patients recovering from COVID-19, consider pretransplantation evaluation by infectious diseases, cardiology, and pulmonary consultants to assess cardiopulmonary status with a cardiac workup, chest computed tomography scan, and pulmonary function tests as clinically appropriate.
# Donor-related issues
Multiple studies have reported detection of SARS-CoV-2 in blood, associated primarily with symptomatic cases; however viremia is transient and low level, with no evidence of clinically significant viral transmission via blood products [31À40]. Current American Association of Blood Banks guidelines and FDA guidelines do not recommend screening for SARS-CoV-2 in blood products. Within 14 days prior to donation, donors should practice good hygiene, social distancing, masking in public, and avoidance of crowded places and large group gatherings.
# Unrelated donors
There is no mandatory SARS-CoV-2 PCR testing requirement for all donors by the NMDP, especially for asymptomatic healthy donors. Transplantation/apheresis center screening policies vary by site and urgency of transplantation. For detailed guidelines and recommendations, we refer the reader to Updates for Donor, Apheresis/Collection and Recruitment Centers (bethematchclinical.org).
# Related donors
a. Donors reporting close contact with a person diagnosed with COVID-19 should be monitored for 5 to 7 days and if remaining asymptomatic, may proceed with the donation. b. Donors with SARS-CoV-2 detected in a respiratory sample should be managed based on their clinical status. If asymptomatic, isolate and defer the donation procedure for at least 5 days. If the donor becomes symptomatic, defer transplantation procedures until clinical improvement (no fever for 24 hours without antipyretics) and at least 7 days from a positive test, whichever is longer. Refer to local policy regarding the need for SARS-CoV-2 PCR testing. A shorter duration can be considered on a case-by-case basis and the urgency of transplantation.
## Treatment considerations key points
Treatment for symptomatic mild to moderate COVID-19 with antivirals or mAbs with activity against circulating variants should be started as early as possible after onset of symptoms.
The optimal duration of therapy, sequential therapy, and combination therapy have not been studied in HCT/cellular therapy recipients. Treatment-related mutations are a concern in immunocompromised patients with persistent high-level viral replication.
Treatment recommendations have been published [bib_ref] How I treat and prevent COVID-19 in patients with hematologic malignancies and..., El Chaer [/bib_ref] (IDSA Guidelines; NIH Guidelines), and these guidelines are continually updated as additional data become available. Given the lack of data in HCT and cellular therapy recipients, treatment type and timing should be considered after a careful review of drug interactions, drug toxicities, and overall level of immunosuppression. Additional information on drug toxicities and drug-drug interactions can be found in the ASTCT Pharmacy Special Interest Group guidance [bib_ref] American Society for Transplantation and Cellular Therapy Pharmacy Special Interest Group position..., Mahmoudjafari [/bib_ref].
## Antiviral therapy remdesivir (veklury)
The efficacy of remdesivir (RDV) against coronaviruses was first demonstrated in in-vitro and mouse studies of Middle East respiratory syndrome coronavirus and SARS-CoV [bib_ref] Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta..., Sheahan [/bib_ref] [bib_ref] Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses, Sheahan [/bib_ref] and in in-vitro models of SARS-CoV-2 [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref]. On October 22, 2020, the FDA approved RDV for the treatment of COVID-19, with the most recent update recommending its use in hospitalized patients age 28 days weighing at least 3 kg or not hospitalized but at risk for progression to severe COVID-19.
Data from the multinational, randomized, placebo-controlled ACTT-1 clinical trial of hospitalized patients (n =1062) with COVID-19 showed that those who received RDV had a significant reduction in time to clinical recovery compared with the placebo group (11 days versus 15 days) and a nonsignificant trend toward lower mortality (8% versus 11.6%) [bib_ref] Remdesivir for the treatment of Covid-19: final report, Beigel [/bib_ref]. In contrast, data from the SOLIDARITY studyand the Dis-CoVeRy trial [bib_ref] Remdesivir plus standard of care versus standard of care alone for the..., Ader [/bib_ref] failed to show any benefit, but both were open-label randomized controlled trials. Retrospective studies have shown mixed results [bib_ref] Association of remdesivir treatment with survival and length of hospital stay among..., Ohl [/bib_ref]. More recently, Diaz et al. [bib_ref] Remdesivir and mortality in patients with coronavirus disease 2019, Diaz [/bib_ref] showed a mortality benefit in patients receiving RDV versus patients receiving best supportive therapy.
The PINETREE study [bib_ref] Early remdesivir to prevent progression to severe Covid-19 in outpatients, Gottlieb [/bib_ref] of ambulatory patients within 7 days of diagnosis of COVID-19 who were randomized to 3 days of RDV versus placebo showed a RR reduction of 87% for hospitalization (.7% hospitalization on the RDV arm versus 5.3% on the placebo arm). These findings suggest that RDV might be beneficial in a subset of patients presenting early in the course of mild or moderate infection.
RDV is administered only via the i.v. route, which poses a challenge to centers without an outpatient biocontainment unit or infusion area. Main side effects reported in trials have included gastrointestinal symptoms, infusion reactions, abnormal liver enzymes, and possible nephrotoxicity, among others. Drug-drug interactions have not been fully elucidated; however, caution is advised against use with other strong CYP3A4 inducers, as they may reduce RDV levels.
The duration of treatment varies from 3-day courses in the outpatient setting (for mild to moderate COVID-19 illness), to 5 to 10 days for hospitalized patients. A randomized trial showed the same benefit regardless of duration of therapy, 5 days or 10 days [bib_ref] Remdesivir for 5 or 10 days in patients with severe Covid-19, Goldman [/bib_ref] ; however, some have suggested longer and repeated courses for immunocompromised patients, particularly in those with protracted courses and in conjunction with passive immunotherapy [bib_ref] Treatment of chronic or relapsing COVID-19 in immunodeficiency, Brown [/bib_ref]. Reports have correlated the use of RDV with temporal improvement of symptoms and increased Ct values, suggesting a benefit [58À61]. There is a growing concern about the emergence of resistance in those with prolonged SARS-CoV2 infection and repeated remdesivir courses; resistance has been documented in immunocompromised patients [bib_ref] A possible role of remdesivir and plasma therapy in the selective sweep..., Colson [/bib_ref] [bib_ref] De novo emergence of a remdesivir resistance mutation during treatment of persistent..., Gandhi [/bib_ref].
## Nirmatrelvir/ritonavir (paxlovid)
This combination of antiviral agents was granted EUA by FDA in December 2021 for mild to moderate COVID-19 with symptom onset <5 days for outpatients or inpatients admitted for reasons other than COVID-19. The EPIC-HR randomized controlled trial showed a lower incidence of hospitalization or death by day 28 in the treatment group compared with the placebo group (P < .001; risk ratio [RR] reduction, 89.1%) with a treatment duration of 5 days; all 13 deaths occurred in the placebo group [bib_ref] Oral nirmatrelvir for highrisk, nonhospitalized adults with COVID-19, Hammond [/bib_ref]. Drug-drug interactions are a major concern, particularly in those patients receiving calcineurin inhibitors for GVHD prophylaxis. Recent case reports document that some patients who were treated with nirmatrelvir/ritonavir experienced rebound respiratory symptoms ("rebound COVID-19") 2 to 8 days after completing a 5-day course of nirmatrelvir/ritonavir. The CDC has recently issued a Health Alert Network Health Advisory to update the public on the potential for COVID-19 rebound after nirmatrelvir/ritonavir treatment. Nirmatrelvir/ritonavir has EUA approval for patients age 12 years.
## Molnupiravir (lagevrio)
The FDA issued an EUA for molnupiravir in December 2021 based on the results from the MOVe-OUT trial, which randomized at-risk nonhospitalized patients with COVID-19 and at <5 days after symptom onset to 5 days of treatment versus placebo [bib_ref] Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients, Bernal [/bib_ref]. In the modified intention-to-treat analysis, 48 patients (6.8%) in the treatment group versus 68 (9.7%) in the placebo group met the primary end point of hospitalization or death (RR, 31%; 95% CI, .48 to 1.01); 1 death occurred in the treatment group, and 9 deaths occurred in the placebo group. Molnupiravir's mechanism of action has raised concerns about the emergence of resistant variants, and thus it is not currently used as first-line therapy. However, a phase 2a trial did not report the emergence of resistance despite nucleotide substitutions, and an infectious virus was not isolated from participants receiving 400 mg or 800 mg of molnupiravir, compared with 11.1% of placebo recipients [bib_ref] A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows..., Fischer Wa 2nd [/bib_ref]. Molnupiravir has EUA approval for patients age 18 years.
## Antibody-mediated therapy monoclonal antibodies
Therapeutic use. mAbs should be considered for recipients of HCT/cellular therapy who are age 12 years and meet all the eligibility criteria specified in the EUA. These agents should be administered as early as possible after confirmed infection and within the time limits specified in the EUA. When local availability of mAbs and resources for administration are limited, priority should be given to individuals deemed at highest risk for severe COVID-19, including patients with recent or planned receipt of autologous or allogeneic HCT or chimeric antigen receptor T cell (CAR-T) therapy.
Five monoclonal antibodies have been granted EUA from the FDA since November 2020 [fig_ref] Table 2: EUA Applications of Monoclonal Antibodies * The recommended dose of tixagevimab plus... [/fig_ref]. Bamlanivimab plus etesevimab, bebtelovimab, casirivimab plus imdevimab, and sotrovimab are indicated for the treatment of mild to moderate COVID-19 in nonhospitalized adult and pediatric patients with laboratory-confirmed SARS-CoV-2 infection who are at high risk for progression to severe disease and/or hospitalization based on clinical trial data [69À71].
The recommendations for the use of mAbs have been fluid, owing to changes in the dominance of circulating SARS-CoV-2 variants. In late December 2021, as B.1.1.529 (Omicron) became the ascendant variant in the United States, the use of bamlanivimab plus etesevimab and casirivimab plus imdevimab was no longer recommended, considering their decreased efficacy against the Omicron variant [bib_ref] REGEN-COV antibody combination and outcomes in outpatients with Covid-19, Weinreich [/bib_ref]. Instead, sotrovimab was recommended for treatment of mild to moderate COVID-19 during the Omicron surge, but its use was halted by the FDA in favor of bebtelovimab in early April 2022 owing to increases in the proportion of cases caused by the Omicron BA.2 subvariants. Bebtelovimab, the newest agent to have received EUA by the FDA, is reported to have neutralizing activity against a broad range of SARS-CoV-2 variants, including Omicron and its most recent subvariants BA.4 and BA.5. Newer agents are currently in development.
Pre-exposure prophylaxis. The combination of tixagevimab plus cilgavimab is authorized under EUA for pre-exposure prophylaxis in moderately to severely immunocompromised patients who may have an inadequate immune response to COVID-19 vaccination or those who are not able to be fully vaccinated with any available COVID-19 vaccines owing to a documented history of severe adverse reaction to a COVID-19 vaccine or its components [bib_ref] Intramuscular AZD7442 (tixage-vimabÀcilgavimab) for prevention of Covid-19, Levin [/bib_ref]. However, tixagevimab plus cilgavimab should not be prioritized over COVID-19 vaccination in unvaccinated individuals for whom COVID-19 vaccination is recommended and who are anticipated to have an adequate response. Although it is recommended to wait 2 weeks after COVID-19 vaccination to give tixagevimab plus cilgavimab, there are no timing restrictions for COVID-19 vaccine administration after receipt of tixagevimab plus cilgavimab.
The FDA has issued revisions in the dosing of tixagevimab plus cilgavimab in response to data indicating that a higher dose may be more protective against the Omicron subvariants BA.1 and BA.1.1 than the originally authorized dose and also may retain activity against BA.2, BA.2.12.1, BA.4, and BA.5 subvariants [fig_ref] Table 2: EUA Applications of Monoclonal Antibodies * The recommended dose of tixagevimab plus... [/fig_ref]. Redosing is recommended every 6 months in patients who need ongoing protection. In addition, there is a need for ongoing rapid surveillance, given data suggesting that selective pressure can lead to antibody-resistant viral variants in patients previously treated with mAbs [bib_ref] Resistance mutations in SARS-CoV-2 Delta variant after sotrovimab use, Rockett [/bib_ref] [bib_ref] Emergence and onward transmission of a SARS-CoV-2 E484K variant among household contacts..., Sabin [/bib_ref].
## Convalescent plasma (cp)
Although the REMAP-CAP investigators did not find meaningful improvement in organ support-free days in critically ill adults with COVID-19, many of whom were immunocompetent, a subgroup analysis of 126 patients with immunodeficiencies suggested a possible benefit (odds ratio, 1.51; 95% CI, .80 to 2.92), although this was not statistically significant [bib_ref] Effect of convalescent plasma on organ support-free days in critically ill patients..., Estcourt [/bib_ref]. However, this result was generated prior to the Omicron surge, and the current supply of CP was not generated from donors who recovered from Omicron infection. Thus, the role of CP is limited at this time.
Given the conflicting data on the benefit of CP in immunocompromised patients, the NIH COVID-19 Panel does not recommend either for or against the use of high titer COVID-19 CP for the treatment of COVID-19 in patients with impaired humoral immunity (NIH COVID-19 Convalescent Plasma).
## Intravenous immunoglobulin (ivig)
Currently available IVIG products may contain variable quantities of antibodies against circulating variants at the time of collection; however, routine IgG products should not be used as COVID-19 therapeutic agents. The national COVID-19 Treatment Guidelines Panel recommends against the use of non-SARS-CoV-2-specific IVIG for the treatment of acute COVID-19, except in clinical trials. HCT and cellular therapy recipients who require use of IVIG for other purposes should continue to receive it as clinically indicated.
## Immunomodulatory and anti-inflammatory agents
A subset of patients with severe COVID-19 display a unique pattern of inflammatory response with multiorgan dysfunction. Variable presentations, such as hyperinflammatory response, immune dysregulation, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, and cytokine release syndrome, have been described [bib_ref] The dysregulated innate immune response in severe COVID-19 pneumonia that could drive..., Blot [/bib_ref]. Other aspects of innate, adaptive immune response signaling cascade and complement pathway activation also might be implicated in the pathogenesis of COVID-19 [bib_ref] Will complement inhibition be the new target in treating COVID-19Àrelated systemic thrombosis?, Campbell [/bib_ref].
## Corticosteroids
Results from a large randomized open-label controlled trial, RECOVERY, of dexamethasone 6 mg daily for up to 10 days (n = 2104) demonstrated a reduction in 28-day mortality compared to standard of care (n = 4321) of 22.9% in patients on dexamethasone and 25.7% in patients allocated to usual care (adjusted RR, .83; 95% CI, .75 to .93) [bib_ref] Dexamethasone in hospitalized patients with Covid-19, Recovery Collaborative Group [/bib_ref]. Although the benefit was across the board, the effect was more pronounced in patients on mechanical ventilation at the time of randomization (n = 1007). The use of corticosteroids in patients with severe disease (requiring oxygen support or mechanical ventilation) is recommended. In contrast, routine use of corticosteroids is not recommended in patients with mild or moderate disease who do not require supplemental oxygen.
## Other immunomodulatory therapies
Multiple anti-inflammatory/immunomodulatory drugs, including anti-interleukin (IL)-6 (tocilizumab and sarilimab), anti-IL-1 (anakinra), and Janus kinase inhibitors (baricitinib, tofacitinib, and ruxolitinib), have been investigated. Hospitalized patients receiving dexamethasone who exhibit worsening inflammation and rapid progression in their oxygen requirement may benefit from adjunct therapy with one of several agents, including oral baricitinib [bib_ref] Efficacy and safety of baricitinib for the treatment of hospitalised adults with..., Marconi [/bib_ref] [bib_ref] Baricitinib plus remdesivir for hospitalized adults with Covid-19, Kalil [/bib_ref] or i.v. tocilizumab [bib_ref] Tocilizumab in hospitalized patients with severe Covid-19 pneumonia, Rosas [/bib_ref] [bib_ref] Interleukin-6 receptor antagonists in critically ill patients with Covid-19, Gordon [/bib_ref]. If either of these is not available, tofacitinib can be used instead of baricitinib and i.v. sarilimab can be substituted for i.v. tocilizumab [bib_ref] Interleukin-6 receptor antagonists in critically ill patients with Covid-19, Gordon [/bib_ref] [bib_ref] Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis, Ytterberg [/bib_ref]. The combination of baricitinib and i.v. tocilizumab is not recommended, as it may result in unnecessary deleterious immunosuppressive effects, leading to additional infectious complications. Caution should be practiced when extrapolating the effects of these agents in HCT and cellular therapy recipients, owing to their underrepresentation in these clinical trials, the potential enhancement of immunosuppression, and unanticipated infectious and noninfectious adverse events. A list of immunomodulatory agents and their characteristics can be found at Immunomodulators: COVID-19 Treatment Guidelines (nih.gov).
There are no current recommendations regarding specific antimicrobial prophylaxis when immunomodulatory agents are used in HCT and cellular therapy recipients specifically for COVID19. Infection-specific screening strategies and antimicrobial prophylactic measures should be individualized based on epidemiologic and underlying disease risk factors, as well as serologic status. The use of immunomodulators for COVID19 in patients with uncontrolled bacterial, fungal, or viral infections is not recommended. Given the lack of supporting data, the use of any combination immunomodulatory therapy for COVID-19 treatment, such as baricitinib plus tocilizumab, other Janus kinase inhibitors (eg, ruxolitinib), siltuximab, fluvoxamine, and inhaled corticosteroids outside the setting of a clinical trial is not recommended.
## Combination therapy
Inhibiting several steps in viral replication for other RNA viruses, such as human immunodeficiency virus and hepatitis C virus, has proven to be an effective approach. Although no antiviral drug combination against SARS-CoV-2 has been tested clinically, various antiviral combinations have been studied in vitro. Molnupiravir-based combinations have shown increased antiviral activity against SARS-CoV-2 in vitro; additive effects were noted when combining nirmatrelvir/ ritonavir with remdesivir and molnupiravir [bib_ref] Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human..., Jonsdottir [/bib_ref] [bib_ref] Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2, Schultz [/bib_ref]. Other novel agents, such as brequinar and pyrazofurin, also have shown synergy when combined with molnupiravir and remdesivir [bib_ref] Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2, Schultz [/bib_ref].
Although not yet studied, the additive effects of combined antiviral therapy may prove particularly beneficial in immunocompromised patients at high risk of prolonged shedding/viral replication and at risk for emergence of resistance. Routine antiviral combination is not recommended at present, however, given the lack of solid data in this setting.
## Surveillance and prevention of opportunistic infections
There have been many reports of opportunistic infections after COVID-19, particularly in patients with underlying immunocompromising conditions.
## Fungal infections
COVID-19-associated pulmonary aspergillosis (CAPA) was described early in the pandemic, particularly in patients treated with steroids and those receiving mechanical ventilation [bib_ref] Coronavirus disease 2019-associated pulmonary aspergillosis in mechanically ventilated patients, Permpalung [/bib_ref] [bib_ref] Aspergillosis complicating severe coronavirus disease, Marr [/bib_ref]. Rates of CAPA as high as 33.3% have been reported, with up to 80% mortality in case series [bib_ref] Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19, Alanio [/bib_ref] [bib_ref] COVID-19 associated pulmonary aspergillosis, Koehler [/bib_ref]. Recently published diagnostic criteria for CAPA may help define the true incidence [bib_ref] Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for..., Koehler [/bib_ref]. Antifungal prophylaxis could be considered for high-risk patients.
Other fungal infections post-COVID-19 have been reported, including invasive candidiasis [bib_ref] Candida auris outbreak in a COVID-19 specialty care unit-Florida, Prestel [/bib_ref] [bib_ref] COVID-19-associated candidiasis (CAC): an underestimated complication in the absence of immunological predispositions?, Arastehfar [/bib_ref] , cryptococcosis [bib_ref] Cryptococcemia in a patient with COVID-19: a case report, Khatib [/bib_ref] [bib_ref] Autoimmune hemolytic anemia in a 24-year-old patient with COVID-19 complicated by secondary..., Woldie [/bib_ref] , Pneumocystis jirovecii [bib_ref] COVID-19 and Pneumocystis jirovecii pneumonia: back to the basics, Mouren [/bib_ref] [bib_ref] A case of COVID-19 and Pneumocystis jirovecii coinfection, Menon [/bib_ref] , and, even more concerning, mucormycosis [bib_ref] The emergence of COVID-19 associated mucormycosis: a review of cases from 18..., Hoenigl [/bib_ref].
## Viral infections
Immunocompromised HCT/cellular therapy recipients may have coinfections with several respiratory viruses; thus screening for other respiratory viruses is recommended during the initial assessment (Section II.A), especially with the ending of mask mandates in the general community and resultant resurgence of the usual community respiratory viral pathogens.
## Infection prevention considerations
The IDSA and CDC have developed national guidelines for infection prevention of COVID-19 in healthcare systems. HCT and cellular therapy recipients are vulnerable patients at increased risk for complications from SARS-CoV-2 and for healthcare-associated COVID-19 within units and clinics in which cohorting of high-risk populations is common. The institution of preventive measures to reduce transmission is of utmost importance; such measures include:
1. Appropriate use of personal protective equipment (PPE) by healthcare workers (HCWs) and patients 2. Symptom screening of patients, HCWs, and visitors and early isolation of symptomatic individuals 3. Early testing 4. Effective HCW vaccination programs.
Efforts to prevent transmission should focus on all key measures, with recommendations that take into consideration the level of community spread and the risk of transmission from mildly symptomatic or asymptomatic individuals. SARS-CoV-2 is transmitted primarily through small and large respiratory droplets [101À103]. Long-range transmission by smallparticle aerosols can occur, which has informed the current CDC guidance for transmission-based precautions.
## Center readiness
For future surges, HCT centers should be ready to rapidly implement COVID-19 protocols during community surges. The CDC's most recent community risk levels should be used by healthcare facilities to implement a tier-based approach that can be used to guide:
Universal PPE practices Rapid scaling of COVID-19 testing availability and protocols for asymptomatic testing (eg, before procedures) Symptom screening and triage Visitor restriction policies Environmental controls and care models for hospitalized patients Resources for outpatient COVID-19 management (infusion centers) Preparation for measures to maintain workforce integrity during surges: testing, return to work policies, special considerations for HCWs in HCT units Remote care Vaccination program for HCWs.
Owing to the unique characteristics of SARS-CoV-2, including asymptomatic transmission, prevention of SARS CoV-2 in recipients of HCT or cellular therapies should be more stringent than prevention of other common community respiratory pathogens. The key recommendations are as follows:
## Environmental controls
Recipients of HCT and cellular therapy should be housed in single rooms under positive pressure to primarily prevent fungal and respiratory viral infections. High-efficiency particulate air systems are standard in these single rooms.
## Air systems
Positive pressure on HCT units is considered a potential but as-yet undefined risk for transmission. Centers must balance the risk of other major pathogens (eg, invasive mold) versus the risk of COVID-19 when deciding whether unit air flows should be modified. Most centers do not have the capacity to modify unit air systems, and there are limited numbers of negative-pressure rooms in clinic and hospital environments. Guidelines recommend using negative-pressure rooms for COVID-19 patients whenever available and to consider cohorting positive patients and staff providing care to COVID-19-positive patients within the unit to limit exposures if a dedicated unit is not available or feasible. Options to modify individual rooms with portable negative-pressure systems, mobile HEPA filtration equipment, and external ventilation can be considered but should be implemented with input from Infection Prevention experts and hospital engineering teams.
## Physical distancing
Staff work rooms should be reconfigured however possible to allow for more physical distancing during periods of high community spread. Modifying waiting areas and community spaces (eg, conference rooms) to prevent close contact when possible in ambulatory areas or repurposing them to increase waiting room space should be considered. Well-ventilated spaces should be made available to staff for meal consumption.
## Environmental cleaning
Policies to ensure appropriate room cleaning and agents used for cleaning rooms are considered sufficient to disinfect high-touch areas. Additional efforts to disinfect frequently touched surfaces, especially in high traffic areas such as waiting rooms, cafeterias, elevators, and other common spaces with EPA-registered hospital-grade disinfectants, should be considered. Supplementary decontamination with UV-C light devices, if available, may be considered, particularly for inpatient locations, procedure suites, and designated COVID-19 units.
## Mandatory covid-19 vaccination
Institutions should strongly consider mandating COVID-19 vaccination for HCWs, or at least for HCWs who work on BM transplantation units.
## Future directions
Since the start of the COVID-19 pandemic, transplantation centers have had to adapt to a rapidly changing landscape. Masking, social distancing, and various forms of telehealth seem to be operative for the foreseeable future. The pandemic provided an impetus for discovery, innovation, and collaboration. Advances in mAb design and manufacturing capacity brought to the bedside several products, which were quickly superseded by emerging variants. Lessons learned from COVID-19 potentially can be applied to other respiratory viruses. Advances in adoptive T cell therapy were applied to generate COVID-19-specific T cells, with ongoing clinical trials for treatment of persistent COVID-19. Administration schedules for COVID-19 vaccines and mAbs are being optimized as our understanding of immunologic correlates of protection expands.
A number of questions remain pertaining to the use of antivirals in HCT/CAR-T recipients who were not included in large clinical trials of COVID-19 therapeutics. There is a lack of data pertaining to optimal doses, duration of treatment, combination or sequential treatment, and risk of antiviral resistance in this patient group. Long COVID-19 is a challenge, particularly in patients with dysregulated immunity, such as HCT/CAR-T recipients. The optimal management of long COVID-19 remains unclear, and the impact of early therapy in preventing long COVID-19 is yet to be determined. Answers to these and more questions will continue to be shaped by the evolution of the virus, our collective immunity, and current and future therapeutics.
# Acknowledgments
Financial disclosure: This work received no outside funding. Authorship statement: V.D. and Z.E.B. contributed equally to this work. R.F.C. and G.A.P. are co-senior authors
[table] Table 1: Summary of Recommendations for Pre-Transplantation Evaluation of HCT and Cellular Therapy Recipients and Donors for SARS-CoV-2 [/table]
[table] Table 2: EUA Applications of Monoclonal Antibodies * The recommended dose of tixagevimab plus cilgavimab was increased due to reduced neutralizing activity against the Omicron subvariants. V. Dioverti et al. / Transplantation and Cellular Therapy 28 (2022) 810À821 [/table]
[table] 1: Universal precautions: A face mask is recommended in all clinical areas regardless of community COVID-19 levels. Staff-staff interaction on campus: Limit staff congregating during breaks and handoffs. Consider policies around safe carpooling and use of public transportation. Prevention, Symptom Screening, and Testing Recommendations for Patients 1. Universal screening of patients at single entry points for respiratory symptoms or close contact with COVID-19 is imperative. 2. Follow PPE and testing protocols as outlined above. 3. Patients and caregivers should be masked at all times in the healthcare environment. 4. Policies and protocols for removing patients from droplet/ contact (or airborne/contact) isolation should be developed with Infection Prevention experts. This remains an area of ongoing discussion both nationally and at individual centers. Options include: a. Viral clearance, as documented by 2 negative SARS-CoV-2 respiratory PCR samples (eg, NP, anterior nasal, saliva) obtained 24 hours apart. b. As of January 14, 2022, CDC guidelines recommend a time-based strategy for severely immunocompromised patients in which discontinuation of isolation precautions can be considered if at least 20 days have passed since the first day of symptoms or a positive viral test (in asymptomatic patients) [104]. There are insufficient data on the relationship between prolonged detection of virus by PCR and viable virus and transmission potential in highly immunosuppressed patients, and thus the precise minimum duration of isolation is unknown at this time. c. There are insufficient data to guide clinical decisions about ending isolation based on Ct values (when/if available) in patients with prolonged SARS-CoV-2 positivity. Consultation with an Infectious Diseases specialist is recommended. 5. Policies and protocols for preprocedure, presurgery, preradiation therapy, and preadmission testing should be developed in coordination with subspecialty services and other stakeholders. 6. Telehealth visits should be considered when appropriate to limit in-person appointments. 7. Patients should be educated on COVID-19 and strategies for community prevention. 8. Criteria are needed for retesting previously positive patients when reinfection is suspected. Symptom Screening, Testing, and Restriction Policies for Caregivers, Family, and Visitors 1. Universal screening of visitors at all entry points for symptoms or contact with a known case of COVID-19 is important. 2. Universal masking is required on entry to the healthcare environment. 3. Restricting primary caregivers on the inpatient units should be considered during periods of high community transmission, along with limiting the number of visitors and the time spent in the healthcare environment and restricting children age <12 years. 4. Signs, posters, and web-based portals are significant methods of educating and disseminating information to caregivers, visitors, and family members. 5. A visitor database should be maintained to facilitate contact investigations. [/table]
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The adverse reactions to vaccines practice parameter 10 years on—what have we learned?
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The adverse reactions to vaccines practice parameter 10 years on—what have we learned?
A B S T R A C TObjective: To provide updated information on the evaluation and management of adverse reactions to vaccines. Data Sources: PubMed (MEDLINE) search since publication of a practice parameter in 2012. Study Selections: Original articles and guidelines on adverse reactions to vaccines, including vaccines against severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19). Results: Current guidelines conclude that patients with egg allergy are not at increased risk for reaction to eggbased influenza vaccines. Except for gelatin, most patients with allergy to vaccine constituents tolerate vaccines containing them. Most patients who have immediate reactions after receiving COVID-19 vaccines go on to receive a subsequent dose uneventfully. Conclusion: The risk of reactions to vaccination should be weighed against the risk of having a vaccine-preventable disease if the vaccine is withheld. There is no need to ask about egg allergy before the administration of influenza vaccines, including on screening forms. In most cases, an allergy to a vaccine constituent is not a contraindication to the vaccine containing it. Patients who have had possible anaphylactic reactions to vaccines should be evaluated by an allergist rather than simply being labeled allergic, because most can go on to receive subsequent doses. Most immediate reactions to COVID-19 vaccines are not allergic, and care should be taken to not label such reactions as anaphylactic. The role, if any, of polyethylene glycol in these reactions has yet to be revealed.
# Introduction
A practice parameter on adverse reactions to vaccines was published in 2009 1 and updated in 2012. [bib_ref] Adverse reactions to vaccines practice parameter 2012 update, Kelso [/bib_ref] Although most of the information contained in the 2012 document remains current, additional progress has been made in our understanding of, and approach to, adverse events following immunization, and lessons learned based on these new data will be presented in this update.
## Weigh the risk of vaccination against the risk of not vaccinating
The circumstances in which allergists are asked to provide recommendations relative to vaccine allergy generally fall into 2 categories; patients who may be allergic to a vaccine constituent and are concerned about receiving a vaccine containing that constituent or patients who have had an apparent allergic reaction after receiving a vaccine and are concerned about receiving additional doses of that or other vaccines. Our goal should be for patients to receive recommended vaccines if possible, given their enormous benefit in disease prevention. [bib_ref] The contribution of vaccination to global health: past, present and future, Greenwood [/bib_ref] We must provide advice based on available evidence regarding the likelihood of a vaccine reaction in a patient allergic to a constituent or the likelihood of a reaction to a subsequent vaccine dose in a patient who may have had an allergic reaction to a previous dose. In almost all circumstances, the data are very reassuring that the vaccines will be well-tolerated. [bib_ref] Vaccine allergy: a decade of experience from 2 large UK allergy centers, Li [/bib_ref] [bib_ref] Vaccine allergy? Skin testing and challenge at a tertiary pediatric hospital in..., Cheung [/bib_ref] Withholding vaccination in patients where there is concern about a reaction to the vaccine may seem prudent or conservative; however, not vaccinating also carries real risk. Whatever risk is posed by receiving a vaccine must be weighed against the risk of not receiving the vaccine and remaining susceptible to a vaccine-preventable disease. We can help patients with their decision about whether to receive a vaccine or not by carefully listening to and addressing their individual concerns about the risks of vaccination. Patients receive a great deal of misinformation about vaccine risks from many sources. In many cases, studies have not revealed any increased risk (eg, autism or infertility), and we do not believe it is possible (biologically plausible) that the vaccine could cause such harm. We must however avoid telling patients that vaccines are completely safe, but rather acknowledge that serious reactions can occur but are exceedingly rare, often in the range of 1 in 1 million, and that the same rare adverse events from vaccination often occur at a higher rate from the disease itself, which can be prevented by vaccination.
## It is not necessary to ask about egg allergy before the administration of influenza vaccines
An addendum to the 2012 practice parameter on adverse reactions to vaccines was devoted to the issue of administering influenza vaccines to recipients with egg allergy. [bib_ref] Adverse reactions to vaccines practice parameter 2012 update, Kelso [/bib_ref] Most influenza vaccines are grown in eggs and contain a residual amount of egg protein measured as ovalbumin content. [bib_ref] Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory..., Grohskopf [/bib_ref] Out of concern that this small amount of ovalbumin would trigger anaphylactic reactions in recipients with egg allergy, for many years, egg allergy was considered a contraindication to receiving influenza vaccination. Nevertheless, a large number of studies have specifically evaluated the administration of eggbased influenza vaccines, both the injectable inactivated influenza vaccine and the intranasal live-attenuated influenza vaccine, to large numbers of patients with egg allergy, including those with severe reactions to the ingestion of egg, and revealed that the recipients have no increased risk of allergic or other adverse reactions. [bib_ref] Administration of influenza vaccines to eggallergic recipients: a practice parameter update 2017, Greenhawt [/bib_ref] This is almost certainly due to a threshold affect, where the amount of ovalbumin contained in the vaccines (<1 mg per dose) is simply not sufficient to provoke a reaction even in the recipients with most severe egg allergy. The overwhelming majority of patients with egg allergy are children because the allergy is almost always outgrown, that is, egg allergy in adulthood is rare. [bib_ref] Food allergy: epidemiology, pathogenesis, diagnosis, and treatment, Sicherer [/bib_ref] Since 2016, recommendations from the American Academy of Pediatrics have stated that no special precautions are required regarding the administration of egg-based influenza vaccines to children with egg allergy,and their guidance regarding the 2021 to 2022 influenza season states unequivocally that such precautions "constitute an unnecessary barrier to immunization" and they further state that "it is not necessary to inquire about an egg allergy before the administration of any influenza vaccine, including on screening forms."The only other vaccine containing egg protein is yellow fever vaccine. Although yellow fever vaccine may contain a somewhat higher quantity of ovalbumin, [bib_ref] Ovalbumin content in the yellow fever vaccine, Smith [/bib_ref] [bib_ref] Yellow fever vaccination in EGG-allergic children, Sharma [/bib_ref] as with influenza vaccine, the amount of ovalbumin may not be sufficient to provoke a reaction even in patients with egg allergy. The package insert for yellow fever vaccine contains a protocol for the evaluation of recipients with egg allergy.It is recommended that patients with egg allergy undergo prick skin testing with the vaccine full-strength, and if the result is negative, undergo intradermal testing with the vaccine diluted 1:100. For patients with negative vaccine skin test results, it is recommended that the vaccine be administered in a single dose under observation. For patients with positive vaccine skin test results, it is recommended that the vaccine be administered in graded doses under observation [fig_ref] Table 1: Administration of a Vaccine in Graded Doses a Dose/dilution 0 [/fig_ref]. Most patients with egg allergy have negative yellow fever vaccine skin test results and receive the vaccine in a single dose uneventfully. [bib_ref] Yellow fever vaccine and egg allergy, Cancado [/bib_ref] [bib_ref] Safety of yellow fever vaccine administration in confirmed eggallergic patients, Gerhardt [/bib_ref] Although studies have validated the safety of administering the vaccine in graded doses to those recipients with egg allergy with positive vaccine skin test results, [bib_ref] Yellow fever vaccine and egg allergy, Cancado [/bib_ref] [bib_ref] Safety of yellow fever vaccine administration in confirmed eggallergic patients, Gerhardt [/bib_ref] yellow fever vaccine has also been administered to children with egg allergy with positive yellow fever vaccine skin test results as a single dose without reaction. [bib_ref] Single-dose yellow fever vaccination is well tolerated in egg-allergic children despite positive..., B Edard [/bib_ref] Thus, consideration can be given to administering yellow fever vaccine to recipients with egg allergy as a single dose without prior vaccine skin testing, but with an observation period afterward. If additional studies support the safety of this approach, as with influenza vaccine, it may not be necessary to inquire about egg allergy before the administration of yellow fever vaccine.
## An allergy to a vaccine constituent is different from an allergic reaction to a vaccine
This journey regarding egg allergy and influenza vaccination from contraindication to nonissue has provided some important lessons. Although it was not illogical to be concerned that vaccine excipients might cause reactions in recipients with allergy to those excipients, making egg allergy a contraindication to influenza vaccination without evidence turned out to be inappropriate. There were undoubtedly many patients who did not receive an annual influenza vaccination for this reason and went on to have the consequences of influenza disease, including death. It is essential that concerns about possible allergic reactions to vaccine constituents not be raised as barriers to vaccination without evidence that allergy to the constituent actually causes reactions in vaccine recipients. There are exceedingly rare reports of patients who have had allergic reactions to vaccines due to excipients, such as neomycin, thimerosal, latex, milk, and yeast. However, most of these allergies are quite rare and the overwhelming majority of patients with allergy to any of these substances tolerate vaccines containing them uneventfully, again likely due to an insufficient amount of the allergen being present in the vaccine to provoke a reaction. [bib_ref] Adverse reactions to vaccines practice parameter 2012 update, Kelso [/bib_ref] Thus, vaccine or excipient skin testing before the administration of vaccines containing these excipients in patients with reported allergic reactions to them is not required, and the vaccines can be administered in the usual manner . However, in patients who have already had an immediate allergic reaction to a vaccine containing one of these excipients, skin testing or serum-specific IgE testing for the constituent may be warranted.
The only exception to this general rule that almost all patients tolerate vaccines that contain substances to which they are allergic is gelatin. A number of vaccines contain milligram quantities of gelatin [fig_ref] Table 2: Gelatin-Containing Vaccines and Possible Alternatives [/fig_ref] , and most of the anaphylactic reactions reported to these vaccines have been determined to be due to IgE directed against the gelatin they contain. [bib_ref] Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin, Kelso [/bib_ref] [bib_ref] IgE antibody to gelatin in children with immediate-type reactions to measles and..., Sakaguchi [/bib_ref] [bib_ref] Food allergy to gelatin in children with systemic immediate-type reactions, including anaphylaxis,..., Sakaguchi [/bib_ref] [bib_ref] IgE-mediated systemic reactions to gelatin included in the varicella vaccine, Sakaguchi [/bib_ref] [bib_ref] The gelatin story, Kelso [/bib_ref] In some circumstances, gelatin-free vaccine alternatives are available [fig_ref] Table 2: Gelatin-Containing Vaccines and Possible Alternatives [/fig_ref]. Allergy to gelatin is quite rare, but patients describing possible immediate-type allergic reactions to the ingestion of gelatin, or to the receipt of gelatin-containing vaccines, should be evaluated before receiving such vaccines . Nevertheless, once again, even a confirmed gelatin allergy does not constitute a contraindication to receiving gelatin-containing vaccines. Rather, patients with gelatin allergy should undergo skin testing with required gelatin-containing vaccines, and those with negative skin test results can receive the vaccine in a single dose under observation, whereas those with positive skin test results could receive the vaccine in graded doses under observation [fig_ref] Table 1: Administration of a Vaccine in Graded Doses a Dose/dilution 0 [/fig_ref]. Gelatin also contains alpha-gal and patients with alpha-gal syndrome may also be at risk for reactions to gelatin-containing vaccines. [bib_ref] Relationship between red meat allergy and sensitization to gelatin and galactose-a-1,3-galactose, Mullins [/bib_ref] [bib_ref] Anaphylaxis after zoster vaccine: implicating alpha-gal allergy as a possible mechanism, Stone [/bib_ref] Most Immediate Reactions to Coronavirus Disease 2019 Vaccines are not Allergic and Should not be Labeled as "Anaphylactic"
Vaccines against severe acute respiratory syndrome coronavirus 2 and the coronavirus disease 2019 (COVID-19) it causes were introduced in late 2020. Although no anaphylactic reactions were reported in the clinical trials leading to their approval, shortly after their use in clinical practice, a number of reactions characterized as anaphylaxis were reported, particularly to the messenger RNA (mRNA) vaccines. [bib_ref] Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US, Shimabukuro [/bib_ref] Immunoglobulin (Ig)E-mediated allergic reactions require previous exposure for sensitization and almost all such reactions are because of protein allergens. Thus, the presumably allergic reactions being reported to the mRNA COVID-19 vaccines were unexpected given that no one had previously been exposed to the vaccines and that they do not contain protein. Although some of the reactions described could meet various criteria for anaphylaxis, most of these reactions have subsequently proved to not be allergic in nature, and most patients have gone on to receive second doses uneventfully. [bib_ref] Misdiagnosis of systemic allergic reactions to mRNA COVID-19 vaccines, Kelso [/bib_ref] [bib_ref] Safety evaluation of the second dose of messenger RNA COVID-19 vaccines in..., Krantz [/bib_ref] [bib_ref] First-dose mRNA COVID-19 vaccine allergic reactions: limited role for excipient skin testing, Wolfson [/bib_ref] The demonstration that most reactions to the mRNA COVID-19 vaccines characterized and treated as anaphylaxis turned out not to be anaphylactic reactions also provides an important lesson. It is clear that many patients have immediate adverse events after immunization that involve both symptoms and signs, which are in fact reactions to vaccination, but are not allergic reactions to the vaccine administered. Many such reactions can be characterized as immunization stress-related responses (ISSRs). [bib_ref] Immunization stress-related response-redefining immunization anxietyrelated reaction as an adverse event following immunization, Gold [/bib_ref] An ISSR may include stressinduced flushing, tachycardia, palpitations and shortness of breath, a vasovagal reaction leading to lightheadedness or syncope, hyperventilation causing tingling sensations, or dissociative neurologic symptoms, such as weakness, abnormal movements, or speech difficulties. Although it is important for vaccine providers to recognize anaphylaxis and treat it promptly, it is also important to realize that ISRRs occur and should be differentiated from anaphylaxis. In ISRRs, symptoms (subjective) often predominate, without signs (objective) to support them. For example, patients may complain of pruritus or tingling without visible skin changes, tongue or throat swelling with a normal oropharyngeal examination, shortness of breath without wheezing or stridor, or lightheadedness with a normal or even elevated blood pressure. Patients who have had these immediate, but not anaphylactic reactions to a COVID-19 vaccine can receive subsequent doses in the usual manner, but be observed for 30 minutes afterward [fig_ref] Figure 2: Recommended approach to patients with previous reactions to vaccine administration [/fig_ref]. Many vaccine reactions characterized as anaphylaxis do not actually meet current diagnostic criteria for the diagnosis of anaphylaxis, and many that do meet the criteria may not actually be anaphylaxis. [bib_ref] The COVID-19 pandemic in 2021: avoiding overdiagnosis of anaphylaxis risk while safely..., Greenhawt [/bib_ref] [bib_ref] Ascertainment bias in anaphylaxis safety data of COVID-19 vaccines, Hourihane [/bib_ref] The Brighton Collaboration case definition for anaphylaxis as an adverse event following immunization 33 is currently undergoing revision to avoid having cases involving only symptoms or nonserious signs classified as anaphylaxis.
A small number of immediate reactions to COVID-19 vaccines describe reactions that are more convincingly anaphylactic. [bib_ref] Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US, Shimabukuro [/bib_ref] The mechanism of these reactions has yet to be elucidated. As with other vaccines, in patients who have had possible anaphylactic reactions to COVID-19 vaccines, it is appropriate to perform prick skin tests with the vaccine full-strength, and if negative intradermal tests with the . Recommended approach to patients with previous reactions to vaccine constituents (for recommended approach to patients with previous reactions to vaccine administration, see [fig_ref] Figure 2: Recommended approach to patients with previous reactions to vaccine administration [/fig_ref]. a For yellow fever vaccine, skin test with vaccine prick full strength and if negative intradermal diluted 1:100. If positive skin test result, administer in graded doses [fig_ref] Table 1: Administration of a Vaccine in Graded Doses a Dose/dilution 0 [/fig_ref] [fig_ref] Table 1: Administration of a Vaccine in Graded Doses a Dose/dilution 0 [/fig_ref]. vaccine diluted 1:100. [bib_ref] Adverse reactions to vaccines practice parameter 2012 update, Kelso [/bib_ref] Negative vaccine skin test results in a patient with such a history implies that the reaction was not mast cell-mediated, or at least not IgE-mediated, and it is recommended that such patients receive the vaccine in a single dose under observation. Positive vaccine skin test results in such patients imply that the vaccine may provoke a reaction, and it is recommended that such patients receive the vaccine in graded doses under observation [fig_ref] Figure 2: Recommended approach to patients with previous reactions to vaccine administration [/fig_ref]. [bib_ref] Administration of a second dose of the moderna COVID-19 vaccine after an..., Mustafa [/bib_ref] Another option in this circumstance would be to offer an alternative vaccine (eg, administration of a viral vector vaccine to a patient who reacted to an mRNA vaccine), also administered under observation, although the mRNA vaccines are now generally preferred over the available adenoviral vector vaccine.In particularly difficult cases, where there is hesitancy to administer a second dose, consideration can be given to measuring a COVID-19 spike protein antibody titer to evaluate the immune response generated to the dose already administered. [bib_ref] Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial, Gilbert [/bib_ref] Nevertheless, it should be noted that a particular titer has not been established as a surrogate for protection and thus the presence of anti−COVID-19 spike protein antibodies does not imply the same level or duration of protection from disease conferred by completing the initial series and appropriate boosters.In evaluating possible allergic reactions to the mRNA COVID-19 vaccines, an early candidate allergen was polyethylene glycol (PEG). PEG, although not an ingredient in any non−COVID-19 vaccine, is present in other medications, such as some injectable corticosteroids and oral laxatives, and in some foods and cosmetics. [bib_ref] Immediate-type hypersensitivity to polyethylene glycols: a review, Wenande [/bib_ref] [bib_ref] Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have..., Stone [/bib_ref] There are very rare reports of patients who have had IgE-mediated reactions to PEG-containing medications. [bib_ref] Immediate-type hypersensitivity to polyethylene glycols: a review, Wenande [/bib_ref] [bib_ref] Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have..., Stone [/bib_ref] Although not a protein, PEGs, particularly those of higher molecular weights, are large enough molecules to rarely provoke IgE responses. Prior exposure and sensitization to PEG through these other sources could potentially explain how someone might have an allergic reaction after the first dose of a novel vaccine. Nevertheless, the other medications to which reactions have been reported contain much larger amounts of PEG than the vaccines. For example, methylprednisolone acetate injectable suspension contains 29.1 mg PEG 3350 per 1 mL dose and the Pfizer COVID-19 vaccine contains 0.05 mg PEG 2000 per 0.3 mL dose. Furthermore, most patients who have had possible immediate allergic reactions to the COVID-19 mRNA vaccines do not have evidence of IgE antibody to PEG, and some of those who do have gone on to receive second doses uneventfully despite their apparent PEG allergy. [bib_ref] First-dose mRNA COVID-19 vaccine allergic reactions: limited role for excipient skin testing, Wolfson [/bib_ref] The PEG in the mRNA COVID-19 vaccines is present in the lipid nanoparticles surrounding the mRNA, and some reports have suggested that these "multivalent" PEGylated nanoparticles may be more likely to cross-link IgE antibody in a way that native PEG may not. [bib_ref] Basophil reactivity to BNT162b2 is mediated by PEGylated lipid nanoparticles in patients..., Troelnikov [/bib_ref] Another mechanism proposed as a possible cause of apparent mast cell-mediated reactions to the PEG in mRNA COVID-19 vaccines is complement activationrelated pseudoallergy (CARPA), where IgG or IgM antibody directed against PEG would activate complement, generating C3a and C5a, which would then lead to mast cell degranulation. 40,41 A recent report describes 11 patients with suspected allergic reactions to mRNA COVID-19 vaccines evaluated for CARPA. [bib_ref] Assessment of allergic and anaphylactic reactions to mRNA COVID-19 vaccines with confirmatory..., Warren [/bib_ref] None had positive skin test results or serum-specific IgE to PEG, and only 1 had a positive skin test result to the vaccine. Nevertheless, 10 had positive basophil activation test (BAT) results to PEG and all 11 had positive BAT results to the vaccines and measurable serum-specific IgG to PEG. The authors conclude that the reactions are likely because of IgG anti-PEG CARPA but acknowledge that additional studies are needed. Among the factors complicating this interpretation are that some of the reported reactions may not have been mast cell-mediated, it is unknown whether the subjects would have reacted to a second dose, only 3 control subjects were evaluated, and a substantial portion of the general population may have anti-PEG IgG. [bib_ref] Antibodies against polyethylene glycol in human blood: a literature review, Hong [/bib_ref] Collectively, these studies argue against PEG skin testing either before administration of or after reactions to mRNA COVID-19 vaccines outside a research setting. 43
# Conclusion
The 2012 update to the adverse reactions to vaccines practice parameter still serves as useful guidance. [bib_ref] Adverse reactions to vaccines practice parameter 2012 update, Kelso [/bib_ref] Evidence published since has allowed us to conclude that we should stop asking about egg allergy before the administration of influenza vaccine, and that, with the exception of gelatin, patients with allergy to vaccine constituents should receive vaccines containing those constituents in the usual manner. Most immediate reactions reported to vaccines against COVID-19 have turned out not to be allergic. Patients with milder reactions to these vaccines should receive subsequent doses in the usual manner, but under observation for 30 minutes. For patients with more severe immediate reactions, consideration can be given to vaccine skin testing and administration in graded doses if positive, or to the administration of an alternative vaccine. PEG skin testing has been found to have no clinical use in the evaluation of such reactions.
[fig] Figure 2: Recommended approach to patients with previous reactions to vaccine administration. [/fig]
[table] Table 1: Administration of a Vaccine in Graded Doses a Dose/dilution 0.05 mL of 1:10 dilution 10% of full-dose full-strength 20% of full-dose full-strength 30% of full-dose full-strength 40% of full-dose full-strength At 15-minute intervals by the usual route for the vaccine (subcutaneous or intramuscular) prepared to treat systemic allergic reaction. [/table]
[table] Table 2: Gelatin-Containing Vaccines and Possible Alternatives [/table]
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http://www.annallergy.org/article/S1081120622000497/pdf
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National Guidelines for Colorectal Cancer Screening in Saudi Arabia with strength of recommendations and quality of evidence
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National Guidelines for Colorectal Cancer Screening in Saudi Arabia with strength of recommendations and quality of evidence
[bib_ref] Screening for colorectal cancer: U.S. Preventive Services task Force recommendation statement, Uspst [/bib_ref] [bib_ref] Screening and surveillance for the early detection of colorectal cancer and adenomatous..., Levin [/bib_ref]
# Methods
The Saudi Centre for Evidenced-Based Healthcare [bib_ref] grADe: an emerging consensus on rating quality of evidence and strength of..., Guyatt Gh, Oxman [/bib_ref] [bib_ref] grADe guidelines: 3. rating the quality of evidence, Balshem [/bib_ref] [bib_ref] grADe guidelines: 1. introduction-grADe evidence profiles and summary of findings tables, Guyatt G, Oxman [/bib_ref] [bib_ref] grADe guidelines: 14. going from evidence to recommendations: the significance and presentation..., Andrews [/bib_ref] The panel identified the target population for the guidelines as persons in the general Saudi population who were asymptomatic and with an average-risk for the development of CRC. The target population excluded persons with a prior family history of CRC or co-morbid conditions, as they would require different screening guidelines. The panel developed key questions to be answered by these guidelines. Those questions addressed the following domains:
1. The need for screening in Saudi Arabia for CRC. 2. The age at which screening should be initiated and abandoned. 3. The modality of screening to be used in Saudi Arabia. 4. A comparison among those modalities to allow the clinician to choose the most appropriate modality. Seven key questions were identified after detailed discussion and prioritization. Outcomes were generated and prioritized (a priori based on panel input). A webinar was held on several occasions to review the methodology used in the development of the guidelines. The team from McMaster University conducted systematic reviews addressing each of the seven research questions. Previously published systematic reviews on screening for colorectal cancer were retrieved and updated if possible with careful attention to Saudi-specific data. The panel members provided all relevant information regarding colorectal cancer specific to the Kingdom. The systematic review also included searches for data about benefits and harms, patient values and preferences, cost of screening, equity, applicability, and feasibility specific to Saudi Arabia [fig_ref] Table 1: Databases researched and references retrieved and included in the guidelines development [/fig_ref].
For each question, an evidence profile was developed to assess the certainty in the evidence across patient-important outcomes. Overall certainties of estimates were evaluated using the GRADE approach. [bib_ref] grADe: an emerging consensus on rating quality of evidence and strength of..., Guyatt Gh, Oxman [/bib_ref] [bib_ref] grADe guidelines: 3. rating the quality of evidence, Balshem [/bib_ref] [bib_ref] grADe guidelines: 1. introduction-grADe evidence profiles and summary of findings tables, Guyatt G, Oxman [/bib_ref] This included assessing the following criteria across outcomes: risk of bias, imprecision, inconsistency, indirectness, publication bias, presence of dose-effect relationship, magnitude of effect, and the effect of plausible residual confounders. [bib_ref] Flexible sigmoidoscopy versus faecal occult blood testing for colorectal cancer screening in..., Balshem [/bib_ref] Those profiles were shared among the panel members.
According to the GRADE approach, 5 overall quality of evidence is defined as:
1. High: There is confidence that the true effect of screening lies close to that estimated by research. More research will not change this confidence. 2. Moderate: There is moderate confidence in the estimated effect of screening according to the current research, but there is a possibility that more research will change the estimated effect of screening. 3. Low: The confidence in the estimated effect of screening is limited. Further research is very likely to change the estimated effect of screening. 4. Very low: The confidence in the estimated effect of screening is very little. In fact, the estimated effect is uncertain. The panel along with the members from the MacGRADE Centre from McMaster University met in Riyadh, Saudi Arabia on March 15th and 16th, 2015 to review the evidence and formulate the final recommendations. The panel developed recommendations based evidence profiles for each recommendation. The GRADE evidence-to-decision (EtD) framework was used to help organize discussion for each recommendation. According to the GRADE EtD framework, each recommendation was evaluated according to benefits and harms, patient values and preferences, cost of screening, equity, applicability, and feasibility specific to Saudi Arabia. Within these domains, specific items for discussion included the desirable and undesirable consequences of CRC, CRC-related mortality, CRC-related incidence, number and proficiency of endoscopists in the country, monitoring of the process of screening, and future research possibilities.
Recommendations including their strength (strong vs. weak) and direction (for vs. against) were generated after consideration of these factors and consensus among panel members. The recommendations were either strong or weak according to the GRADE approach. [bib_ref] grADe: an emerging consensus on rating quality of evidence and strength of..., Guyatt Gh, Oxman [/bib_ref] We used the terminology "we recommend" for strong recommendations or "we suggest" for conditional recommendations. A strong recommendation is offered when the desirable effects of the intervention clearly outweigh the undesirable effects of not intervening. A weak (conditional) recommendation is offered when the desirable effects and the undesirable effects are closely balanced or when there is less certainty in the desirable effects compared with the undesirable effects.
## Use of the guidelines
The guidelines target asymptomatic Saudi persons at average risk of developing CRC. In Saudi Arabia, the average risk of developing colorectal cancer is 9.6/100 000.The recommendations should never be extrapolated to other clinical scenarios. The recommendations are not dictums and they are not to be applied in isolation of the clinical situation.
# Discussion and recommendations
Question 1: Should CRC screening be used in asymptomatic average-risk persons compared with no screening?
Pooled results from eight randomized controlled trials 2,10,11 with a total population of 743 587 subjects who underwent colorectal cancer screening found high quality evidence for reducing colorectal cancer mortality (relative risk (RR) 0.8; 95% confidence interval (CI): 0.75-0.85). The evidence was moderate quality for reducing the incidence of colorectal cancer (RR 0.88; 95% CI: 0.80-0.96). A meta-analysis of six observational studies found low quality evidence with 34 serious complications per 100 000 procedures (95% CI: 0.06-1.9) with flexible sigmoidoscopy (FS) compared with no screening. 2 Serious complications included: perforation, bleeding or death. A local study found 71% of Saudis questioned are willing to undergo CRC screening. Saudis preferred the following modalities in descending order: CT colonography (CTC), stool based-test, colonoscopy and FS.There were no cost-analysis studies from Saudi Arabia. Indirect evidence on the incidence of adenomatous polyps [bib_ref] Prevalence and characteristics of colonic polyps and adenomas in 2654 colonoscopies in..., Almadi [/bib_ref] and median age at presentation, which is 55 years for women and 60 years for men, 1 suggests screening should start at the age of 45 years.
## Recommendation 1:
The panel recommends offering colorectal cancer screening to asymptomatic, averagerisk persons rather than no screening (strong recommendation; low quality evidence).
The recommendation was based on overall low quality evidence; however, it was agreed that future research is unlikely to change this recommendation.
Question 2: Should CRC screening be used in averagerisk persons aged 70 years or older compared with no screening?
There are no clinical trials addressing this question specifically other than the previous trials presented in recommendation 1. 10-12 This age group may experience a higher risk of serious complications coupled with increased cost due to co-interventions related to their co-morbidities. Consequently, the undesirable effects outweigh the desirable effects. One should also consider that if cancer is discovered, surgery or chemotherapy might not be offered or feasible due to frailty. In healthy individuals with no co-morbidities and a predicted survival beyond 10 years at the time of screening, there may be a benefit in screening.
## Recommendation 2:
The panel suggests not offering CRC screening for asymptomatic persons at average risk aged 70 years or older (conditional recommendation; low quality evidence).
## Remarks:
* Consider that some persons aged 70 years or older might still benefit from screening (if healthy, lack comorbidities, and life expectancy is judged to be greater than 10 years at time of screening).
## Question 3:
Should colonoscopy be used for CRC screening in asymptomatic average-risk persons compared with no screening? A meta-analysis of three observational studies 11 found low quality evidence for screening using colonoscopy compared with no screening for CRC-related mortality (RR 0.32; 95% CI: 0.32-0.43). A meta-analysis of five observational studies found very low quality evidence for screening using colonoscopy over no screening for CRC-related incidence (RR 0.31; 95% CI: 0.12-0.77). [bib_ref] effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and..., Brenner [/bib_ref] A meta-analysis of 12 non-randomized studies with 57 742 participants found low-quality evidence for increased complications and death from colonoscopy (2.8 events per 1000 [1.5-5.2 events per 1000]). 2 A local study found 71% of Saudis questioned are willing to undergo CRC screening. Saudis preferred the following modalities in descending order: CTC, stool based-test, colonoscopy and FS.There is a shortage of endoscopists in Saudi Arabia. Consideration to privilege other clinicians was discussed. Studies from the region suggests indirectly that colonoscopy is cost-effective. [bib_ref] cost-effectiveness analysis of colorectal cancer screening methods in iran, Allameh [/bib_ref] [bib_ref] the economic evaluation of screening for colorectal cancer: case of iran, Barouni [/bib_ref] Colonoscopy is considered the golden standard against which all other modalities of screening are tested. It must be repeated every 10 years. 2
## Recommendation 3:
The panel recommends screening colonoscopy rather than no screening for asymptomatic, average-risk persons (strong recommendation; low quality evidence).
## Remarks:
* Colonoscopy is considered the "gold standard" and there is high confidence in the estimate of its effect, even though that is based on low quality evidence.
* As with the other recommendations a small amount of uncertainty is recognized given the indirect evidence on resources, values and preferences, health inequalities, and feasibility.
## Question 4:
Should FS be used for CRC screening in asymptomatic average-risk persons compared with no screening?
A meta-analysis of four trials with 413 945 participants found high-quality evidence that FS reduces CRCrelated mortality (RR 0.72; 95% CI: 0.65-0.80) and low quality evidence that FS reduces CRC-related incidence (RR 0.82; 95% CI: 0.75-0.89). [bib_ref] effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and..., Brenner [/bib_ref] A meta-analysis of six observational studies found moderate-quality evidence for 34 serious complications per 100 000 procedures (95% CI 0.06-1.9) in association with FS compared with no screening. 2 Serious complications included: perforation, bleeding or death. FS was least appreciated by Saudis as a screening modality.FS fails to rule out right-sided polyps or tumors. These can be detected if FS is combined with guaiac fecal occult blood testing (gFOBT). [bib_ref] Screening for colorectal cancer: U.S. Preventive Services task Force recommendation statement, Uspst [/bib_ref] Fecal immunochemical testing (FIT) is superior to guaiac fecal occult blood testing (gFOBT). 2 FS is more feasible than colonoscopy since it does not require sedation or oral preparation. Studies from the region suggests indirectly that FS is cost-effective. [bib_ref] cost-effectiveness analysis of colorectal cancer screening methods in iran, Allameh [/bib_ref] [bib_ref] the economic evaluation of screening for colorectal cancer: case of iran, Barouni [/bib_ref] The desired effect of FS clearly outweighs the undesired effects. FS must be repeated every 3 years if performed alone or every 5 years if combined with FIT. 2
## Recommendation 4:
The panel recommends offering FS for CRC screening rather than no screening for asymptomatic persons at average risk (strong recommendation; moderate quality evidence)
## Remarks:
* This recommendation refers to FS screening every 5 years when combined with annual FIT or every 3 years without annual FIT. There are no clinical trials comparing colonoscopy directly to CTC. A meta-analysis of four non-randomized studies with 4018 participants found low-quality evidence for a sensitivity of 0.83 (95% CI: 0.74-0.89) and a specificity of 0.91 (95% CI: 0.84-0.96) for CTC compared with colonoscopy for polyps or adenomas ≥10 mm.A meta-analysis of 12 non-randomized studies with a total of 57 742 participants found low quality evidence of increased complications for colonoscopy 2 while CTC had a low complication rate. CTC is associated with additional harm related to radiation exposure; however, the new CT scans use lower radiation doses. [bib_ref] ct colonography: accuracy, acceptance, safety and position in organised population screening, De Haan [/bib_ref] Saudis preferred CTC over colonoscopy.CTC is more cost effective in Britain,but requires bowel preparation-like colonoscopy and confirmatory screening when in doubt using colonoscopy.
## Recommendation 5:
The panel suggests using colonoscopy rather than CT colonography for the diagnosis of asymptomatic, average-risk persons (conditional recommendation; low quality evidence).
## Remarks:
* The decision to use colonoscopy instead of CT colonography should be driven by feasibility and availability of the tests. * For persons preferring non-invasive screening, one may choose to undergo CT colonography.
Question 6: Should FS be utilized in screening for CRC in average-risk persons compared with gFOBT? There are no clinical trials comparing FS directly to gFOBT. A meta-analysis of 4 trials with a total of 329 642 participants found moderate quality evidence for gFOBT; it was not significantly associated with a reduction in CRC incidence (RR 0.93; 95% CI: 0.84-1.04), but it reduced all-cause mortality (odds ratio (OR) 0.84; 95% CI: 0.78-0.90). 10 There are no serious direct complications resulting from the use of gFOBT, while there are in association with FS. FIT is superior to gFOBT with regard to sensitivity and specificity. [bib_ref] Screening for colorectal cancer: U.S. Preventive Services task Force recommendation statement, Uspst [/bib_ref] Saudis preferred a stool-based test over FS.Both FS and gFOBT are cost-effective based on regional studies. [bib_ref] cost-effectiveness analysis of colorectal cancer screening methods in iran, Allameh [/bib_ref] [bib_ref] the economic evaluation of screening for colorectal cancer: case of iran, Barouni [/bib_ref] The two modalities FS and gFOBT complement each other rather than compete with each other. FS cannot rule out polyps or tumors in the right colon while gFOBT can help close that gap. 2
## Recommendation 6:
The panel suggests offering FS rather than gFOBT for CRC screening among asymptomatic, average-risk persons (conditional recommendation; very low quality evidence)
## Remarks:
* gFOBT is a less sensitive method, but depending on the availability of other screening modalities, setting, and resources it can still be used. * FS is often performed in combination with FOBT or FIT to ensure the entire colon is screened.
## Implementation and challenges
The panel identified the need to increase awareness and knowledge of CRC screening among the population. Moreover, the panel recognized that any implementation process must be monitored using key performance indicators that gauge every step including patient acceptability, population uptake of screening, quality of screening, quality of the supportive services like pathology, cost of screening and waiting time to undergo screening. All participants' data must be included in an electronic health record that is analysable for epidemiological and quality assurance reporting. Subject identification must be linked to the national identification system and must be conducted through a central call center to secure confidential communication. The panel recognized the urgent need to develop a local certification process for endoscopy and to train into endoscopy to meet the high demand of the population. Finally, the Joint Advisory Group on GI Endoscopy has released guidelines for the screening colonoscopists, which should be reviewed and adopted locally. 20
# Limitations
The panel noticed that the literature from Saudi Arabia lacked national data on the incidence of adenomatous polyps and the age groups most affected by the surge in its incidence. Moreover, it noted that there were no national clinical trials assessing the effectiveness of the different modalities of CRC screening and their impact on mortality to weigh the benefit-to-risk ratio.
# Conclusion
Screening for CRC among asymptomatic persons at average-risk in Saudi Arabia is recommended. It should probably be initiated at the age of 45 years; however, further research on the threshold age for screening is needed. Screening is not recommended for persons above the age of 70 years in most cases. Colonoscopy alone every 10 years is the recommended modality; however, if unavailable, FS every 5 years coupled with annual gFOBT or FIT should be considered. FIT is preferred over gFOBT. The least recommended modality is CTC. All CRC screening modalities should be performed at high load centres where skilled and experienced clinical staff is available.
[table] Table 1: Databases researched and references retrieved and included in the guidelines development. MacGRADE Centre) in the Department of Clinical Epidemiology & Biostatistics at McMaster University in Hamilton, Ontario, Canada were employed to help with the process of developing the guidelines. The team has vast experience in developing clinical and public health guidelines for different topic areas using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. [/table]
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http://www.annsaudimed.net/files.php?force&file=189_195_176909064.pdf
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BACKGROUND Colorectal cancer is the most common cancer among Saudi men and the third commonest among Saudi women. Given the predominance of colorectal cancer compared with other cancers in Saudi Arabia, context-specific guidelines are needed for screening. METHODS The Saudi Centre for Evidence-Based Healthcare assembled a panel of experts from the Saudi Society of Colon and Rectal Surgery, Saudi Gastroenterology Association, the Saudi Oncology Society, the Saudi Chapter of Enterostomal Therapy, the Family Medicine and Department of Public Health at the Saudi Arabian Ministry of Health and a patient advocate. The panel collaborated with a methodological team from McMaster University, Canada to develop national guidelines for colorectal cancer screening. After identifying key questions, the panel conducted a systematic review of all reports on the utility of screening, the cost of screening for colorectal cancer in Saudi Arabia and on the values and preferences of Saudi patients. Meta-analyses, when appropriate, were performed to generate pooled estimates of effect. Using the GRADE approach, the panel used the evidence-to-decision (EtD) framework to assess all domains important in determining the strength and direction of the recommendations (benefits and harms, values and preferences, resource implications, equity, acceptability, and feasibility). Judgments related to the EtD domains were resolved through consensus or voting, if consensus was not reached. The final recommendations were developed during a two-day meeting held in Riyadh, Saudi Arabia in March 2015. Conflicts of interests among the panel members were handled according to the World Health Organization rules. LIMITATIONS There is lack of national data on the incidence of adenomatous polyps or the age groups in which the incidence surges. There were no national clinical trials assessing the effectiveness of the different modalities of screening for colorectal cancer and their impact on mortality. CONCLUSION The panel recommends screening for colorectal cancer in Saudi Arabia in asymptomatic Saudi patients at average risk of colorectal cancer. An infrastructure should be built to achieve that goal.
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0c21d7f7eaa1dd5ba80405a972d3cbd2ffa17f4c
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pubmed
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Position paper on the preparation of immune plasma to be used in the treatment of patients with COVID-19
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Position paper on the preparation of immune plasma to be used in the treatment of patients with COVID-19
Passive immunotherapy with plasma derived from patients convalescent from SARS-CoV-2 infection can be a promising approach in the treatment of COVID-19 patients. It is important that Blood Establishments are prepared to satisfy requests for immune plasma by defining the requirements applicable to plasma donors and the standards for preparation, qualification, storage, distribution and control of use of the product. This position paper is aimed to give recommendations on biological characteristics of a plasma preparation from convalescent donors and to support the evaluation of this therapeutic approach in more rigorous investigations.
# Introduction
Passive immunotherapy with plasma derived from patients that have recovered from SARS-CoV-2 infection can be a promising approach in the treatment of COVID-19 patients, as suggested by recent experiences [bib_ref] Convalescent plasma as a potential therapy for COVID-19, Chen [/bib_ref] [bib_ref] Treatment of 5 critically ill patients with COVID-19 with convalescent plasma, Shen [/bib_ref] and discussed in two very recent relevant editorials [bib_ref] The convalescent sera option for containing COVID-19, Casadevall [/bib_ref] [bib_ref] Convalescent plasma to treat COVID-19: possibilities and challenges, Roback [/bib_ref]. The use of convalescent plasma has a high level of safety, as documented in any previous situation of its use during the last years [bib_ref] The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of..., Mair-Jenkins [/bib_ref]. Therefore, collection of convalescent plasma for the treatment of COVID-19 patients has started in different countries (among which are the USA, Italyand the Netherlandsand others will follow in the very next days. Due to this, many clinical trials are ongoing, as regularly updated by the WHOand also by the NIH. These protocols are expected to clarify the effective role (if any) of immune plasma in improving the prognosis of patients affected by severe forms of the disease and we cannot exclude a rapid and sustained increase in the request for this product, if clinical trials would demonstrate its therapeutic efficacy; the increase could be even more pronounced in case of a limited access to other therapeutic options due to the possible shortage of some drugs (as recently highlighted by some regional health authorities. Therefore, it is now of utmost importance that Blood Establishments are prepared to satisfy requests for "hyperimmune plasma" or "convalescent plasma", by defining the requirements for the recruitment and the selection of plasma donors and the standards for preparation, qualification, storage and distribution of the product, in compliance with Good Manufacturing Practices and with European and national legislation, without neglecting its safe and appropriate use.
This "position paper" is not a protocol for the treatment of patients with COVID-19 by means of convalescent plasma: clinical protocols and trials require, in almost all jurisdictions, an approval by local or national ethical committees and sometimes also by national Competent Authorities on blood or drugs. In the present phase of this pandemic, we are aware that in Italy (as well as in the rest of the world) Transfusion Services have been urged by clinicians in hospitals to provide immune plasma for a possible utilisation in the therapy of COVID-19 patients. We need to support the possibility of evaluating this therapeutic approach in more rigorous investigations. T recommendations on biological characteristics of a plasma preparation from convalescent donors can be helpful, to make future comparison among studies easier.
## Requirements to the donors
The attention for a possible source of immune plasma is focused, at present, on patients with a very recent documented infection by SARS-CoV-2 who volunteer, upon informed consent, to undergo apheresis procedures to collect plasma specifically intended for therapy of severe infections by SARS-CoV-2. This target population requires some caution because of some exceptions with respect to the standards defined by the selection criteria defined by Italian legislation enforcing European directives; this derogation refers to the age of the donor and to the deferral period after clinical recovery (probably less than twice the incubation period, as suggested by the "Guide for preparation, use and quality assurance of blood components", published by the EDQM -Council of Europe; finally, we must be aware of the fact that we will collect plasma for clinical use from patients that, in the majority of cases, have not been previously regular blood donors, thus lacking a previous safety profile. All the remaining selection criteria must be applied, first of all the exclusion of donors with a previous history of pregnancy and/or blood transfusion.
Plasma will be collected by apheresis from patients recently recovered from laboratory confirmed infection by SARS-CoV-2 (either hospitalised or self-isolated at home) with the following characteristics:
-at least 14 days from clinical recovery of the patient (no symptoms) and with a negative result of two NAT tests on nasopharyngeal swab and on serum/plasma, performed 24 h apart, following recovery or prior to discharge if hospitalized; -not mandatory (and not required by the majority of protocols in place) is a further negative result of a NAT testing on a nasopharyngeal swab and on serum/plasma, performed 14 days after the first one; -an adequate serum titer of specific neutralizing antibodies (> 160 by EIA method or equivalent with other methods, as previously suggested [bib_ref] Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS..., Soo [/bib_ref] [bib_ref] Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients..., Arabi [/bib_ref] [bib_ref] Use of convalescent plasma therapy in SARS patients in Hong Kong, Cheng [/bib_ref].
It should be pointed out that these persons are selected to donate immune plasma because they are COVID-19 convalescent patients: the scope of plasma collection is only related to the use for COVID-19 patients and not as a plasma for clinical use. However, from now on, we can expect a large number of people who have recovered from an asymptomatic infection (or from a disease with minor clinical signs); many among them are probably regular blood donors, as suggested by the number of post-donation information we are receiving in these days on fever and cough appearance, but also considering the high number of asymptomatic carriers of the virus. As soon as a serology testing is available, the demonstration in their sera of an antibody titer > 160 by EIA method (or equivalent with other methods) will represent a unique pool of immune plasma providing donors because they are regular blood donors, they are fully compliant with the selection criteria for plasma donation, and an adequate interval (28 days) can separate the resolution of symptoms from the donation. Therefore, this second group of persons can become a relevant source of immune plasma, not requiring any derogation from legal provisions on donor selection. Their recruitment can easily follow a screening for SARS-CoV-2 (eventually followed by a titration of the antibody) in the population of donors at the time of the donation. This could also contribute to havinga deeper insight into the epidemiology of the disease outside the context of a severe clinical disease leading to hospitalisation of patients.
## Standard for the product
A previous reference is offered by the definition of standards for immune plasma that have already been published during the MERS epidemic in 2015.
When dealing with convalescent patients, not previously blood donors, collected units should be initially tested as required by the Italian legislation for plasma intended for clinical transfusion (HIV, HCV, HBV NAT and serology testing, syphilis). Convalescent patients, from both first-time donors and regular donors, should be tested as required by the Italian legislation; regarding plasma from first-time donors (recovering patients), it is advisable to further test by NAT for HAV e PVB19, as well as to treat the units by pathogen reduction technologies. This would probably not be necessary when collecting plasma from regular donors. A negative result of NAT testing for SARS-CoV-2 is also clearly expected in both cases.
On each plasma unit it is advisable to determine the total content of immunoglobulins (IgG, IgA e IgM) and neutralizing antibody titer (> 160 by EIA method or equivalent with other methods as previously discussed); this is intended to have a rough evaluation of the amount of immunoglobulins administered to the patients, which will allow subsequent comparison between dose and effectiveness.
Due to the schedule of administration (see later), it is suggested to freeze and store the units in aliquots of around 300 mL.
## Standard for labelling and traceability of the product
When the collection of plasma is intended solely for administering anti SARS-CoV-2 antibodies to patients, it is advisable to label the product with a specific ISBT or UNI code, in order to allow exclusive use for the therapy of COVID-19 patients and to assure a full traceability.
## Pooling of plasma
The use of hyperimmune immunoglobulin concentrates (derived from plasma of immunised donors), is likely to be an even more effective method for administering specific antibodies and this is, at present, a field of research for pharmaceutical companies; however, in the medium term period, the availability of immune plasma from regular fully recovered donors could allow the preparation of units of human plasma pooled and treated for virus inactivation, with the standard described by the European Pharmacopoeia. This would allow production of hyperimmune plasma with a known and standardized antibody titre. A preliminary discussion with pharmaceutical companies and with the National Competent Authority (AIFA, in Italy) is clearly necessary.
## Indications and instructions for use
## Indications
There is no conclusive evidence for the indications of this product. As a preliminary result from the literature and from consensus among experts (mainly related to experiences made recently in Asia), eligible patients must have laboratory confirmed COVID-19 (better if NAT positive but seronegative) and must have severe or rapidly progressive or immediately life-threatening COVID-19. It would be, however, advisable to consider, in a controlled study, the use of immune plasma also in patients in an earlier stage of the disease.
Many clinical studies which have now been presented require a severity stratification based on clinical and /or biological parameters [bib_ref] Assessment of heart rate, acidosis, consciousness, oxygenation, and respiratory rate to predict..., Duang [/bib_ref] such as:
-respiratory frequency ≥30/min -PaO 2 /FiO 2 < 300 mm Hg in oxygen -blood oxygen saturation ≤93 % -tracheal intubation with mechanical ventilation -Sequential Organ Failure Assessment (SOFA) score -ICU length of stay P. Accorsi, et al.
Transfusion and Apheresis Science 59 (2020) 102817 -Hospital length of stay
## Volume and posology
Also, for volume and dose there is now no conclusive evidence and the first trials are based on schedules of administration defined in previous epidemics [bib_ref] Convalescent plasma as a potential therapy for COVID-19, Chen [/bib_ref] [bib_ref] Treatment of 5 critically ill patients with COVID-19 with convalescent plasma, Shen [/bib_ref] and on consensus among experts, as there is no conclusive evidence until now. An administration of volumes from 200 to 600 mL of immune plasma (roughly corresponding to 8-10 mL/kg, with a maximum of 600 mL) once per day on up to three consecutive days is suggested. This scheme could be eventually repeated once. Higher volumes could be contraindicated due to the risk of transfusion associated circulatory overload.
## Time for administration
An early onset of the therapy with immune plasma: the optimal period is within 7 days from the onset of symptoms but the therapy seems to also be effective within two weeks. Administration of immune plasma does not seem to be effective after 3 weeks from the onset of the disease.
## Drug interaction
Until now there are no descriptions of synergic or negative effects in the interaction with other drugs used in the treatment of COVID-19. In the absence of any conclusion, immune plasma can be administered on the basis of locally approved protocols.
## Adverse reactions
Clinicians must be aware that all adverse reactions and contraindications described for the administration of human plasma can also take place in treatment with this product; in particular Blood Establishments should remind treating physicians of:
-the absolute contraindication of administering human plasma to patients with a complete IgA deficit (we recommend to test for IgA before the beginning of plasma administration), -the caution for a possible onset of transfusion associated circulatory overload (TACO).
Another risk (hypothesised in an animal model) is related to a possible decrease in the immune response of the patient against the virus due to the passive immunisation following antibody administration with plasma, leaving patients more susceptible to reinfection. This event must be clearly taken into account and evaluated [bib_ref] Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice immunized..., Je [/bib_ref].
A caution on the use of this product must be given due to the fact that this is an off label indication in the clinical use of plasma.
## Final recommendations
We recommend that Blood Establishments obtain an informed consent from blood donors in order to store their sera after donation, so as to make possible epidemiologic evaluation as soon as validated serology testing is available.
We also recommend collection of any data from donors, possibly related to SARS-CoV-2 infection, that could be useful for subsequent epidemiological analysis (e.g. blood collection and deferral during pandemic, number and characteristics of post-donation information, results from look-back, when performed, etc.).
## Declaration of competing interest
The Authors declare no conflicts of interest.
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http://www.trasci.com/article/S1473050220301129/pdf
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8dcbdf4aa8f41d015c552b242401c1a3da9f98f9
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pubmed
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The difficult airway with recommendations for management – Part 1 – Difficult tracheal intubation encountered in an unconscious/induced patient
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The difficult airway with recommendations for management – Part 1 – Difficult tracheal intubation encountered in an unconscious/induced patient
# Abstract
Background Previously active in the mid-1990s, the Canadian Airway Focus Group (CAFG) studied the unanticipated difficult airway and made recommendations on management in a 1998 publication. The CAFG has since reconvened to examine more recent scientific literature on airway management. The Focus Group's mandate for this article was to arrive at updated practice recommendations for management of the unconscious/ induced patient in whom difficult or failed tracheal intubation is encountered. Methods Nineteen clinicians with backgrounds in anesthesia, emergency medicine, and intensive care joined this iteration of the CAFG. Each member was assigned topics and conducted reviews of Medline, EMBASE, and Cochrane databases. Results were presented and discussed during multiple teleconferences and two face-to-face meetings. When appropriate, evidence-or consensus-based recommendations were made together with assigned levels of evidence modelled after previously published criteria. Conclusions The clinician must be aware of the potential for harm to the patient that can occur with multiple attempts at tracheal intubation. This likelihood can be minimized by moving early from an unsuccessful primary intubation technique to an alternative ''Plan B'' technique if oxygenation by face mask or ventilation using a supraglottic device is non-problematic. Irrespective of the technique(s) used, failure to achieve successful tracheal intubation in a maximum of three attempts defines failed tracheal intubation and signals the need to engage an exit strategy. Failure to oxygenate by face mask or supraglottic device ventilation occurring in conjunction with failed tracheal intubation defines a failed oxygenation, ''cannot intubate, cannot oxygenate'' situation. Cricothyrotomy must then be undertaken without delay, although if not already tried, an expedited and concurrent attempt can be made to place a supraglottic device. récente concernant la prise en charge des voies aériennes. Dans cet article, le CAFG s'est donné pour mission d'émettre des recommandations visant la prise en charge du patient inconscient ou anesthésié qui présente des difficultés d'intubation significatives. Méthode Dix-neuf cliniciens ayant une formation en anesthésie, en médecine d'urgence ou en soins intensifs composent le CAFG actuel. Les participants ont passé en revue des sujets précis en consultant les bases de données Medline, EMBASE et Cochrane. Les résultats de ces revues ont été présentés et discutés dans le cadre de téléconférences et de deux réunions en personne. Lorsqu'indiqué, des recommandations fondées sur des données probantes ou sur un consensus ont été émises. Le niveau de confiance attribué à ces recommandations a aussi été défini. Conclusion Le clinicien doit avoir conscience des lésions qu'il peut infliger lors de tentatives multiples d'intubation trachéale. Il est possible d'éviter de telles lésions en abandonnant rapidement une technique d'intubation infructueuse afin d'opter pour une méthode alternative (ou 'plan B') à condition que l'oxygénation par masque facial ou par l'utilisation d'un dispositif supraglottique s'avère possible. Nonobstant la ou les techniques choisies, un maximum de trois tentatives infructueuses mène à la conclusion qu'il s'agit d'un échec d'intubation et devrait inciter le clinicien à adopter une stratégie de retrait. Une situation dans laquelle il est impossible de procéder à l'oxygénation du patient à l'aide d'un masque facial, d'un dispositif supraglottique ou de l'intubation endotrachéale est qualifiée de scénario cannot intubate, cannot ventilate. Il est alors impératif de procéder sans délai à une cricothyrotomie, à moins que l'insertion d'un dispositif supraglottique n'ait été tentée. Celle-ci peut alors être effectuée rapidement et parallèlement à la réalisation de la cricothyrotomie.
What other statements of recommendation are available on this topic?
In 1998, Canadian recommendations were published on management of the unanticipated difficult airway. More recent national recommendations and guidelines on difficult airway management have been published in the USA, the United Kingdom, and other western European countries.
Why were these recommendations developed?
Canadian recommendations were overdue for an update. Since the last review, many new devices useful in difficult airway management have been introduced. In addition, the Anesthesia Closed Claims Project and other observational studies have highlighted potential areas for improvement in management of the difficult and failed airway.
How do these statements differ from existing recommendations? These statements reflect current evidence and thinking on an appropriate response to difficult airway management encountered in the unconscious/induced patient. The importance of engaging an exit strategy after a limited number of attempts at tracheal intubation is emphasized, as is a simplified response to a failed oxygenation, ''cannot intubate, cannot oxygenate'' situation.
Why do these statements differ from existing recommendations? These statements differ from existing recommendations in order to simplify decision-making when failed tracheal intubation or failed oxygenation is encountered in the unconscious/induced patient. Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. The authors accept that medical knowledge is an ever-changing science that continually informs, improves, and alters attitudes, beliefs, and practices.
## Contents
Recommendations are not intended to represent or be referred to as a standard of care in the management of the difficult or failed airway.
Application of the information provided in a particular situation remains the professional judgement and responsibility of the practitioner.
Bedside predictors of difficult tracheal intubation are imperfect. Accordingly, when general anesthesia (GA) is induced despite predictors of difficult intubation, many cases prove unchallenging. Conversely, unanticipated failure of tracheal intubation by direct laryngoscopy or other technique can occur when no such challenges were expected. Encountering difficult tracheal intubation in the unconscious patient is a concern, as many studies involving several specialties have documented increasing patient morbidity with multiple tracheal intubation attempts. [bib_ref] The importance of first pass success when performing orotracheal intubation in the..., Sakles [/bib_ref] [bib_ref] Association between repeated intubation attempts and adverse events in emergency departments: an..., Hasegawa [/bib_ref] [bib_ref] 423 emergency tracheal intubations at a university hospital: airway outcomes and complications, Martin [/bib_ref] [bib_ref] Complications of endotracheal intubation in the critically ill, Griesdale [/bib_ref] [bib_ref] Emergency tracheal intubation: complications associated with repeated laryngoscopic attempts, Mort [/bib_ref] Other hazards associated with difficulty in airway management have been highlighted in recent publications. Studies of closed legal actions 6-8 related to airway management and the recent 4 th National Audit Project (NAP4) of the Royal College of Anaesthetists and the Difficult Airway Society in the United Kingdom 9,10 have helped direct attention to problem areas. In the NAP4 study, a prospective registry was created of major complications related to airway management occurring over a 12-month period in all 309 National Health Service hospitals in the United Kingdom. Complications were reported if they led to death, brain damage, need for emergency surgical airway, unanticipated intensive care unit (ICU) admission, or prolongation of ICU stay. [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] The results of the audit provide considerable insight into causes of airway management-related morbidity and potential areas for improvement.
This first of two publications addresses airway management in the unconscious patient when difficult tracheal intubation is encountered. The second publication will focus on options and the approach to the patient when difficult airway management is anticipated. [bib_ref] for the Canadian Airway Focus Group. The difficult airway with recommendations for..., Law [/bib_ref] Taken together, the articles are intended to assist the practitioner with recommendations for airway management when confronted with a difficult or failed airway, regardless of where in the hospital an airway intervention occurs.
# Methods
The Canadian Airway Focus Group (CAFG) was originally formed in the mid-1990s and published recommendations for the management of the unanticipated difficult airway in 1998. [bib_ref] The unanticipated difficult airway with recommendations for management, Crosby [/bib_ref] Four of the original CAFG members rejoined the current iteration, and the first author invited an additional 14 clinicians with an interest in airway management to participate. The current Focus Group includes representatives from anesthesiology, emergency medicine, and critical care.
Topics for review were divided among the members, and participants conducted a literature review on their topic(s). Electronic literature searches were not conducted according to a strict protocol, but participants were instructed to search, at a minimum, Medline and EMBASE databases together with the Cochrane Central Register of Controlled Trials (CENTRAL). Search strings were determined by individual participants. A worksheet was completed for each topic with details of the search strategy, a synopsis of the relevant studies, an overall summary of findings, the perceived quality of evidence, and the author's suggestion(s) for strength of recommendation (see below). Once finished, worksheets were made available to the CAFG membership on a file hosting service.
The Focus Group convened regularly by teleconference, and face-to-face meetings occurred twice during the 24 months taken to complete the process. Worksheet authors presented their topics to the members, who then arrived at consensus on overall quality of evidence and any recommendations. In the event that evidence was of low quality or altogether lacking, ''expert opinion'' by consensus was sought. Finally, a draft of the completed manuscript was distributed to all members for review prior to submission.
The strength of a recommendation and the accompanying level of evidence were modelled after the GRADE system, as per previously published criteria. [bib_ref] Grading strength of recommendations and quality of evidence in clinical guidelines: report..., Guyatt [/bib_ref] [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] When made, formal strength of recommendations adhere to the following descriptors:
- Strong recommendation for -most patients should receive the intervention; most patients in this situation would want the recommended course of action; - Weak recommendation for -most patients would want the suggested course of action, but some would not; the appropriate choice may vary for individual patients. - Strong recommendation against -most patients should not receive the intervention; most patients in this situation would not want the suggested course of action;
- Weak recommendation against -most patients would not want the suggested course of action, but some would; the appropriate choice may vary for individual patients.
Three levels of evidence were applied, 13 as follows:
- Level of evidence A (High) -systematic reviews of randomized controlled trials (RCTs), RCTs without important limitations, or observational studies providing overwhelming evidence; - Level of evidence B (Moderate) -RCTs with limitations, observational studies with significant therapeutic effect; - Level of evidence C (Low) -RCTs with significant limitations, observational studies, case series, or published expert opinion.
When a level of evidence is not specifically supplied in this manuscript, recommendations reflect the consensus opinion of the authors.
## Definitions
The following definitions of terms are presented to clarify their use in the text. Some definitions have changed from the 1998 iteration of these recommendations to reflect the increased use of alternatives to direct laryngoscopy (DL) and ventilation with a supraglottic device (SGD).
Difficult airway: A difficult airway can be defined as one where an experienced provider anticipates or encounters difficulty with any or all of face mask ventilation, direct or indirect (e.g., video) laryngoscopy, tracheal intubation, SGD use, or surgical airway.
Difficult face mask ventilation: It has been suggested that inadequate mask ventilation may be more difficult to recognize than its complete absence. [bib_ref] Prediction and outcomes of impossible mask ventilation: a review of 50,000 anesthetics, Kheterpal [/bib_ref] Although various definitions relating to difficulties with mask ventilation have been proposed, [bib_ref] Prediction of difficult mask ventilation, Langeron [/bib_ref] [bib_ref] Practice guidelines for management of the difficult airway: an updated report by..., Apfelbaum [/bib_ref] [bib_ref] Incidence and predictors of difficult and impossible mask ventilation, Kheterpal [/bib_ref] ease of mask ventilation is best described as a continuum from no difficulty to impossible. Difficult face mask ventilation may be signified by manipulations required for its facilitation, including adjustments of the head and neck, the use of adjuvants (e.g., an oral or nasal airway), use of exaggerated jaw lift, two-handed face mask application, and the assistance of a second operator.
Difficult laryngoscopy: Laryngeal exposure using DL is generally quantified using the Cormack-Lehane grade [bib_ref] Difficult tracheal intubation in obstetrics, Cormack [/bib_ref] or one of its modifications. [bib_ref] A new practical classification of laryngeal view, Cook [/bib_ref] [bib_ref] Evaluation of an improved scoring system for the grading of direct laryngoscopy, Yentis [/bib_ref] Most authorities agree that grade 1 and 2 views, where most or some portion of the glottis is seen, represent easy DL, while grade 3 and 4 views represent difficult and failed DL, respectively, even if tracheal intubation itself succeeds. The same classification can be employed when indirect techniques, such as video laryngoscopy, are utilized. Regardless of the technique used (DL or indirect laryngoscopy), the specific device should always be described in addition to the view obtained, the number of attempts, and the ancillary maneuvers required to achieve the result.
Difficult tracheal intubation: The success of direct or indirect laryngoscopy and tracheal intubation should be assessed independently, regardless of the technique. Difficult tracheal intubation can be defined as one or all of the following: [bib_ref] The unanticipated difficult airway with recommendations for management, Crosby [/bib_ref] - Multiple attempts or more than one operator required;
- An adjunct such as a tracheal tube introducer (''bougie'') is required to facilitate tracheal intubation; - An alternative intubation device is required after unsuccessful use of the primary, ''Plan A'' device.
A common reason for difficulty with tracheal intubation is a poor laryngeal view; however, if a Cormack-Lehane 1 or 2 view is obtained but difficulty occurs with directing or advancing the endotracheal tube (as may happen with video laryngoscopy), it is reasonable to describe this in some form of narrative. Alternatively, difficulty can be quantified using a scale based on several parameters. [bib_ref] A survey of tracheal intubation difficulty in the operating room: a prospective..., Adnet [/bib_ref] Difficult SGD use: Difficult or failed oxygenation and ventilation with an SGD may result from difficulties accessing the patient's mouth or hypopharynx, achieving a seal, [bib_ref] Advances in airway management, Hung [/bib_ref] or ventilating the lungs.
Difficult transtracheal surgical airway: A surgical airway can be achieved by percutaneous needle-guided cannula methods or by an open operative technique. A difficult transtracheal surgical airway is one that requires excess time or multiple efforts.
Failed airway: Defining a failed airway helps serve notice to the clinician that a different course of action may be needed to minimize the potential for harm to the patient:
- Failed tracheal intubation can be defined as failure to achieve successful tracheal intubation in a maximum of three attempts, irrespective of the technique(s) used. [bib_ref] The emergency airway algorithms, Walls [/bib_ref] has occurred if, in the face of failed tracheal intubation, the patient cannot be successfully oxygenated by employing face mask or SGD ventilation.
[formula] - Failed oxygenation (''cannot intubate, cannot oxygenate'' [CICO]) [/formula]
Extubation of the difficult airway: Extubation is unsuccessful when a tracheal tube is removed but requires unanticipated replacement. This replacement (including tracheal tube exchange) can be difficult or fail. A clear definition of difficulty does not exist, but it is reasonable to assume that the difficulty further contributes to rather than resolves a deteriorating situation. A high-risk extubation can be described on two axes: the risk of not tolerating extubation and the risk of re-intubation being difficult or unsuccessful. Extubation of the patient with a difficult airway is addressed in the second article in this series. [bib_ref] for the Canadian Airway Focus Group. The difficult airway with recommendations for..., Law [/bib_ref] Incidence and scope of the problem
The published incidence of difficult airway management interventions varies substantially [fig_ref] Table 1: Approximate incidence of difficulty with various airway interventions -by hospital location [/fig_ref]. Although different definitions, patient populations, and clinician experience make these figures difficult to compare directly, a few trends emerge. Perhaps one of the more significant trends is the higher occurrence of difficulty encountered in locations outside of the operating room (OR).
## Management of the difficult and failed airway in the unconscious/induced patient
Most airway management is performed in an unconscious patient, usually pharmacologically induced for surgical anesthesia. Outside the OR environment, a critically ill patient may be induced for the sole purpose of securing the airway or may already have been unconscious on initial presentation.
Airway management in the induced surgical patient may involve SGD or face mask ventilation, tracheal intubation, or rarely, a primary cricothyrotomy or tracheotomy. Difficulty may be encountered with any of these modalities and should be met with an appropriate response.
The primary approach to tracheal intubation: ''Plan A''
For the unconscious/induced patient requiring tracheal intubation, the clinician's primary ''Plan A'' approach may have been facilitated by DL or an alternative to DL, such as video laryngoscopy. Alternatives to DL may be chosen as the primary approach due to anticipated difficulty with DL, their utility in teaching, or clinician preference. The chosen technique should be suited to the context of patient anatomy and pathophysiology, operator familiarity, and the practice environment. The probability of first-attempt success should be maximized by familiarity with and attention to equipment and adjunct (e.g., malleable stylet or tracheal tube introducer) preparation, patient positioning, and optimal pharmacotherapy. [bib_ref] Difficult laryngoscopy: obtaining the best view, Benumof [/bib_ref] Response to difficulty encountered in the unconscious patient Difficult direct laryngoscopy: If a poor view is obtained during attempted DL despite proper positioning of the patient and the laryngoscope blade tip, optimizing maneuvers should occur, such as application of external laryngeal pressure (Strong recommendation for, level of evidence B). Unless contraindicated by C-spine precautions, additional head lift (to accentuate lower neck flexion and head/upper neck extension) may also be helpful. [bib_ref] Head-elevated laryngoscopy position: improving laryngeal exposure during laryngoscopy by increasing head elevation, Levitan [/bib_ref] [bib_ref] Head and neck elevation beyond the sniffing position improves laryngeal view in..., Schmitt [/bib_ref] [bib_ref] Analysis of the forces and position required for direct laryngoscopic exposure of..., Hochman [/bib_ref] External laryngeal pressure is effective at improving the view during DL. [bib_ref] Quantitative improvement in laryngoscopic view by optimal external laryngeal manipulation, Benumof [/bib_ref] [bib_ref] Tracheal intubation using the mobile C-MAC video laryngoscope or direct laryngoscopy for..., Byhahn [/bib_ref] [bib_ref] Survey of the use of the gum elastic bougie in clinical practice, Latto [/bib_ref] [bib_ref] Bimanual laryngoscopy: a videographic study of external laryngeal manipulation by novice intubators, Levitan [/bib_ref] [bib_ref] A videographic analysis of laryngeal exposure comparing the articulating laryngoscope and external..., Ochroch [/bib_ref] [bib_ref] Difficult intubation in acromegalic patients: incidence and predictability, Schmitt [/bib_ref] [bib_ref] The efficacy of the ''BURP'' maneuver during a difficult laryngoscopy, Takahata [/bib_ref] [bib_ref] Predicting difficult intubation, Wilson [/bib_ref] [bib_ref] Left-molar approach improves the laryngeal view in patients with difficult laryngoscopy, Yamamoto [/bib_ref] This maneuver is distinct from cricoid pressure, applied to the cricoid cartilage to help prevent passive regurgitation of gastric contents. In studies, cricoid pressure resulted in no improvement [bib_ref] The gum elastic bougie eases tracheal intubation while applying cricoid pressure compared..., Noguchi [/bib_ref] [bib_ref] Cricoid pressure does not increase the rate of failed intubation by direct..., Turgeon [/bib_ref] [bib_ref] Cricoid pressure and laryngeal manipulation in 402 pre-hospital emergency anaesthetics: essential safety..., Harris [/bib_ref] or a worse 64,67-69 view with DL; hence, a recommendation can be made against its use for the sole purpose of improving the view during DL if used instead of laryngeal pressure (Weak recommendation against, level of evidence C). External laryngeal pressure and head lift can be performed sequentially during the first attempt at DL.
There is little evidence that an automatic blade change is an effective strategy for a second attempt at DL unless a specific anatomic finding during the initial laryngoscopy suggests a benefit. Examples include a long, floppy epiglottis that could be directly elevated with a longer curved, or straight blade, or a suspicion that a Macintosh blade is too short to completely advance into the vallecula, thus failing to engage the underlying hyoepiglottic ligament. The tracheal tube introducer has been extensively studied as an adjunct to DL. It is an effective aid to tracheal intubation faced with a restricted view during DL [bib_ref] A new practical classification of laryngeal view, Cook [/bib_ref] [bib_ref] An algorithm for difficult airway management, modified for modern optical devices (Airtraq..., Amathieu [/bib_ref] [bib_ref] Unanticipated difficult airway in anesthetized patients: prospective validation of a management algorithm, Combes [/bib_ref] [bib_ref] Unanticipated difficult airway management in the prehospital emergency setting: prospective validation of..., Combes [/bib_ref] [bib_ref] Simulated difficult intubation. Comparison of the gum elastic bougie and the stylet, Gataure [/bib_ref] [bib_ref] Use of gum elastic bougie for prehospital difficult intubation, Jabre [/bib_ref] [bib_ref] Orotracheal intubation in patients with potential cervical spine injuries. An indication for..., Nolan [/bib_ref] [bib_ref] Comparison of the Levitan FPS Scope TM and the single-use bougie for..., Greenland [/bib_ref] and may also be useful with some video laryngoscopes. If a restricted (e.g., Cormack-Lehane grade 2b or 3) 19,20 view obtained during DL persists after optimization maneuvers such as external laryngeal pressure or additional head lift, use of a tracheal tube introducer should be considered (Strong recommendation for, level of evidence B). The CAFG recommends immediate availability of a tracheal tube introducer at all airway management locations.
Difficult video laryngoscopy: There are three independent tasks with video laryngoscopy, namely, laryngeal exposure, delivery of the tracheal tube to the laryngeal inlet, and advancement within the trachea. Use of a video laryngoscope will generally result in a good laryngeal view, although blades with more angulation or curvature will enable better exposure. The following techniques can facilitate passage of the tracheal tube: preparing a tracheal tube with a preloaded stylet with a curvature matching that of the video laryngoscope blade, partial withdrawal of the blade to provide a wider visual field, and deliberately not seeking a full view of the larynx before attempting passage of the tube. Once placed through the glottic opening, withdrawing the stylet 5 cm will help circumvent impingement of the tracheal tube tip on the anterior tracheal wall, permitting gentle tube advancement. Rotation of the tube may also address impingement. Video laryngoscopes with channeled blades (e.g., Airtraq Ò , Ambu Ò AWS, and KingVision TM ) also exist to facilitate delivery of the tracheal tube. Failure to achieve a view of the larynx with video laryngoscopy can be minimized by suctioning the oropharynx prior to initial blade insertion.
Difficult face mask ventilation: Difficult face mask ventilation of the unconscious patient before or between tracheal intubation attempts should be addressed with a graduated response, including placement of an appropriately sized oropharyngeal and/or nasopharyngeal airway, use of a two-handed mask hold, and exaggerated head extension, unless contraindicated (Strong recommendation for, level of evidence C).
The two-handed face mask hold facilitates ventilation by projecting the mandible anteriorly into the mask, which pulls the tongue forward and further opens the airway. It also provides an improved mask seal. Ventilation can be provided by an assistant or by the anesthesia machine ventilator if the patient is in the OR.
Cricoid pressure may make face mask ventilation difficult, especially if applied with excess force. [bib_ref] Airway obstruction with cricoid pressure, Hartsilver [/bib_ref] If cricoid pressure has been applied and difficult face mask ventilation is deemed unresponsive to the foregoing measures, progressive release of pressure should be considered (Weak recommendation for, level of evidence C).
If difficult or impossible face mask ventilation persists despite corrective maneuvers, a SGD should be placed or tracheal intubation should be undertaken if not already attempted. [bib_ref] Prediction and outcomes of impossible mask ventilation: a review of 50,000 anesthetics, Kheterpal [/bib_ref] [bib_ref] Impossible mask ventilation, Calder [/bib_ref] [bib_ref] Muscle relaxants and airway management, Calder [/bib_ref] Failure to ventilate with a SGD can often be resolved by ensuring an adequate depth of anesthesia, appropriate (e.g., no more than 60 cm H 2 O) cuff inflation, reinsertion of the device with a fully deflated cuff, or placement of a larger SGD.
## Unsuccessful primary approach to tracheal intubation
An attempt at tracheal intubation may be unsuccessful despite optimized conditions and technique. In the induced/ unconscious patient, this will most often be followed by face mask ventilation or, optionally, placement of a SGD. The success of oxygenation by face mask or SGD ventilation in this context dictates subsequent actions . As long as oxygenation is non-problematic, the situation is stable, and if deemed appropriate, time exists for additional careful attempts at tracheal intubation. Conversely, the failure of face mask ventilation or a SGD to maintain adequate oxygenation after a failed attempt at tracheal intubation indicates a failed oxygenation/CICO situation (represented in the Emergency pathway on the right-hand side of the
## Flow diagram).
With non-problematic oxygenation, a second attempt at tracheal intubation can occur using the primary ''Plan A'' technique, but only if it is reasonable to presume that the factors contributing to the initial unsuccessful attempt can be addressed during the subsequent attempt. For example, an unsuccessful primary attempt at intubation using video laryngoscopy may yield information about the ideal curvature of a tracheal tube with preloaded stylet required for a second attempt.
The alternative approach to tracheal intubation: ''Plan B'' in the adequately oxygenated patient An alternative ''Plan B'' approach to tracheal intubation should be employed if the primary approach is unsuccessful, if oxygenation remains non-problematic, and if further intubation attempts are planned. Experienced providers will often proceed to the alternative approach after only a single failed attempt with the primary device, recognizing the low incremental probability of successful intubation with a second attempt using the same device. In general, the alternative approach should be used after no more than two failed attempts at tracheal intubation using the primary approach and should employ a different device or operator.
Numerous alternatives to DL, used alone or in combination, have been proven effective in obtaining an improved view of the larynx and/or enabling successful tracheal intubation when DL is unsuccessful [fig_ref] Table 2: Effectiveness of a selection of alternatives to direct laryngoscopy in the difficult... [/fig_ref]. Many of the devices presented in [fig_ref] Table 2: Effectiveness of a selection of alternatives to direct laryngoscopy in the difficult... [/fig_ref] are indirect (e.g., video) laryngoscopes, although other techniques are also effective in experienced hands. Equally, there is also some evidence that DL-facilitated intubation may succeed should primary use of some of these same alternatives fail. [bib_ref] Routine clinical practice effectiveness of the Glidescope in difficult airway management: an..., Aziz [/bib_ref] [bib_ref] Mallampati class does not affect the success rate of intubation through an..., Ye [/bib_ref] As such, an argument can be made that these alternative devices should complement and not necessarily replace DL at this time. Irrespective of the technique chosen, proficiency demands elective experience in human subjects.
There should be a reasonable expectation that the selected ''Plan B'' technique will address the reason, anatomic or otherwise, for failure of the primary approach. As with the primary approach, each use of the alternative device should be optimized, and a second attempt using the same device should occur only if made with a substantive change, e.g., a change in the size of the device, altered endotracheal tube/stylet conformation, or use by a more experienced operator. All clinicians with a mandate for airway management should be familiar with at least one alternative technique (e.g., video laryngoscopy) to DL to enable tracheal intubation (Strong recommendation for, level of evidence C), and such equipment should be immediately available. When difficult or failed DL is encountered, proceeding with a ''Plan B'' alternative intubation technique without awakening the elective surgical patient is common practice and is probably safe, provided that oxygenation remains unchallenged.
Failed tracheal intubation in the adequately oxygenated patient: exit strategies
## Limits to tracheal intubation attempts
Evidence continues to emerge that patient morbidity increases with the number of attempts at tracheal intubation [fig_ref] Table 3: Adverse effects associated with multiple attempts at tracheal intubation [/fig_ref]. Mainly derived from the critically ill population, it must be acknowledged that there is marked heterogeneity in harmful ''outcomes'' reported in these studies (e.g., aspiration, hypoxemia, hypotension, trauma etc.), including composite outcomes. Furthermore, there is variable use of neuromuscular blockade, and it is unclear if the apparent risk relates to the number of attempts required, additional exerted force, or the associated delay in successful intubation. Nevertheless, the studies do provide a warning that the number of attempts at tracheal intubation should be minimized, irrespective of practice location. Incremental risk must be assumed with each failed attempt such that a second or third tracheal intubation attempt should occur only if a different tactic is used and there is a reasonable expectation of success. Proceeding with more than three attempts at tracheal intubation requires compelling justification.
With the evidence of harm accruing from multiple attempts at tracheal intubation, an argument can be made for always including first-attempt success rates in future studies of intubation devices, techniques, or skills acquisition.
## Failed tracheal intubation: exit strategies
Three failed attempts at tracheal intubation should be taken as an indication to declare a failed intubation situation. This should signal the team to pause and consider an exit strategy, to avoid repetitive ineffective intubation attempts that might result in harm to the patient. In the adequately oxygenated unconscious/induced patient, a number of exit strategies exist:
- Awakening the patient. The option of allowing the induced oxygenated patient to wake after failed tracheal intubation should be considered when feasible (Weak recommendation for, level of evidence C). Once awake and cooperative, awake tracheal intubation can be attempted in the spontaneously breathing patient. Alternatively, an elective surgical case could be deferred or potentially performed under regional or infiltration anesthesia. Oxygenation should be maintained with face mask or a SGD until the patient emerges from general anesthesia. Awakening the patient may not be possible or appropriate in an emergency, during an attempted resuscitation, or if the patient cannot cooperate with awake intubation or surgery under regional anesthesia. While there is no evidence to support the contention that awakening the elective surgical patient will confer an outcome benefit when tracheal intubation has failed, this option is supported by expert consensus to prevent deterioration to a failed oxygenation, ''cannot intubate, cannot oxygenate'' scenario.
- Proceeding with surgery (or temporizing an emergency situation) using face mask or SGD ventilation. As an exit strategy for failed tracheal intubation in the induced/unconscious patient, the benefit of proceeding with surgery under face mask or SGD ventilation must exceed the risk of foregoing tracheal intubation. In general, this will be easier to justify for brief or urgent surgeries, although risk of aspiration must be considered. If surgery proceeds under face mask or SGD ventilation, a plan should exist for difficulty with or failure of oxygenation during the case. The critically ill non-surgical patient temporized with face mask or SGD ventilation will likely still require tracheal intubation or a surgical airway, sooner rather than later. - Obtaining equipment or additional expert help for a further controlled attempt at tracheal intubation.
There is no doubt that minimizing tracheal intubation attempts is a sound principle. Nevertheless, the goal of engaging an exit strategy is not necessarily to prohibit more than three intubation attempts so much as to serve as a warning that further attempts may be attended by increasing patient harm and decreasing chances of success. Consequently, an ''exit strategy'' attempt at tracheal intubation should occur only with a high likelihood of success and a low probability of creating complications. For example, if a SGD had been placed after three failed attempts at tracheal intubation, bronchoscopy-aided intubation could have ensued via the SGD once an appropriate flexible bronchoscope became available. Alternatively, if additional expert help had been available, another attempt at intubation could have occurred with the same or a different device, being mindful of the need to avoid traumatizing the airway during the attempt. - Proceeding with surgical access. In rare circumstances, it may be appropriate to proceed with surgical access (cricothyrotomy or tracheotomy) following failed tracheal intubation in the adequately oxygenated unconscious/induced patient. This may be required if awakening the patient is not an option, i.e., most often in urgent or emergency situations.
Failed tracheal intubation may be apparent and an exit strategy engaged before three attempts at intubation have occurred, even after a single unsuccessful attempt. . Three corrective measures are vital: immediate recognition, a call for help, and preparation for proceeding rapidly with a surgical/ transtracheal airway (most often cricothyrotomy in the adult patient). Due to the rarity of this situation, clinicians commonly exhibit a lack of situation awareness when failed oxygenation/CICO is encountered, having become fixated on multiple unproductive attempts at tracheal intubation or SGD placement. The failure to recognize failed oxygenation/CICO and respond appropriately has been shown to delay cricothyrotomy, resulting in cerebral hypoxia and cardiac arrest. [bib_ref] Management of the difficult airway: a closed claims analysis, Peterson [/bib_ref] [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] It is imperative that all members of the assembled team be empowered to call for help or raise the need for emergency cricothyrotomy.
The Focus Group was reluctant to recommend a specific arterial oxygen saturation (SaO 2 ) trigger for cricothyrotomy in a failed oxygenation/CICO situation. Nevertheless, given the sigmoid shape of the oxyhemoglobin dissociation curve, as SaO 2 descends through 90%, the rate of desaturation will accelerate if efforts at oxygenation remain unsuccessful. A failed oxygenation/CICO situation with a rapidly declining SaO 2 despite maximum attempts at oxygenation should be taken as an indication for cricothyrotomy, especially with the onset of bradycardia. [bib_ref] Equipment and strategies for emergency tracheal access in the adult patient, Hamaekers [/bib_ref] Published case series [bib_ref] The laryngeal mask airway reliably provides rescue ventilation in cases of unanticipated..., Parmet [/bib_ref] [bib_ref] Laryngeal mask airway and bougie intubation failures: the Combitube as a secondary..., Mort [/bib_ref] [bib_ref] Failed obstetric tracheal intubation and postoperative respiratory support with the ProSeal TM..., Keller [/bib_ref] and reports 38,177-180 have described successful rescue oxygenation in failed oxygenation/CICO scenarios with placement of a SGD. Although recommended by national guidelines in many countries, [bib_ref] The unanticipated difficult airway with recommendations for management, Crosby [/bib_ref] [bib_ref] Practice guidelines for management of the difficult airway: an updated report by..., Apfelbaum [/bib_ref] [bib_ref] Intubation difficile, Boisson-Bertrand [/bib_ref] [bib_ref] Recommendations for airway control and difficult airway management, Petrini [/bib_ref] evidence is lacking on whether outcome is improved with attempted SGD placement prior to cricothyrotomy in failed oxygenation/CICO situations. Regardless, if failed oxygenation/CICO occurs, one attempt should be made at placing an appropriately sized SGD familiar to the operator, unless this has previously failed (Strong recommendation for, level of evidence C). During this SGD attempt, a second individual should simultaneously prepare equipment and the patient's neck for cricothyrotomy. If oxygenation is not restored via the SGD, immediate cricothyrotomy should proceed without further attempts at either SGD placement or transglottic tracheal intubation (Strong recommendation for, level of evidence C). As it takes longer than cricothyrotomy, retrograde intubation is not recommended in failed oxygenation/CICO scenarios.
For emergency subglottic transtracheal access, cricothyrotomy is most often recommended in adults over tracheotomy, particularly when performed by a nonsurgeon. This is advocated because the space is less vascular and more readily palpable.
Cricothyrotomy can be categorized as surgical or nonsurgical. Surgical cricothyrotomy involves the use of a scalpel to incise the skin and cricothyroid membrane, with placement of a small (e.g., 6.0-mm internal diameter in the adult) endotracheal or tracheostomy tube. Other instruments needed for the procedure may include a tracheal hook, a Trousseau dilator, or a tracheal tube introducer. [bib_ref] The bougie-aided cricothyrotomy, Braude [/bib_ref] Non-surgical cricothyrotomy involves one of two options: percutaneous insertion of a wide bore (C 4-mm ID) cannula by either cannula-over-needle or Seldinger wireguided (e.g., Melker) techniques, or percutaneous insertion of a narrow bore (B 2-mm) intravenous-type cannula. Narrow-bore cricothyrotomy with jet ventilation requires a high-pressure ventilation source in adults (not universally available in all airway management locations); it is more likely to result in breath stacking, barotrauma, catheter kinking, or dislodgement, and does not provide airway protection with a cuff. Of the available options, it is associated with the highest complication and failure rates. [bib_ref] Management of the difficult airway: a closed claims analysis, Peterson [/bib_ref] [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] Unless the clinician is very experienced with jet ventilation, this suggests that options in failed oxygenation/ CICO in the adult patient should be limited to either the percutaneous needle-guided wide-bore cannula or the open surgical technique (Strong recommendation for, level of evidence C). Both percutaneous wide-bore cannula and open surgical choices allow the desirable option of placing a cuffed tracheal cannula/tube.
There is some evidence that the percutaneous needleguided wide-bore cannula technique may be less effective than the open surgical procedure. 9,10,184 Nevertheless, a recent survey suggested that Canadian anesthesiologists were most comfortable with a percutaneous technique. [bib_ref] Cannot intubate-cannot ventilate and difficult intubation strategies: results of a Canadian national..., Wong [/bib_ref] On balance, we recommend that adult cricothyrotomy should proceed with either a percutaneous needle-guided wide-bore cannula or an open surgical technique, governed by operator preference and equipment availability. Even so, mindful of the significant reported failure rates of the percutaneous techniques, clinicians must be prepared for immediate conversion to an open surgical technique should the percutaneous needle-guided technique fail.
Recent studies suggest that anesthesia providers may have difficulty with correctly identifying the cricothyroid membrane using external landmarks. [bib_ref] Accuracy of surface landmark identification for cannula cricothyroidotomy, Elliott [/bib_ref] [bib_ref] Accuracy of identification of the cricothyroid membrane in female subjects using palpation:..., Aslani [/bib_ref] This may argue for always beginning cricothyrotomy with a 3-cm vertical midline incision over the presumed location of the cricothyroid membrane (Weak recommendation for, level of evidence C), at least in the patient with indistinct external landmarks. The cricothyroid membrane may then be more accurately identified within the incision, and the cricothyrotomy can continue with either a needle-guided wide-bore cannula or surgical technique.
As one of the major complications of cricothyrotomy placement is false passage, correct cannula or tube location must be objectively confirmed using capnography or endoscopy.
Even if administering (or re-dosing) a neuromuscular blocking agent is not indicated as part of the initial management plan, once a failed oxygenation/CICO situation occurs, it should be considered to address possible laryngospasm and facilitate face mask ventilation (Weak recommendation for, level of evidence C).Secondly, if bradycardia should occur, administration of epinephrine or atropine may forestall cardiac standstill. In both instances, these actions are to be delegated to an assistant and must not delay cricothyrotomy.
As an infrequently-performed yet life-saving procedure, all airway managers must acquire and maintain cricothyrotomy skills through educational programs. Cricothyrotomy equipment should be readily accessible, and all clinicians and ancillary staff should know its location.
## Tracheal intubation confirmation
The persistent presence of exhaled carbon dioxide ''appropriate to the clinical circumstance'' provides objective confirmation of tracheal intubation. 12 Visualization of a tracheal tube between the cords or endoscopic visualization of the subglottic airway through a tracheal tube can provide additional confirmation. [bib_ref] The unanticipated difficult airway with recommendations for management, Crosby [/bib_ref] Chest rise and auscultation, tube misting, chest radiography, and pulse oximetry are not robust indicators of successful tracheal intubation.
In the NAP4 study, many complications of airway management reported in the emergency department (ED) and ICU were related to unrecognized esophageal intubation or tracheal tube dislodgements. The inconsistent use of capnography for confirmation of tracheal intubation or the lack of continuous capnographic monitoring of already intubated patients was judged contributory. [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] Thus, capnographic confirmation of tracheal tube placement should occur for all hospitalized patients (Strong recommendation for, level of evidence B), and ongoing continuous waveform capnographic monitoring should occur for the duration of intubation and ventilation (Strong recommendation for, level of evidence C). The latter recommendation will facilitate early detection of tube dislodgement as well as inadvertent hyper-or hypoventilation.
Additionally, NAP4 found that the absence of a capnographic waveform in the setting of cardiac arrest was sometimes incorrectly ascribed to the absence of pulmonary perfusion without consideration of either esophageal intubation or a completely obstructed tracheal tube or trachea. [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] This occurred in OR, ED, and ICU environments. In actual fact, the first 30 min of cardiac arrest with adequate chest compressions is often associated with an attenuated but present capnography trace when the tracheal tube is correctly situated and unobstructed. [bib_ref] Use of capnography to confirm correct tracheal intubation during cardiac arrest, Cook [/bib_ref] A flat capnograph should prompt exclusion of a misplaced or blocked tracheal tube.
Continuous capnographic monitoring has also been recommended for patients without tracheal intubation who are undergoing deeper levels of procedural sedation (e.g., Ramsay sedation scores 4-6). [bib_ref] Guidelines to the practice of anesthesia revised edition 2013, Merchant [/bib_ref] The obstetric airway: special considerations A higher incidence of failed tracheal intubation has been reported in the parturient than in the general surgical population. [bib_ref] ANZCA Trials Group. Difficult and failed intubation in obstetric anaesthesia: an observational..., Mcdonnell [/bib_ref] [bib_ref] Incidence of unanticipated difficult airway in obstetric patients in a teaching institution, Tao [/bib_ref] [bib_ref] Failed tracheal intubation in obstetric anaesthesia: 2 yr national casecontrol study in..., Quinn [/bib_ref] Nevertheless, in series originating in jurisdictions with either a high volume of obstetrical general anesthetics or coverage limited to senior trainee or consultant anesthesia staff, the incidence of failed intubation is more consistent with that of general surgical cases. [bib_ref] Relative risk analysis of factors associated with difficult intubation in obstetric anesthesia, Rocke [/bib_ref] [bib_ref] Difficult and failed intubation in 3430 obstetric general anaesthetics, Djabatey [/bib_ref] [bib_ref] Difficult and failed intubation: incident rates and maternal, obstetrical, and anesthetic predictors, Mckeen [/bib_ref] This should not induce complacency, however, as multiple issues can converge and potentially contribute to airway-related morbidity in the parturient [bib_ref] The obstetric airway: things are seldom as they seem, Douglas [/bib_ref]. To help mitigate these factors, it is essential that obstetrical units have appropriately trained staff and airway equipment that is immediately accessible and of the same quality and type (e.g., video laryngoscopes) as that used in the main surgical ORs of the facility (Strong recommendation for, level of evidence C).
Difficult and failed tracheal intubations may be avoided by the more frequent use of regional anesthesia for obstetric surgical procedures. [bib_ref] Difficult and failed intubation: incident rates and maternal, obstetrical, and anesthetic predictors, Mckeen [/bib_ref] [bib_ref] General anesthesia for cesarean section at a tertiary care hospital 1990-1995: indications..., Tsen [/bib_ref] [bib_ref] General anesthesia for cesarean delivery at a tertiary care hospital from 2000..., Palanisamy [/bib_ref] High levels of anesthetic skill and experience facilitate effective and rapid neuraxial anesthesia in many emergency situations. [bib_ref] General anesthesia for cesarean delivery at a tertiary care hospital from 2000..., Palanisamy [/bib_ref] On the other hand, as general anesthesia rates continue to fall, there is ongoing concern that trainees are not being adequately exposed to airway management of the parturient-many tertiary care centres now typically have general anesthesia rates of 5-7% for Cesarean delivery. [bib_ref] Incidence of unanticipated difficult airway in obstetric patients in a teaching institution, Tao [/bib_ref] [bib_ref] General anesthesia for cesarean delivery at a tertiary care hospital from 2000..., Palanisamy [/bib_ref] Avoiding a bad airway-related outcome -first steps: Antenatal airway screening of all parturients should ideally occur to identify potential challenges. [bib_ref] Relative risk analysis of factors associated with difficult intubation in obstetric anesthesia, Rocke [/bib_ref] [bib_ref] Prevalence and prediction of difficult intubation in Chinese women, Wong [/bib_ref] [bib_ref] Prediction of difficult laryngoscopy in obstetric patients scheduled for caesarean delivery, Honarmand [/bib_ref] [bib_ref] Failure to predict difficult tracheal intubation for emergency caesarean section, Basaranoglu [/bib_ref] Once a parturient with difficult airway anatomy is identified, good communication is crucial. A plan should be formulated with the attending obstetrician with the understanding that, if operative delivery is likely, it should occur under controlled conditions. Early placement of an epidural catheter should be considered. The catheter should be tested to confirm its efficacy so that rapid conversion to a surgical level of anesthesia can occur for emergency Cesarean delivery. If the epidural is not working and time permits, it should be re-sited. Once the need for general anesthesia becomes apparent, the attending anesthesiologist should perform a formal assessment of the airway. The patient should be given pharmacologic anti-aspiration prophylaxis (Strong recommendation for, level of evidence C).
For induction of general anesthesia, all parturients should be appropriately positioned (e.g., ''ramped'' as needed to ensure the patient's external auditory meatus is level with the sternal notch). [bib_ref] Laryngoscopy and morbid obesity: a comparison of the ''sniff'' and ''ramped'' positions, Collins [/bib_ref] Pre-oxygenation should occur using high flow rates of oxygen, with tidal volume breathing for three minutes, if time permits, or eight deep breaths over 60 sec 207 (Strong recommendation for, level of evidence B). Cricoid pressure should be applied with induction and maintained as appropriate until the airway is secured. Succinylcholine is generally used to facilitate laryngoscopy if no contraindication exists. After induction, face mask ventilation with low insufflation pressures can occur while awaiting full onset of neuromuscular blockade. This is carried out both to extend oxygenated apnea time during tracheal intubation and to anticipate ease of face mask ventilation should a first attempt at intubation fail (Strong recommendation for, level of evidence C). Although this recommendation is a departure from the classic teaching of avoiding face mask ventilation during rapid sequence induction, the potential benefit of oxygenation probably outweighs the small risk of gastric insufflation causing regurgitation, especially if insufflation pressures are kept \ 20 cm H 2 O. [bib_ref] Rapid sequence induction and intubation: current controversy, El-Orbany [/bib_ref] Failed primary attempt at intubation encountered in an induced/unconscious parturient: If a first attempt at tracheal intubation fails despite optimized technique, gentle face mask ventilation should be resumed [fig_ref] Figure 2: Flow diagram [/fig_ref] , and help summoned. Cricoid pressure should be maintained unless thought to be contributing to difficulty. Any difficulty with face mask ventilation should be met with a standard response of oropharyngeal airway insertion, two-handed mask hold with exaggerated jaw thrust, incremental release of cricoid pressure, and if necessary, SGD placement. If oxygenation is non-problematic, a second tracheal intubation attempt can occur with the following provisos: there must be a reasonable likelihood of success based on findings at the initial attempt and a different technique (e.g., video laryngoscopy) or operator should be employed.
Exit strategy -failed tracheal intubation in the oxygenated parturient with NO fetal or maternal emergency: If tracheal intubation has failed and further attempts are predicted to have a low incremental likelihood of succeeding, the acuteness of the situation should be assessed. With no fetal or maternal emergency, the goal should be to maintain oxygenation and allow the parturient to emerge from general anesthesia. At that point, a decision can be made to revisit regional anesthesia (if not contraindicated) or proceed with awake tracheal intubation for general anesthesia. If face mask ventilation becomes difficult, a SGD should be placed to assist oxygenation while awaiting emergence from anesthesia. Factors with the potential to have an adverse impact on airway-related morbidity in the parturient Parturient anatomy and physiology - Reduced oxygenated apnea time due to increased oxygen consumption and decreased functional residual capacity. [bib_ref] Closing volume in normal pregnancy, Russell [/bib_ref] [bib_ref] Pre-oxygenation and apnoea in pregnancy: changes during labour and with obstetric morbidity..., Mcclelland [/bib_ref] [bib_ref] A randomized crossover study to determine the effect of a 30°head-up versus..., Hignett [/bib_ref] Exacerbated by labour, increased body mass index (BMI), sepsis, [bib_ref] Pre-oxygenation and apnoea in pregnancy: changes during labour and with obstetric morbidity..., Mcclelland [/bib_ref] or suboptimal pre-oxygenation; - Increases in parturient age and BMI increase the tendency toward pre-eclampsia and snoring; [bib_ref] The upper airway in pregnancy and pre-eclampsia, Izci [/bib_ref] - Anatomic factors: weight gain, breast enlargement, and upper airway edema occurring with pregnancy-induced hypertension or prolonged labour; [bib_ref] Airway changes during labor and delivery, Kodali [/bib_ref] [bib_ref] Mallampati class changes during pregnancy, labour, and after delivery: can these be..., Boutonnet [/bib_ref] - Propensity to regurgitate gastric contents. System issues - Jurisdictions allowing unsupervised junior trainees to perform general anesthetics in parturients -poor judgement and inexperience are the commonest extrinsic factors contributing to airway disasters. [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] [bib_ref] A firm foundation for progress in airway management, Norris [/bib_ref] Use of a SGD with a second lumen to allow esophageal and gastric venting should be considered. Exit strategy -failed tracheal intubation in the oxygenated parturient WITH fetal or maternal emergency: If persistent fetal distress or a maternal emergency exists following failed tracheal intubation in the adequately oxygenated parturient, Cesarean delivery and/or maternal resuscitation can proceed with face mask or SGD ventilation. Cricoid pressure should be released for SGD insertion. Most Focus Group members agree that reapplying cricoid pressure is unlikely to be beneficial after placement of a SGD with an esophageal port. After failed tracheal intubation for Cesarean delivery under face mask or SGD ventilation in an emergency, the obstetrician should be requested to make a generous surgical incision and to minimize fundal pressure or use vacuum extraction at the time of delivery 209 (Strong recommendation for, level of evidence B). With uncomplicated and expeditious surgery, the procedure can be completed with face mask or SGD ventilation. If the case is complex, once the fetus has been delivered or the maternal emergency is stabilized, a cuffed tracheal tube can be placed under more controlled conditions (e.g., flexible bronchoscopic-aided intubation through a SGD), if required. If conditions permit, the surgery should be halted temporarily while the airway is secured, with optimized patient positioning and obstructing drapes moved aside.
A number of observational studies from outside North America have been published on using SGDs for elective Cesarean delivery in a select group of women. The subjects in these studies were of normal body mass index and wellfasted; they had anti-aspiration prophylaxis and underwent quick uncomplicated surgery. Although each study used a different version of the Laryngeal Mask Airway (LMA TM ), they were consistent in reporting a high rate of successful SGD placement and ventilation. [bib_ref] The laryngeal mask airway is effective (and probably safe) in selected healthy..., Han [/bib_ref] [bib_ref] The LMA Supreme in 700 parturients undergoing cesarean delivery: an observational study, Yao [/bib_ref] [bib_ref] The use of ProSeal laryngeal mask airway in caesarean section-experience in 3000..., Halaseh [/bib_ref] In North America, with general anesthesia reserved mainly for emergency cases and with parturients typically having a higher body mass index, SGDs cannot be recommended for elective Cesarean delivery at this time (Strong recommendation against, level of evidence B). Nevertheless, these and other studies 190 do support the early use of a SGD in any airway rescue scenario in the parturient (Strong recommendation for, level of evidence B).
Emergency strategy -failed intubation, oxygenation NOT possible with face mask or SGD ventilation: Following a failed attempt at tracheal intubation, the failure to oxygenate the parturient with face mask or SGD ventilation (failed oxygenation/CICO) will also quickly result in fetal compromise. As with the general surgical patient, the default response to this scenario is cricothyrotomy, with a parallel bridging attempt at oxygenation with a SGD if not already tried. Once the patient is re-oxygenated via SGD or cuffed cricothyrotomy cannula, Cesarean delivery or further resuscitation can occur if a fetal or maternal emergency exists; however, if the situation is now stable, optionally, the patient can be awakened and a plan can be made for definitive care. It must be emphasized that the failed oxygenation/CICO scenario implies a complete inability to oxygenate the patient. In this situation, the parturient will undergo rapid oxygen desaturation, indicating why further attempts at tracheal intubation are contraindicated and also why it would be impractical to allow the mother to wake.
Extubation and the postpartum period: Recent maternal mortality statistics from both the United States and United Kingdom indicate a shift in many airway catastrophes from induction of general anesthesia to the postpartum period, i.e., at emergence, in the postanesthesia unit, or when applied for postpartum surgical procedures. [bib_ref] Anesthesia-related maternal mortality in the United States: 1979-2002, Hawkins [/bib_ref] [bib_ref] Saving mothers' lives: reviewing maternal deaths to make motherhood safer: 2006-8: a..., Mcclure [/bib_ref] Heightened vigilance during these phases is clearly required.
## The pediatric airway: special considerations
Respiratory complications continue to be a major source of morbidity in children requiring airway management. [bib_ref] Anesthesia-related cardiac arrest in children: update from the Pediatric Perioperative Cardiac Arrest..., Bhananker [/bib_ref] [bib_ref] Perioperative anaesthetic morbidity in children: a database of 24,165 anaesthetics over a..., Murat [/bib_ref] Despite this, difficult DL is rare in an otherwise healthy child. In an audit of 11,219 pediatric general anesthetics in a tertiary care centre, the incidence of difficult DL (Cormack-Lehane grade 3 or 4 views) was 4.7% in children less than one year of age and 0.7% in children older than one year. [bib_ref] Incidence and predictors of difficult laryngoscopy in 11,219 pediatric anesthesia procedures, Heinrich [/bib_ref] In another audit of 24,165 anesthetics in a tertiary care pediatric centre, the frequency of unanticipated difficult tracheal intubations was 0.24% in children less than one year of age and 0.07% in children older than one year. [bib_ref] Perioperative anaesthetic morbidity in children: a database of 24,165 anaesthetics over a..., Murat [/bib_ref] These figures may reflect a higher than expected incidence compared with that encountered in community hospitals due to referral bias.
Unexpected difficult face mask ventilation is also rare in pediatrics. When difficult mask ventilation is encountered, causes such as laryngospasm or gastric distension must be considered. Clinicians should include the unexpected in their differential diagnosis, such as congenital airway anomalies or airway obstruction by foreign bodies. [bib_ref] Proposal for the management of the unexpected difficult pediatric airway, Weiss [/bib_ref] The pediatric airway is very susceptible to trauma when compared with the adult airway, and repeated attempts at intubation may result in more swelling and subsequent airway compromise. Rapid desaturation during apnea and a lack of patient cooperation are additional significant considerations.
Video laryngoscopy: Many case reports describe video laryngoscopy facilitating successful tracheal intubation in children with difficult airways. As with adults, the majority of current studies show that use of certain video laryngoscopes can facilitate an improved glottic view when compared with DL in pediatric patients with a reassuring airway exam. However, time to intubation is either unchanged or prolonged. [bib_ref] A comparison of the STORZ video laryngoscope and standard direct laryngoscopy for..., Vlatten [/bib_ref] [bib_ref] Pediatric airway management: comparing the Berci-Kaplan Video Laryngoscope with direct laryngoscopy, Macnair [/bib_ref] [bib_ref] GlideScope Ò video laryngoscope: a randomized clinical trial in 203 paediatric patients, Kim [/bib_ref] [bib_ref] A prospective randomized equivalence trial of the GlideScope Cobalt Ò video laryngoscope..., Fiadjoe [/bib_ref] In one pilot study in pediatric patients with known or anticipated difficult airways, use of the GlideScope Cobalt TM resulted in a significantly improved glottic view compared with DL in 17 of 18 patients, although tracheal intubation failed when using the device in three of the 18 patients. [bib_ref] A comparison between the GlideScope Video Laryngoscope and direct laryngoscope in paediatric..., Armstrong [/bib_ref] Despite the lack of published pediatric studies, video laryngoscopy has the potential to be useful in the pediatric difficult airway.
Cuffed vs uncuffed tracheal tubes in children: There is no direct evidence that use of a cuffed tracheal tube in children will cause more subglottic injury or iatrogenic stenosis than an uncuffed tube. [bib_ref] Prospective randomized controlled multi-centre trial of cuffed or uncuffed endotracheal tubes in..., Weiss [/bib_ref] [bib_ref] The use of cuffed versus uncuffed endotracheal tubes in pediatric intensive care, Newth [/bib_ref] Use of a cuffed tracheal tube will minimize need for re-intubation, [bib_ref] Prospective randomized controlled multi-centre trial of cuffed or uncuffed endotracheal tubes in..., Weiss [/bib_ref] decrease the potential for loss of effective ventilation, [bib_ref] Perioperative use of cuffed endotracheal tubes is advantageous in young pediatric burn..., Dorsey [/bib_ref] and may protect against micro-aspiration. [bib_ref] Assessment of the prevalence of microaspiration by gastric pepsin in the airway..., Gopalareddy [/bib_ref] As long as close attention is paid to maintaining an adequate air leak (i.e., occurring at\ 20-25 cm H 2 O) and/or monitoring cuff pressure, a recommendation can be made to use cuffed tracheal tubes for all difficult or emergency pediatric tracheal intubations (Strong recommendation for, level of evidence B).
SGDs in the difficult pediatric airway: Apart from case reports, little published evidence exists on the use of SGDs in the setting of difficult DL, difficult airway, or failed oxygenation/CICO situations in children. Case series support the use of SGDs, such as the LMA Classic TM and the air-Q Ò Intubating Laryngeal Airway, as conduits for intubation when difficult pediatric DL is encountered or anticipated. [bib_ref] The new air-Q intubating laryngeal airway for tracheal intubation in children with..., Jagannathan [/bib_ref] [bib_ref] The laryngeal mask airway in the difficult paediatric airway: an assessment of..., Walker [/bib_ref] [bib_ref] Management of difficult airways with a laryngeal mask airway under propofol anaesthesia, Bahk [/bib_ref] [bib_ref] Intubation via LMA in pediatric patients with difficult airways, Selim [/bib_ref] In most of these series, intubation was facilitated with flexible or semi-rigid endoscopy through the SGD. In a failed oxygenation/CICO situation, as with adult recommendations, an attempt should be made to oxygenate the pediatric patient with a SGD while equipment is being prepared for a surgical airway.
Transtracheal/surgical airway: Failed oxygenation/ CICO situations are rare in children. The best strategy for emergency transtracheal oxygenation in children under 8-10 years of age remains unclear. In this population, the cricothyroid space is underdeveloped, leaving needle tracheotomy or surgical tracheotomy below the cricoid ring as the only options for transtracheal access. Depending on the pathology (e.g. subglottic stenosis, tracheal foreign body), rigid bronchoscopy may be the intervention of choice. In children older than eight to ten years of age, the vertical span of the cricothyroid space enlarges sufficiently to accommodate several of the commercially available cricothyrotomy products, although some of these devices have been associated with tracheal damage in animal models. [bib_ref] Pediatric transtracheal and cricothyrotomy airway devices for emergency use: which are appropriate..., Cote [/bib_ref] [bib_ref] Emergency cricothyrotomy in infants-evaluation of a novel device in an animal model, Metterlein [/bib_ref] The few reports on emergency transtracheal airway access in children under age 18 vary greatly in circumstances, equipment used, and patient age. [bib_ref] Fourth National Audit Project. Major complications of airway management in the UK:..., Cook [/bib_ref] [bib_ref] Percutaneous transtracheal ventilation for anaesthesia and resuscitation: a review and report of..., Smith [/bib_ref] [bib_ref] Additional techniques for managing the difficult pediatric airway, Auden [/bib_ref] [bib_ref] The failed intubation attempt in the emergency department: analysis of prevalence, rescue..., Bair [/bib_ref] [bib_ref] Failed intubation and failed oxygenation in a child, Santoro [/bib_ref] Experience with transtracheal catheters placed for elective pediatric surgical procedures suggests that, despite controlled conditions, use of jet ventilation through such catheters is associated with a significant rate of complications, including barotrauma. [bib_ref] Transtracheal high frequency jet ventilation for endoscopic airway surgery: a multicentre study, Bourgain [/bib_ref] [bib_ref] Complications of different ventilation strategies in endoscopic laryngeal surgery: a 10-year review, Jaquet [/bib_ref] [bib_ref] Percutaneous transtracheal jet ventilation for paediatric endoscopic laser treatment of laryngeal and..., Depierraz [/bib_ref] [bib_ref] Percutaneous transtracheal emergency ventilation during respiratory arrest: comparison of the oxygen flow..., Yildiz [/bib_ref] and bench 239 modelling indicate that adequate oxygenation can be provided through transtracheal catheters without the use of jet ventilation.
In children younger than eight to ten years in a failed oxygenation/CICO situation, help should be summoned, and if not already attempted, a SGD should be placed while equipment is readied for surgical or needle tracheotomy (or rigid bronchoscopy, when indicated) (Strong recommendation for, level of evidence C). For the needle tracheotomy option, a kink-resistant 240 catheter specifically made for this purpose should be used. Oxygenation can be provided via an Enk Oxygen Flow Modulator TM (Cook Medical, Bloomington, IN) with a flow rate of 1 L per year of age [bib_ref] Experimental adaptation of the Enk oxygen flow modulator for potential pediatric use, Baker [/bib_ref] and an inspiratory-to-expiratory (I:E) ratio sufficient to allow expiration. As full expiration of tidal volume will not occur through the transtracheal catheter, continued attempts at airway-opening maneuvers and securing a definitive airway are essential.
## Documentation following an encounter with a difficult airway
Appropriate documentation should be completed following every airway intervention, difficult or otherwise. The record should make specific mention of ease of face mask or SGD ventilation, the device used to perform tracheal intubation, the view obtained, and the number of attempts (Strong recommendation for, level of evidence C).
If airway management is difficult once, it seems intuitive that subsequent attempts will also be difficult, although patient, operator, or equipment factors may differ significantly. There is some evidence that a previously designated difficult or failed DL or intubation does confer a higher likelihood of encountering similar circumstances on a subsequent occasion. [bib_ref] Preoperative airway assessment: predictive value of a multivariate risk index, El-Ganzouri [/bib_ref] [bib_ref] Preoperative assessment for difficult intubation in general and ENT surgery: predictive value..., Arne [/bib_ref] [bib_ref] A documented previous difficult tracheal intubation as a prognostic test for a..., Lundstrom [/bib_ref] However, pertinent high-level prospective outcome studies using precise definitions are currently lacking, and may never be published. Even so, experts agree that it seems likely that good documentation and dissemination of difficult airway information may reduce critical airway events. The CAFG advocates a multi-layered strategy appropriate to the local system when a difficult airway situation has been encountered. At a minimum, this should include clear and accurate documentation in the patient's medical record, personally informing the patient and the patient's surgeon, and providing a difficult airway letter to the patient with copies to both the chart and the primary care provider.
Electronic recording and alert systems are advances over traditional handwritten records. In-hospital alert bracelets and local or national databases (e.g., the MedicAlert Foundation) should also be considered. Such databases have the advantage of being widely accessible without restriction of space or jurisdiction.
While subjective, the trigger for invoking this multilayered strategy may include factors such as an inability to visualize the larynx, very difficult or impossible face mask ventilation, or opinion that future airway interventions would occur most safely with the patient awake.
Copies of a difficult airway alert letter (e.g., Appendix 1) should be stocked in locations where airway management regularly occurs. The content and structure of information contained in airway alerts should be clear and complete to maximize both patient safety and the potential for future database research.
The corollary of performing good documentation is the need for clinicians to augment the bedside airway assessment by seeking additional information from a hospital chart, letter, or database sources, when available, especially when significant difficulty is anticipated. Nevertheless, as highlighted by NAP4, anticipating difficulty is of no benefit unless the airway management strategy is modified accordingly.
## Education in difficult airway management
Management of the difficult airway requires technical and non-technical skills. [bib_ref] Assessment of clinical performance during simulated crises using both technical and behavioral..., Gaba [/bib_ref] Technical skills are defined as the specific medical knowledge and procedural ability required for managing the airway. Non-technical skills are generalizable skills required to manage dynamic highrisk/low-frequency crisis situations. These non-technical skills include leadership, teamwork, situational awareness, task management, and decision-making. [bib_ref] Anaesthetists' Non-Technical Skills (ANTS): evaluation of a behavioural marker system, Fletcher [/bib_ref] Dedicated experiential learning and deliberate practice is beneficial for airway management, but because difficult airways are low-frequency events, it is not appropriate to learn best management algorithms and techniques in the clinical setting. [bib_ref] Review article: simulation in anesthesia: state of the science and looking forward, Leblanc [/bib_ref] As an alternative, simulation provides a proven platform for the acquisition of airway-related technical skills without risk to patients. These skills transfer well to the clinical setting across different learner experience and various device and simulation modalities. [bib_ref] Learning fibreoptic intubation with a virtual computer program transfers to 'hands on'..., Boet [/bib_ref] [bib_ref] Teaching lifesaving procedures: the impact of model fidelity on acquisition and transfer..., Friedman [/bib_ref] [bib_ref] Fiberoptic orotracheal intubation on anesthetized patients: do manipulation skills learned on a..., Naik [/bib_ref] Unfortunately, learning patterns and curves of airway-related technical skills cannot be generalized, as they vary and depend on a clinician's cumulative experience in the simulated and live setting. [bib_ref] Learning curves for bag-andmask ventilation and orotracheal intubation: an application of the..., Komatsu [/bib_ref] [bib_ref] Learning endotracheal intubation in a clinical skills learning center: a quantitative study, Plummer [/bib_ref] [bib_ref] Learning curves of the Glidescope, the McGrath and the Airtraq laryngoscopes: a..., Savoldelli [/bib_ref] [bib_ref] What is the minimum training required for successful cricothyroidotomy?: a study in..., Wong [/bib_ref] There is no ''magic number'' for competence in using a particular device or for managing a specific situation. Nontechnical skills must also be learned and have been shown to improve with repeated simulation scenarios; [bib_ref] Nontechnical skills in anesthesia crisis management with repeated exposure to simulation-based education, Yee [/bib_ref] [bib_ref] The use of cognitive task analysis to improve the learning of percutaneous..., Sullivan [/bib_ref] [bib_ref] Evaluation of multidisciplinary simulation training on clinical performance and team behavior during..., Nishisaki [/bib_ref] however, further research is needed to show that the acquisition of nontechnical skills translates to improved patient outcomes in the clinical setting.
Most importantly, there is demonstrable evidence that both technical and non-technical skills in difficult airway management weaken with time. [bib_ref] High-fidelity simulation demonstrates the influence of anesthesiologists' age and years from residency..., Siu [/bib_ref] [bib_ref] Advanced airway management in the emergency department: what are the training and..., Graham [/bib_ref] The infrequency of these clinical events demands that proficiency be addressed through continuing education workshops that provide an opportunity for active experiential learning and formative assessment with feedback. Simulation has been used to improve difficult airway management skills in practicing physicians, with improvement being retained for as long as a year. [bib_ref] Complex procedural skills are retained for a minimum of 1 yr after..., Boet [/bib_ref] Educators are currently researching the maximum time interval before significant attrition of skills in order to guide continuing professional development revalidation guidelines.
## Summary of recommendations
## At least in the patient with indistinct external
landmarks in the neck, cricothyrotomy (by any technique) should begin with a 3-cm vertical midline incision over the presumed location of the cricothyroid membrane -Weak recommendation for, level of evidence C. 4. Even if not indicated as part of the initial management plan, once a patient is in a failed oxygenation/CICO situation, administering (or re-dosing) a neuromuscular blocking agent should be considered to address possible laryngospasm and facilitate face mask ventilation -Weak recommendation for, level of evidence C.
Obstetrics 1. After failed tracheal intubation during induction of GA for emergency Cesarean delivery, if proceeding under face mask or SGD ventilation, the obstetrician should be requested to make a generous surgical incision and to minimize fundal pressure or use vacuum extraction at the time of delivery -Strong recommendation for, level of evidence B. 2. Early use of a SGD should be considered in any airway rescue scenario in the parturient -Strong recommendation for, level of evidence B. 3. As with the general surgical patient, the default response to a failed oxygenation/CICO scenario in a parturient is cricothyrotomy, with a parallel bridging attempt at oxygenation with a SGD if not already tried -Strong recommendation for, level of evidence B. 4. Obstetrical units should have appropriately trained staff and good, easily accessible airway equipment of the same quality and type (e.g., video laryngoscopy) as that used in the main surgical ORs of the facility -Strong recommendation for, level of evidence C. 5. Once the need for general anesthesia becomes apparent, the attending anesthesiologist should perform a formal airway assessment of the obstetrical patient, including localization of the cricothyroid membrane -Strong recommendation for, level of evidence C. 6. For induction of general anesthesia in the parturient, appropriate patient positioning and pre-oxygenation should occur -Strong recommendation for, level of evidence C. 7. With induction of general anesthesia in the parturient, face mask ventilation with low insufflation pressures can occur after induction while awaiting onset of the full effect of a neuromuscular block -Strong recommendation for, level of evidence C.
## Pediatrics
1. Cuffed endotracheal tubes should be used in difficult or emergency pediatric tracheal intubation -Strong recommendation for, level of evidence B. 2. For children younger than 8-10 years in a failed oxygenation/CICO situation, help should be summoned, and if not already attempted, a SGD should be placed while equipment is readied for surgical or needle tracheotomy (or rigid bronchoscopy, when indicated) -Strong recommendation for, level of evidence C.
## Documentation
1. Appropriate documentation should be completed following every airway intervention, difficult or otherwise. The record should make specific mention of the ease of face mask or SGD ventilation, the device used to perform tracheal intubation, the view obtained, and the number of attempts -Strong recommendation for, level of evidence C.
J. Adam Law MD Focus group chair; data acquisition, analysis, and interpretation; writing and critically revising article.
Work supported by the Department of Anesthesia, Dalhousie University.
Co-director of and royalty recipient from Airway Interventions and Management in Emergencies (AIME) course.
## Recipient of equipment (as loan or gift) from ambu
[fig] Figure 2: Flow diagram: difficult tracheal intubation encountered after induction of general anesthesia in the parturient. SGD = supraglottic device The difficult airway with recommendations -Part I 1103 [/fig]
[table] Table 1: Approximate incidence of difficulty with various airway interventions -by hospital location [/table]
[table] Table 2: Effectiveness of a selection of alternatives to direct laryngoscopy in the difficult airway LMA Fastrach TM (LMA North America Inc., San Diego, CA) GlideScope Ò videolaryngoscope (Verathon Medical Canada ULC, Burnaby, BC) McGrath Ò Series 5 video laryngoscope (LMA North America Inc., San Diego, CA) Storz C-MAC Ò (with D-blade) (Karl Storz Endoscopy, El Segundo, CA) [/table]
[table] Table 3: Adverse effects associated with multiple attempts at tracheal intubation [/table]
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A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2013 Recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)a
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A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2013 Recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)a
The critical role of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician and the microbiologists who provide enormous value to the health care team. This document, developed by both laboratory and clinical experts, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. Sections are divided into anatomic systems, including Bloodstream Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. There is redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a reference to guide physicians in choosing tests that will aid them to diagnose infectious diseases in their patients.
# Introduction
Unlike other areas of the diagnostic laboratory, clinical microbiology is a science of interpretive judgment that is becoming more complex, not less. Even with the advent of laboratory automation and the integration of genomics and proteomics in microbiology, interpretation of results still depends on the quality of the specimens received for analysis. Prokaryotic microorganisms, while genetically less complex than multicellular eukaryotes, are uniquely suited to adapt to environments where antibiotics and host responses apply pressures that encourage their survival. A laboratory instrument may or may not detect those mutations, so a specialist in microbiology is needed to facilitate microbiology laboratory result interpretation. Clearly, all microbes grow, multiply, and die very quickly. If any of those events occur during specimen collection, transport, or storage, the results of analysis will be compromised and interpretation could be misleading. Therefore, attention to preanalytical specimen management in microbiology is critical to accuracy.
Physicians need confidence that the results provided by the microbiology laboratory are accurate, significant, and clinically relevant. Anything less is below the community standard of care. In order to provide that level of quality, however, the laboratory requires that all microbiology specimens be properly selected, collected, and transported to optimize analysis and interpretation. Because result interpretation in microbiology depends entirely on the quality of the specimen submitted for analysis, specimen management cannot be left to chance, and those that collect specimens for microbiologic analysis must be aware of what the physician needs as well as what the laboratory needs, including ensuring that specimens arrive at the laboratory for analysis as quickly as possible after collection (Introduction- .
At an elementary level, the physician needs answers to 3 very basic questions from the laboratory: Is my patient's illness caused by a microbe? If so, what is it? What is the susceptibility profile of the organism so therapy can be targeted? To meet those needs, the laboratory requires very different information. The microbiology laboratory needs a specimen that has been appropriately selected, collected, and transported to the laboratory for analysis. Caught in the middle, between the physician and laboratory, are those who select and collect the specimen and who may not know or understand what the physician or the laboratory needs to do their work. Enhancing the quality of the specimen is everyone's job, so communication between the physicians, nurses, and laboratory staff should be encouraged and open with no punitive motive or consequences.
The diagnosis of infectious disease is best achieved by applying in-depth knowledge of both medical and laboratory science along with principles of epidemiology and pharmacokinetics of antibiotics and by integrating a strategic view of host-parasite interactions. Clearly, the best outcomes for patients are the result of strong partnerships between the clinician and the laboratorian specialist. This document illustrates this partnership and emphasizes the importance of appropriate specimen management to clinical relevance of the results. One of the most valuable laboratory partners in infectious disease diagnosis is the certified microbiology specialist, particularly a specialist certified as a Diplomate by the American Board of Medical Microbiology (ABMM), the American Board of Pathology (ABP), or the American Board of Medical Laboratory Immunology (ABMLI) or their equivalent certified by other organizations. Clinicians should recommend and medical institutions should provide this kind of leadership for the microbiology laboratory or provide formal access to this level of laboratory expertise through consultation.
## Impact of specimen management
Microbiology specimen selection and collection are the responsibility of the medical staff, not usually the laboratory, although the certified specialist may be called upon for consultation or assistance. The impact of proper specimen management on patient care is enormous. It is the key to accurate laboratory diagnosis and confirmation, it directly affects patient care and patient outcomes, it influences therapeutic decisions, it impacts hospital infection control, it impacts patient length of stay, hospital costs, and laboratory costs, and influences laboratory efficiency. Clinicians should consult the laboratory to ensure that selection, collection, transport, and storage of patient specimens are performed properly.
## Tenets of specimen management
Throughout the text, there will be caveats that are relevant to specific specimens and diagnostic protocols for infectious disease diagnosis. However, there are some strategic tenets of specimen management and testing in microbiology that stand as community standards of care and that set microbiology apart from other laboratory departments such as chemistry or hematology. Ten points of importance are:
1. Specimens of poor quality must be rejected. Microbiologists act correctly and responsibly when they call physicians to clarify and resolve problems with specimen submissions.
2. Physicians should not demand that the laboratory report "everything that grows," thus providing irrelevant information that could result in inaccurate diagnosis and inappropriate therapy.
3. "Background noise" must be avoided where possible. Many body sites have normal microbiota that can easily contaminate the specimen. Therefore, specimens from sites such as lower respiratory tract (sputum), nasal sinuses, superficial wounds, fistulae, and others require care in collection. [bib_ref] Utility of extended blood culture incubation for isolation of Haemophilus, Actinobacillus, Cardiobacterium,..., Petti [/bib_ref]. The laboratory requires a specimen, not a swab of a specimen. Actual tissue, aspirates, and fluids are always specimens of choice, especially from surgery. A swab is not the specimen of choice for many specimens because swabs pick up extraneous microbes, hold extremely small volumes of the specimen (0.05 mL), make it difficult to get bacteria or fungi away from the swab fibers and onto media, and the inoculum from the swab is often not uniform across several different agar plates. Swabs are expected from nasopharyngeal and viral respiratory infections. Flocked swabs have become a valuable tool for specimen collection and have been shown to be more effective than Dacron, rayon, and cotton swabs in many situations. The flocked nature of the swab allows for more efficient release of contents for evaluation. [bib_ref] Optimal testing parameters for blood cultures, Cockerill Fr 3rd [/bib_ref]. The laboratory must follow its procedure manual or face legal challenges. These manuals are usually supported by the literature. [bib_ref] Role of volume of blood cultured in detection of disseminated infection with..., Reller [/bib_ref]. A specimen should be collected prior to administration of antibiotics. Once antibiotics have been started, the flora changes, leading to potentially misleading culture results. [bib_ref] Detection of bloodstream infections in adults: how many blood cultures are needed?, Lee [/bib_ref]. Susceptibility testing should be performed on clinically significant isolates, not on all microorganisms recovered in culture. [bib_ref] Guidelines for the management of intravascular catheter-related infections, Mermel [/bib_ref]. Microbiology laboratory results that are reported should be accurate, significant, and clinically relevant. [bib_ref] Laboratory diagnosis of catheter-related bacteremia, Pfaller [/bib_ref]. The laboratory should be allowed to set technical policy; this is not the purview of the medical staff. Good communication and mutual respect will lead to collaborative policies. [bib_ref] A semiquantitative culture method for identifying intravenous-catheter-related infection, Maki [/bib_ref]. Specimens must be labeled accurately and completely so that interpretation of results will be reliable. Labels such as "eye" and "wound" are not helpful to the interpretation of results without more specific site and clinical information (eg, dog bite wound right forefinger).
The microbiology laboratory policy manual should be available at all times for all medical staff to review or consult and it would be particularly helpful to encourage the nursing staff to review the specimen collection and management portion of the manual. This can facilitate collaboration between the laboratory, with the microbiology expertise, and the specimen collection personnel, who may know very little about microbiology or what the laboratory needs in order to establish or confirm a diagnosis.
Welcome and engage the microbiology laboratory as an integral part of the healthcare team and encourage the hospital or the laboratory facility to have board-certified laboratory specialists on hand or available to optimize infectious disease laboratory diagnosis.
## How to use this document
The full text of this document, available online, is organized by body system, although many organisms are capable of causing disease in more than one body system. There may be a redundant mention of some organisms because of their propensity to infect multiple sites. One of the unique features of this document is its ability to assist clinicians who have specific suspicions regarding possible etiologic agents causing a specific type of disease. Another unique feature is that in most sections, there are targeted recommendations and precautions regarding selecting and collecting specimens for analysis for a disease process. Within each section, there is a table describing the specimen needs regarding a variety of etiologic agents that one may suspect as causing the illness. The test methods in the tables are listed in priority order according to the recommendations of the authors and reviewers.
When room temperature (RT) is specified for a certain time period, such as 2 hours, it is expected that the sample should be refrigerated after that time unless specified otherwise in that section. Almost all specimens for virus detection should be transported on wet ice and frozen at −80°C if testing is delayed >48 hours, although specimens in viral transport media may be transported at room temperature when rapid (<2 hours) delivery to the laboratory is assured.
## History and update
The document has been endorsed by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). Future modifications are to be expected, as diagnostic microbiology is a dynamic and rapidly changing discipline.
## I. bloodstream infections and infections of the cardiovascular system
## A. bloodstream infections and infective endocarditis
The diagnosis of bloodstream infections (BSIs) is one of the most critical functions of clinical microbiology laboratories. For the great majority of etiologic agents of BSIs, conventional blood culture methods provide results within 48 hours; incubation for more than 5 days seldom is required when modern automated continuous-monitoring blood culture systems and media are used. This includes recovery of historically fastidious organisms such as HACEK(Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella) bacteria and Brucella spp [bib_ref] Prolonged incubation and extensive subculturing do not increase recovery of clinically significant..., Baron [/bib_ref] [bib_ref] Utility of extended blood culture incubation for isolation of Haemophilus, Actinobacillus, Cardiobacterium,..., Petti [/bib_ref]. Some microorganisms, such as mycobacteria and dimorphic fungi, require longer incubation periods; others may require special culture media or non-culture-based methods. Although filamentious fungi often require special broth media or lysis-centrifugation vials for detection, Candida spp tend to grow very well in standard blood culture broths unless the patient has been on antifungal therapy. Unfortunately, blood cultures from patients with suspected candidemia do not yield positive results in almost half of patients. [fig_ref] Table I - 1: [/fig_ref] -1 below provides a summary of diagnostic methods for most BSIs.
For most etiologic agents of infective endocarditis, conventional blood culture methods will suffice [bib_ref] Prolonged incubation and extensive subculturing do not increase recovery of clinically significant..., Baron [/bib_ref] [bib_ref] Utility of extended blood culture incubation for isolation of Haemophilus, Actinobacillus, Cardiobacterium,..., Petti [/bib_ref] [bib_ref] Optimal testing parameters for blood cultures, Cockerill Fr 3rd [/bib_ref]. However, some less common etiologic agents cannot be detected with current blood culture methods. The most common etiologic agents of culture-negative endocarditis, Bartonella spp and Coxiella burnetii, often can be detected by conventional serologic testing. However, molecular amplification methods may be needed for detection of these organisms as well as others (eg, Tropheryma whipplei). In rare instances of culture-negative endocarditis, 16S polymerase chain reaction (PCR) and DNA sequencing of valve tissue may help determine an etiologic agent.
The volume of blood that is obtained for each blood culture request (also known as a blood culture set, consisting of all bottles procured from a single venipuncture or during one catheter draw) is the most important variable in recovering bacteria and fungi from patients with bloodstream infections [bib_ref] Optimal testing parameters for blood cultures, Cockerill Fr 3rd [/bib_ref] [bib_ref] Role of volume of blood cultured in detection of disseminated infection with..., Reller [/bib_ref]. For adults, 20-30 mL of blood per culture set (depending on the manufacturer of the instrument) is recommended and may require more than 2 bottles depending on the system. For children, an age-and weight-appropriate volume of blood should be cultured (see [fig_ref] Table I - 1: [/fig_ref] -1a for recommended volumes). A second important determinant is the number of blood culture sets performed during a given septic episode. Generally, in adults with a suspicion of BSI, 2-4 blood culture sets should be obtained in the evaluation of each septic episode [bib_ref] Optimal testing parameters for blood cultures, Cockerill Fr 3rd [/bib_ref] [bib_ref] Detection of bloodstream infections in adults: how many blood cultures are needed?, Lee [/bib_ref].
The timing of blood culture orders should be dictated by patient acuity. In urgent situations, 2 or more blood culture sets can be obtained sequentially over a short time interval, after which empiric therapy can be initiated. In less urgent situations, obtaining blood culture sets may be spaced over several hours or more.
Contaminated blood culture bottles are common, very costly to the healthcare system, and frequently confusing to clinicians. To minimize the risk of contamination of the blood culture with commensal skin flora, meticulous care should be taken in skin preparation prior to venipuncture. Consensus guidelinesand expert panelsrecommend peripheral venipuncture as the preferred technique for obtaining blood for culture based on data showing that blood obtained in this fashion is less likely to be contaminated than blood obtained from an intravascular catheter or other device. Several studies have documented that iodine tincture, chlorine peroxide, and chlorhexidine gluconate (CHG) are superior to povidone-iodine preparations as skin disinfectants for blood culture (data summarized in refsand. Iodine tincture and CHG require about 30 seconds to exert an antiseptic effect compared with 1.5-2 minutes. for povidoneiodine preparations. CHG is not recommended for use in infants less than 2 months of age. 20-30 mL of blood per culture in adults injected into at least 2 blood culture bottles g Inoculated culture vials should be transported ASAP at RT to the laboratory for early incubation Infants and children: 2 or more blood culture sets (see above)
As much blood as can be conveniently obtained from children; volume depends on weight of child (see [fig_ref] Table I - 1: [/fig_ref] Organisms will usually survive in inoculated culture vials even if not incubated immediately. Malassezia spp require lipid supplementation; lysis-centrifugation is recommended for their recovery. Filamentous and dimorphic fungi h 2 or more lysis-centrifugation (Isolator) blood culture vials 10 mL of blood should be inoculated directly into each lysiscentrifugation culture vial
Lysis-centrifugation culture vials should be transported to the laboratory ASAP and processed within 8 h of blood inoculation Mycobacteria 3 cultures using AFB-specific blood culture bottles 5 mL of blood inoculated directly into AFB-specific blood culture bottle Inoculated culture vials should be transported to the laboratory ASAP for early incubation Abbreviations: AFB, acid fast bacillus; IFA, indirect fluorescent antibody; NAAT, nucleic acid amplification test; RT, room temperature. a Typically, blood specimens are split between aerobic and anaerobic blood culture bottles. There may be circumstances in which it is prudent to omit the anaerobic vial and split blood specimens between 2 aerobic vials. One example is when fungemia due to yeast is strongly suspected. Most manufacturers' bottles accept a maximum of 10 mL per bottle. b Recommended volumes of blood for culture in pediatric patients [fig_ref] Table I - 1: [/fig_ref].
Blood cultures contaminated with skin flora during collection are common, but contamination rates should not exceed 3%. Laboratories should have policies and procedures for abbreviating the work-up and reporting of common blood culture contaminants (eg, coagulase-negative staphylococci, viridans group streptococci, diphtheroids, Bacillus species other than B. anthracis). These procedures may include abbreviated identification of the organism, absence of susceptibility testing, and a comment that instructs the clinician to contact the laboratory if the culture result is thought to be clinically significant and requires additional work-up and susceptibility results.
Physicians should expect to be called and notified by the laboratory every time a blood culture becomes positive because these specimens often represent life-threatening infections. If the physician wishes not to be notified during specific times, arrangements must be made by the physician for a delegated healthcare professional to receive the call and relay the report.
Key points for the laboratory diagnosis of bacteremia/fungemia:
- Volume of blood collected, not timing, is most critical.
- Disinfect the venipuncture site with chlorhexidine or 2% iodine tincture in adults and children >2 months old (chlorhexidine NOT recommended for children <2 months old).
- Draw blood for culture before initiating antimicrobial therapy.
- Catheter-drawn blood cultures have a higher risk of contamination (false positives).
- Do not submit catheter tips for culture without an accompanying blood culture obtained by venipuncture.
- Never refrigerate blood prior to incubation.
- Use a 2-3 bottle blood culture set for adults, at least one aerobic and one anaerobic; use 1-2 aerobic bottles for children.
- Streptococcus pneumoniae and some other gram-positive organisms may grow best in the anaerobic bottle.
## B. infections associated with vascular catheters
The diagnosis of catheter-associated BSIs often is one of exclusion, and a microbiologic gold standard for diagnosis does not exist. Although a number of different microbiologic methods have been described, the available data do not allow firm conclusions to be made about the relative merits of these various diagnostic techniques [bib_ref] Guidelines for the management of intravascular catheter-related infections, Mermel [/bib_ref] [bib_ref] Laboratory diagnosis of catheter-related bacteremia, Pfaller [/bib_ref]. Fundamental to the diagnosis of catheter-associated BSI is documentation of bacteremia. The clinical significance of a positive culture from an indwelling catheter segment or tip in the absence of positive blood cultures is unknown. The next essential diagnostic component is demonstrating that the infection is caused by the catheter. This usually requires exclusion of other potential primary foci for the BSI.
Numerous diagnostic techniques for catheter cultures have been described and may provide adjunctive evidence of catheter-associated BSI; however, all have potential pitfalls that make interpretation of results problematic. Routine culture of intravenous (IV) catheter tips at the time of catheter removal has no clinical value and should not be done [bib_ref] A semiquantitative culture method for identifying intravenous-catheter-related infection, Maki [/bib_ref]. Although not performed in most laboratories, the methods described include the following:
- Time to positivity (not performed routinely in most laboratories): Standard blood cultures (BCs) obtained at the same time, one from the catheter or port and one from peripheral venipuncture, processed in a continuous-monitoring blood culture system. If both BCs grow the same organism and the BC drawn from the device becomes positive more than 2 hours before the BC drawn by venipuncture, there is a high probability of catheter-associated BSI [bib_ref] Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections, Raad [/bib_ref].
- Quantitative BCs (not performed routinely in most laboratories): one from catheter or port and one from peripheral venipuncture obtained at the same time using lysis-centrifugation (Isolator) or pour plate method. If both BCs grow the same organism and the BC drawn from the device has 5-fold more When 10 mL of blood or less is collected, it should be inoculated into a single aerobic blood culture bottle.
organisms than the BC drawn by venipuncture, there is a high probability of catheter-associated BSI [bib_ref] Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection, Safdar [/bib_ref].
- Catheter tip or segment cultures: The semiquantitative method of Maki et al [bib_ref] A semiquantitative culture method for identifying intravenous-catheter-related infection, Maki [/bib_ref] is used most commonly; interpretation requires an accompanying peripheral blood culture. However, meticulous technique is needed to reduce contamination and to obtain the correct length (5 cm) of the distal catheter tip. This method only detects organisms colonizing the outside of the catheter, which is rolled onto an agar plate after which the number of colonies is counted; organisms that may be intraluminal are missed. Modifications of the Maki method have been described as have methods that utilize vortexing of the catheter tip or an endoluminal brush (not performed routinely in most laboratories). Biofilm formation on catheter tips prevents antimicrobial therapy from clearing agents within the biofilm, thus requiring removal of the catheter to eliminate the organisms.
## C. infected (mycotic) aneurysms and vascular grafts
Infected (mycotic) aneurysms and infections of vascular grafts may result in positive blood cultures. Definitive diagnosis requires microscopic visualization and/or culture recovery of etiologic agents from representative biopsy or graft material [fig_ref] Table I - 1: [/fig_ref].
## D. pericarditis and myocarditis
Numerous viruses, bacteria, rickettsiae, fungi, and parasites have been implicated as etiologic agents of pericarditis and myocarditis. In many patients with pericarditis and in the overwhelming majority of patients with myocarditis, an etiologic diagnosis is never made and patients are treated empirically. In selected instances when it is important clinically to define the specific cause of infection, a microbiologic diagnosis should be pursued aggressively. Unfortunately, however, the available diagnostic resources are quite limited, and there are no firm diagnostic guidelines that can be given. Some of the more common and clinically important pathogens are listed in [fig_ref] Table I - 1: [/fig_ref] below. When a microbiologic diagnosis of less common etiologic agents is required, especially when specialized techniques or methods are necessary, consultation with the laboratory director should be undertaken. There is considerable overlap between pericarditis and myocarditis with respect to both etiologic agents and disease manifestations.
## Ii. central nervous system (cns) infections
Clinical microbiology tests of value in establishing an etiologic diagnosis of infections within the central nervous system are outlined below. In this section, infections are categorized as follows: meningitis, encephalitis, focal infections of brain parenchyma, central nervous system shunt infections, subdural empyema, epidural abscess, and suppurative intracranial thrombophlebitis.
Organisms usually enter the central nervous system by crossing a mucosal barrier into the bloodstream followed by penetration of the blood-brain barrier. Other routes of infection include direct extension from a contiguous structure, movement along nerves, or introduction by foreign devices.
Usually 3 or 4 tubes of cerebrospinal fluid (CSF) are collected by lumbar puncture for diagnostic studies. The first tube has the highest potential for contamination with skin flora and should not be sent to the microbiology laboratory for direct smears, culture, or molecular studies. A minimum of 0.5-1 mL of CSF should be sent to the microbiology laboratory in a sterile container for bacterial testing. Larger volumes (5-10 mL) increase the sensitivity of culture and are required for optimal recovery of mycobacteria and fungi. When the specimen volume is less than required for multiple test requests, prioritization of testing must be provided to the laboratory. Whenever possible, specimens for culture should be obtained prior to initiation of antimicrobial therapy.
CSF Gram stains should be prepared after cytocentrifugation and positive results reported immediately to the caregiver. Identification and susceptibility testing of bacteria recovered from cultures is routinely performed unless contamination during collection or processing is suspected. Abbreviations: KOH, potassium hydroxide; RT, room temperature. a Tissue specimens or a portion of the graft material are always superior to swab specimens of infected sites, even when collected using sterile technique during surgery. b If aerobic bacteria are suspected. If anaerobes are suspected, then the culture should consist of an aerobic and anaerobic bacterial culture. c Calcofluor stain is a fluorescent stain and requires special microscopy equipment and may not be available at all facilities.
Most clinical microbiology laboratories do not perform all of the testing listed in the tables. This is especially true of serologic and many molecular diagnostic tests. NAATs for most agents are not commercially available, so only laboratory-developed tests can be used, with variable sensitivities and specificities. Serologic diagnosis is based on CSF to serum antibody index, 4fold rise in acute to convalescent immunoglobulin G (IgG) titer, or a single positive immunoglobulin M (IgM). Detection of antibody in CSF may indicate CNS infection, blood contamination, or transfer of antibodies across the blood-brain barrier. Submission of acute (3-10 days after onset of symptoms) and convalescent (2-3 weeks after acute) serum samples is recommended. Serum should be separated from red cells as soon as possible.
Key points for the laboratory diagnosis of central nervous system infections:
- Whenever possible, collect specimens prior to initiating antimicrobial therapy.
- Two to four blood cultures should also be obtained if bacterial meningitis is suspected.
- Inform the Microbiology Laboratory if unusual organisms are possible (such as Nocardia, fungi, mycobacteria, etc.), for which special procedures are necessary.
- Do not refrigerate cerebrospinal fluid.
- Attempt to collect as much sample as possible for multiple studies (minimum recommended is 1 mL); prioritize multiple test requests on small volume samples.
## A. meningitis
The most common etiologic agents of acute meningitis are enteroviruses ( primarily echoviruses and coxsackieviruses) and bacteria (Streptococcus pneumoniae and Neisseria meningitidis; [fig_ref] Table I - 1: [/fig_ref]. Patient age and other factors (ie, immune status, post neurosurgery, trauma) are associated with specific bacterial pathogens. Molecular testing has replaced viral culture for the diagnosis of enteroviral meningitis, but is not routinely available for the detection of bacteria in CSF. The sensitivity of the Gram stain for the diagnosis of bacterial meningitis is 60%-80% in patients who have not received antimicrobial therapy and 40%-60% in patients who have received treatment [bib_ref] Approach to diagnosis of meningitis. Cerebrospinal fluid evaluation, Greenlee [/bib_ref]. Bacterial antigen testing on CSF is not recommended but may have some value in patients who received therapy prior to specimen collection with negative Gram stain and negative culture results [bib_ref] Practice guidelines for the management of bacterial meningitis, Tunkel [/bib_ref]. In patients suspected of having bacterial meningitis, at least 2-4 blood cultures should be performed, but therapy should not be delayed.
Organisms expected to cause chronic meningitis (symptoms ≥4 weeks) include Mycobacterium tuberculosis, fungi, and spirochetes [fig_ref] Table I - 1: [/fig_ref]. Because the sensitivity of nucleic acid amplification tests (NAAT) for M. tuberculosis in nonrespiratory specimens may be poor, culture should also be requested [bib_ref] A systematic review of rapid diagnostic tests for the detection of tuberculosis..., Dinnes [/bib_ref]. The reported sensitivity of culture for diagnosing tuberculous meningitis is 25%-70% [bib_ref] Tuberculosis of the central nervous system, Garg [/bib_ref]. The highest yields for acid fast bacillus (AFB) smear and AFB culture occur when large volumes (≥5 mL) of CSF are used to perform the testing. The cryptococcal antigen test has replaced the India ink stain for rapid diagnosis of meningitis caused by C. neoformans or C. gattii and should be readily available in most laboratories. This test is most sensitive when performed on CSF rather than serum. The sensitivity and specificity of cryptococcal antigen tests are >90%, but false negative and false positive results may occur, for example, in patients with HIV/AIDS. Complement fixation test performed on CSF is recommended for the diagnosis of coccidioidal meningitis since direct fungal smear and culture are often negative. Detection of Coccidioides antibody in CSF by immunodiffusion has lower specificity than complement fixation.
## B. encephalitis
Encephalitis is an infection of the brain parenchyma causing abnormal cerebral function (altered mental status, behavior or speech disturbances, sensory or motor deficits). Despite advancements in molecular technology for the diagnosis of CNS infections, the etiologic agent of encephalitis often cannot be identified. The California Encephalitis Project identified a definite or probable etiologic agent for only 16% of 1570 immunocompetent patients enrolled from 1998 to 2005 (69% viral, 20% bacterial, 7% prion, 3% parasitic, 1% fungal); a possible cause was identified for an additional 13% of patients [bib_ref] Beyond viruses: clinical profiles and etiologies associated with encephalitis, Glaser [/bib_ref]. Immune status, travel, and other exposure history (insects, animals, water, sexual) should guide testing. IDSA practice guidelines provide a detailed listing of risk factors associated with specific etiologic agents [bib_ref] The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society..., Tunkel [/bib_ref].
Although the diagnosis of a specific viral cause is usually based on testing performed on CSF, testing of specimens collected from other sites may be helpful. The virus most commonly identified as causing encephalitis is herpes simplex virus (HSV) with 90% HSV-1. The sensitivity and specificity of NAAT for HSV encephalitis are >95%; HSV is cultured from CSF in <5% of cases [bib_ref] Molecular methods for diagnosis of viral encephalitis, Debiasi [/bib_ref] [bib_ref] Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain..., Weil [/bib_ref]. The sensitivity of NAAT performed on CSF for enterovirus encephalitis is >95% and the sensitivity of culture is 65%-75% (recovery from throat or stool is circumstantial etiologic evidence) [bib_ref] Molecular methods for diagnosis of viral encephalitis, Debiasi [/bib_ref]. Because the performance characteristics of molecular testing for other causes of viral encephalitis are not well established, serology and repeat molecular testing may be required [fig_ref] Table I - 1: [/fig_ref].
## C. focal infections of brain parenchyma
Focal parenchymal brain infections start as cerebritis, then progress to necrosis surrounded by a fibrous capsule. There are 2 broad categories of pathogenesis: (1) contiguous spread (otitis media, sinusitis, mastoiditis, and dental infection), trauma, neurosurgical complication or (2) hematogenous spread from a distant site of infection (skin, pulmonary, pelvic, intraabdominal, esophageal, endocarditis). A brain abscess in an immunocompetent host is usually caused by bacteria [fig_ref] Table I - 1: [/fig_ref]. A wider array of organisms is encountered in immunocompromised individuals.
## D. central nervous system shunt infections
Shunts are placed to divert cerebrospinal fluid for the treatment of hydrocephalus. The proximal portion is placed in a cerebral ventricle, intracranial cyst, or the subarachnoid space (lumbar region). The distal portion may be internalized (peritoneal, vascular, or pleural space) or externalized. In total, 5%-15% of shunts become infected [fig_ref] Table I - 1: [/fig_ref]. Potential routes of shunt infection include contamination at time of placement, contamination from the distal portion (retrograde), breakdown of the skin over the shunt, and hematogenous seeding. Blood cultures should also be collected if the shunt terminates in a vascular space (ventriculoatrial shunt). Most CNS shunt infections are caused by bacteria. Fungi are more likely to cause shunt infections in immunocompromised patients and those receiving total parenteral nutrition, steroids, or broad-spectrum antibiotics.
## E. subdural empyema, epidural abscess, and suppurative intracranial thrombophlebitis
Cranial subdural empyema and cranial epidural abscess are neurosurgical emergencies that are usually caused by bacteria (streptococci, staphylococci, aerobic gram-negative bacilli, The pathogenesis of spinal epidural abscess includes hematogenous spread (skin, urinary tract, mouth, mastoid, lung infection), direct extension (vertebral osteomyelitis, discitis), trauma, or post-procedural complication (surgery, biopsy, lumbar puncture, anesthesia). Spinal epidural abscess is usually caused by staphylococci, streptococci, aerobic gram-negative bacilli, and anaerobes. Nocardia spp, mycobacteria, and fungi may also cause spinal epidural abscess. Spinal subdural empyema is similar to spinal epidural abscess in clinical presentation and causative organisms.
Magnetic resonance imaging (MRI) is the optimal diagnostic procedure for suppurative intracranial thrombophlebitis. The etiologic agent may be recovered from cerebrospinal fluid and blood cultures. Causative organisms are similar to cranial epidural abscess and cranial subdural empyema. Empiric antimicrobial therapy is usually based on the predisposing clinical condition.
## Iii. ocular infections
The spectrum of ocular infections can range from superficial, which may be treated symptomatically or with empiric topical antimicrobial therapy, to those sight-threatening infections that require aggressive surgical intervention and either topical and/or parenteral antimicrobial therapy. Infections may occur in the anatomical structures surrounding the eye (conjunctivitis, blepharitis, canniculitis, dacryocystitis, orbital and periorbital cellulitis), on the surface of the eye (keratitis), or within the globe of the eye (endophthalmitis and uveitis/retinitis). Recommendations for the laboratory diagnosis of ocular infections are often based on studies where only small numbers of clinical specimens were examined so the evidence base for many recommendations is limited. Studies comparing multiple diagnostic approaches to determine the optimal means for detection of the infectious etiology of keratitis and endophthalmitis are further hampered by small specimen size. Finally, frequent pretreatment with topical antibacterial agents further complicates laboratory diagnosis of both bacterial conjunctivitis and keratitis. Key points for the laboratory diagnosis of ocular infections:
- Specimens should be labeled with the specific anatomic source, ie conjunctiva or cornea, but not just "eye."
- The Gram stain is useful in the diagnosis of conjunctivitis so two swabs per site may be appropriate; a paired specimen from the uninfected eye can be used as a "control" to assist in culture or Gram stain interpretation.
- Swab specimens are routinely used but provide a minimum amount of material. Consult the laboratory regarding suspicious agents. Corneal scrapings are preferred for keratitis diagnosis.
- Normal skin flora are usually not involved in conjunctivitis.
## Specimen collection, processing, and transport
Because ocular infections may involve one or both eyes and etiologies may differ, clinicians must clearly mark specimens as to which eye has been sampled, especially in those patients who have bilateral disease. Collection of specimens from anatomical structures surrounding the eye is typically performed using swabs [fig_ref] Table I - 1: [/fig_ref]. The most commonly collected specimens are from the conjunctiva. Cultures for aerobic bacteria and detection of Chlamydia and viruses either by culture or nucleic acid amplification testing (NAAT) are most commonly performed. Because direct microscopic examination may be useful in preliminary diagnosis of conjunctivitis, obtaining dual swabs, one for culture and one for smear preparation, is recommended. Smears may be made for Gram stain, calcofluor stain for fungi and Acanthamoeba, or direct fluorescent antibody (DFA) for Chlamydia trachomatis. Appropriate transport media should be provided by the laboratory and available at the collection site for specimens submitted for Chlamydia and/or viral culture or NAAT. Specimens for viral cultures should be submitted on ice, especially if specimen transport is prolonged. Specimens obtained from either the surface or the globe of the eye are almost always collected by ophthalmologists. Specimen types include swabs of ulcers, corneal scrapings, biopsies, or anterior chamber or vitreous aspirates. The volume of specimens is always limited. This specimen limitation makes it necessary for the laboratory to prioritize procedures depending on what organisms are sought, and this should always be done after discussion with the ophthalmologist who collects the specimen and the infectious disease consultant when appropriate. This is particularly important because all major pathogen groups-viruses, parasites, bacteria, mycobacteria, and fungican cause ocular infection. Both epidemiology and clinical presentation are used to narrow the organism(s) sought and the laboratory tests requested. Because of the limited specimen size seen with scrapings and biopsies, the laboratory and ophthalmologist may agree to inoculate these specimens onto media and prepare smears at the bedside. In this case, the laboratory should supply the necessary media and slides to the ophthalmologist. If these supplies are stored in the clinic or operating suite for ready access by the surgeon, it is the laboratory's responsibility to assure that these materials are not outdated. Aspirates from the anterior chamber or vitreous are the optimal specimens for detection of anaerobic bacteria and viral agents; they can be submitted in syringes with needles removed. Syringes should be placed in a leakproof outer container for transport. Injection of the fluid into a small sterile vial ( provided by the laboratory) is preferable. The same principles for specimen collection and transport described for conjunctival specimens apply to these specimens as well.
## A. orbital and periorbital cellulitis
Orbital cellulitis is almost always a complication of sinusitis, and the organisms associated with it include Streptococcus pneumoniae, nontypeable Haemophilus influenzae, Streptococcus pyogenes, Moraxella spp, anaerobic bacteria, Aspergillus spp, and the zygomycetes. Periorbital cellulitis usually arises as a result either of localized trauma or bacteremia most often caused by Staphylococcus aureus, S. pyogenes, or S. pneumonia [bib_ref] Periorbital versus orbital cellulitis, Givner [/bib_ref]. Diagnosis of these infections is either based on positive blood cultures or in the case of orbital cellulitis, culture of drainage material aspirated from the subperiosteal region of the sinuses.
## B. infection of the eyelids and lacrimal system
Blepharitis, canaliculitis, and dacryocystitis are all superficial infections that are generally self-limited. The organisms associated with these infections are predominantly gram-positive bacteria although various gram-negative bacteria, anaerobes, and fungi all have been recovered. A limitation of many studies of these infections is that microbiologic data on control populations are frequently lacking. The organisms commonly recovered are part of the indigenous skin microflora such as coagulase negative staphylococci and diphtheroids, so attributing a pathogenic role to these organisms in these conditions is difficult. Cultures from these sites are rarely submitted for diagnostic work-up. If cultures for canaliculitis are considered, concretions recovered during canalicular compression or canaliculotomy are recommended. Strategies for the diagnosis of these superficial infections should be similar to those for conjunctivitis.
## C. conjunctivitis
Most cases of conjunctivitis are caused by bacteria or viruses that are typically associated with upper respiratory tract infections [bib_ref] A randomised controlled trial of management strategies for acute infective conjunctivitis in..., Everitt [/bib_ref] [bib_ref] Etiology of acute conjunctivitis in children, Gigliotti [/bib_ref]. Because of the distinctive clinical presentation of both bacterial and viral conjunctivitis coupled with the selflimited nature of these infections, determining its etiology is infrequently attempted [bib_ref] The red eye, Leibowitz [/bib_ref]. When tests are requested, diagnosis of bacterial conjunctivitis is often compromised by the prior use of empiric antibacterial therapy [bib_ref] A randomised controlled trial of management strategies for acute infective conjunctivitis in..., Everitt [/bib_ref] [bib_ref] Etiology of acute conjunctivitis in children, Gigliotti [/bib_ref]. Sexually active patients who present with bacterial conjunctivitis should have an aggressive diagnostic work-up with Gram stain and cultures because of their risk for Neisseria gonorrhoeae conjunctivitis. This is a sight-threatening infection that can result in perforation of the globe. In the developing world, trachoma, a form of conjunctivitis due to specific strains of Chlamydia trachomatis, is a leading cause of blindness, especially in children. Offlabel use of commercial NAAT assays is used for detection of this agent in research settings [bib_ref] Quality assessment of conjunctival specimens for detection of Chlamydia trachomatis by PCR..., De Barbeyrac [/bib_ref]. Certain organisms that are part of the indigenous skin and mucous membrane microflora such as coagulase negative staphylococci, Corynebacterium spp, and viridans streptococci are generally considered nonpathogenic when recovered from the conjunctival mucosa and are considered to be "normal flora." In specimens taken from the surface or interior of the eye, these organisms along with Propionibacterium acnes are considered pathogens, especially in patient post-cataract or LASIK surgery. Adenovirus, the etiologic agent of "pink eye," is highly transmissible in a variety of settings. This is almost always a clinical diagnosis although Abbreviations: NAAT, nucleic acid amplification test; RT, room temperature a NAATs for detection of C. trachomatis have not yet been approved in the United States for use with conjunctival swab specimens. Individual laboratories, however, may have validated NAATs for examination of specimens obtained from patients with conjunctivitis and studies suggest that NAATs are more sensitive than cultures. b Use of NAAT for detection of C. trachomatisis is considered an "off label" use of this test. Laboratories that offer such testing must conduct in house validation of these assays before offering NAAT as a diagnostic test. c Culturing of specimens thought to harbor Herpes B virus (primate origin) requires use of biosafety level 4 precautions in the laboratory and testing is almost always referred to a specialized reference laboratory. Consult the laboratory when Herpes B virus is suspected. for epidemiologic purposes culture or NAAT can be done. Most cases of neonatal conjunctivitis are due to either Neisseria gonorrhoeae, Chlamydia trachomatis, or herpes simplex virus. Commercial NAATs for both N. gonorrhoeae and C. trachomatis are not FDA approved for this specimen type, so culture or in the case of C. trachomatis, direct fluorescent antibody testing, if available, can be used.
## D. keratitis
Corneal infections usually occur in 3 distinct patient populations: those with ocular trauma by foreign objects, those with postsurgical complications of corneal surgery, and in patients who practice poor hygiene associated with their extended wear contact lenses [bib_ref] Infectious keratitis, Thomas [/bib_ref]. Corneal infections can also result from reactivation of herpes viruses including herpes simplex virus and varicella zoster virus [bib_ref] The eye in systemic infection, Lynn [/bib_ref]. Post-vaccination keratitis is a well-recognized complication of vaccinia vaccination and should be considered in the appropriate clinical setting [bib_ref] Ocular complications of smallpox vaccination, Pepose [/bib_ref]. It is important to note that the use of dyes and topical anesthetics may inhibit NAAT reactions used to diagnose keratitis. The eye surface should be thoroughly rinsed with nonbacteriostatic saline before specimens for NAATs are obtained [bib_ref] Effects of topical anaesthetics and fluorescein on the real-time PCR used for..., Goldschmidt [/bib_ref] [bib_ref] Rose bengal and lissamine green inhibit detection of herpes simplex virus by..., Seitzman [/bib_ref] [fig_ref] Table I - 1: [/fig_ref].
The most common corneal infections occur in patients who improperly use their contact lens system. Because these patients are usually treated with antimicrobial agents prior to obtaining specimens for bacterial cultures, some ophthalmologists favor culturing contact lens solution and cases. However, culture of such solutions and cases is not recommended because of the frequency with which they are falsely positive [bib_ref] Bacterial biofilm on contact lenses and lens storage cases in wearers with..., Mclaughlin-Borlace [/bib_ref]. Pseudomonas aeruginosa is the most common cause of sporadic contact lens associated keratitis but outbreaks of keratitis due to contamination of contact lens care solutions have been recently reported with both Fusarium and Acanthamoeba [bib_ref] Bacterial biofilm on contact lenses and lens storage cases in wearers with..., Mclaughlin-Borlace [/bib_ref] [bib_ref] Multistate outbreak of Fusarium keratitis associated with use of a contact lens..., Chang [/bib_ref]. Post-surgical keratitis infections are frequently due to either coagulase-negative staphylococci and P. acnes, so in this setting these organisms should not be considered contaminants but as potential pathogens.
Keratitis following trauma due to foreign objects is frequently caused by organisms found in the environment. Included in this group are environmental gram-negative rods such as P. aeruginosa, Nocardia spp, moulds including dematiceous fungi, and environmental mycobacteria.
## E. endophthalmitis
Endophthalmitis can arise either by exogenous introduction of pathogens into the eye following trauma or surgery, or as a result of endogenous introduction of pathogens across the blood-eye barrier. Depending on the mode of pathogenesis, the spectrum of causative agents will vary [fig_ref] Table I - 1: [/fig_ref]. Specimens for diagnosis of endophthalmitis can be obtained by aspiration of aqueous or vitreous fluid or via biopsy [bib_ref] Diagnostic testing of vitrectomy specimens, Davis [/bib_ref]. Specimen amounts are small, so discretion must be exercised in determining for which agents the specimen should be examined. Post-operative endophthalmitis is most often caused by gram-positive organisms with coagulase-negative staphylococci predominating; chronic post-operative endophthalmitis can be due to P. acnes, so this organism should not be dismissed as a contaminant [bib_ref] Postoperative endophthalmitis, Hanscom [/bib_ref] [bib_ref] Endophthalmitis: a review of current evaluation and management, Lemley [/bib_ref]. Environmental organisms such as dematiaceous fungi, Fusarium spp, Bacillus cereus, Nocardia spp, Mycobacterium chelonae, and glucose fermenting gram-negative rods are more commonly encountered in patients with exogenous endophthalmitis [bib_ref] Endophthalmitis: a review of current evaluation and management, Lemley [/bib_ref] [bib_ref] Post-traumatic endophthalmitis, Essex [/bib_ref]. Endogenous endophthalmitis, because of its association with bacteremia and fungemia, is usually caused by those organisms most responsible for bloodstream infections (eg Candida albicans and related species, Aspergillus spp, S. aureus, S. pneumoniae, the Enterobacteriaceae, especially Klebsiella pneumoniae, and Pseudomonas aeruginosa) [bib_ref] Endophthalmitis: a review of current evaluation and management, Lemley [/bib_ref] [bib_ref] Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported..., Jackson [/bib_ref] [bib_ref] Endogenous endophthalmitis: microorganisms, disposition and prognosis, Ness [/bib_ref]. Viruses and parasites are rarely found to cause endophthalmitis, however, as in cases of trauma or severe immunosuppression, infection due to agents such as the herpes viruses, Toxoplasma gondii, Toxocara spp, Echinococcus spp, and Onchocerca volvulus do occur [bib_ref] Bacterial biofilm on contact lenses and lens storage cases in wearers with..., Mclaughlin-Borlace [/bib_ref] [bib_ref] Ocular toxoplasmosis: clinical features and prognosis of 154 patients, Bosch-Driessen [/bib_ref] and typically involve the uvea and retina. For further information on the diagnosis of ocular infections caused by Onchocerca volvulus, see Section XV-C.
## F. uveitis/retinitis
The inflammation characteristic of uveitis/retinitis is typically due to either autoimmune conditions or is idiopathic [bib_ref] Referral patterns of uveitis in a tertiary eye care center, Rodriguez [/bib_ref]. Only infrequently is it due to infection that is almost always caused by endogenous microbes accessing the eye via a breach in the blood-eye barrier. Because uveitis and retinitis, like endogenous endophthalmitis, are localized manifestations of systemic infections, diagnosis of the etiology of systemic infections should be coupled with a careful ocular examination performed preferably by an ophthalmologist with specific infectious disease expertise. Important causes of uveitis/retinitis include Toxoplasma gondii, cytomegalovirus, HSV, VZV, Mycobacterium tuberculosis, and Treponema pallidum [bib_ref] Ocular toxoplasmosis: clinical features and prognosis of 154 patients, Bosch-Driessen [/bib_ref] [bib_ref] Syphilis: reemergence of an old adversary, Chao [/bib_ref] [bib_ref] High prevalence of fastidious bacteria in 1520 cases of uveitis of unknown..., Drancourt [/bib_ref] [bib_ref] HIV-associated retinopathy in the HAART era, Goldberg [/bib_ref].
T. gondii is the most common infectious cause of retinitis. Diagnosis is typically made on clinical grounds supported by serology. In the industrialized world, the presence of T. gondii IgG lacks specificity for the diagnosis of ocular toxoplasmosis; therefore, serology is only valuable in the setting of acute infection or when the patient has an ocular examination pathognomonic for toxoplasmosis, demonstrating retinochoroiditis in a majority of cases. The comparison of intraocular antibody levels in aqueous humor to that in serum has been found to be a useful means for diagnosing ocular toxoplasmosis but because the specimen needed for testing can only be obtained by a highly invasive procedure, it is unlikely that this technique will be used outside the research setting [bib_ref] Comparison of enzyme-linked immunosorbent assay, immunoblotting, and PCR for diagnosis of toxoplasmic..., Villard [/bib_ref]. NAAT of blood, vitreous or aqueous fluids, is not as sensitive as intraocular antibody determinations, but the specimens for testing may be b Culture plates, including a sheep blood agar plate and a chocolate agar plate, should be inoculated directly with material collected on the Kimura spatula directly at the patient's bedside at the time corneal scrapings are obtained,usually applied to the agar surface as a number of small "C" shaped inocula. If sufficient sample is available, a smear on a glass slide may also be prepared at the patient's bedside after the plates are inoculated. The inoculated plates and slide (if prepared) are then transported directly to the microbiology laboratory. c The laboratory should be notified when Nocardia spp is suspected so that culture plates may be incubated for longer periods than normal, thus enhancing the chance of recovering this slow growing organism. Additional media, such as buffered charcoal yeast extract, can enhance recovery of Nocardia. d Acid fast smears and mycobacterial cultures should be performed in all post-operative infections of the cornea. Mycobacterium chelonei is a common finding in such cases. e At least 1 culture plate or slant containing a nonselective fungal growth medium should be inoculated directly at the patient's bedside at the time corneal scrapings are obtained. If sufficient sample is available, a smear on a glass slide may also be prepared at the patient's bedside. This should be attempted only after plates/slants have been inoculated. The inoculated plates/slants and slide (if prepared) are then transported directly to the microbiology laboratory. The smear is stained with Calcofluor-KOH in the laboratory and examined for fungal elements. f A corneal swab specimen is used to inoculate an agar plate containing nonnutritive medium at the patient's bedside and then transported immediately to the laboratory. In the laboratory, the plate is overlaid with a lawn of viable E. coli or some other member of the Enterobacteriaceae (ie, cocultivation) prior to incubation. Alternatively, plates seeded with the bacteria are inoculated with a bit of corneal scraping material or a drop of a suspension of the scraped sample in sterile saline. Other Candida spp Abbreviations: AFB, acid fast bacillus; KOH, potassium hydroxide; RT, room temperature. a Among the long list of bacterial causes of endophthalmitis, Streptococcus agalactiae; Listeria monocytogenes and Neisseria meningitidis occur almost exclusively as a result of endogenous seeding of the eye. The other bacteria listed may cause endophthalmitis either secondary to trauma or surgery or following hematogenous seeding. b Culture plates, including a sheep blood agar plate and a chocolate agar plate, should be inoculated directly at the patient's bedside at the time corneal scrapings are obtained (see footnote for . If sufficient sample is available, a smear on a glass slide may also be prepared at the patient's bedside after plates are inoculated. The inoculated plates and slide (if prepared) are then transported directly to the microbiology laboratory. c The laboratory should be notified when Nocardia spp is suspected so that special media can be used and routine culture plates will be incubated for up to 7 days. d The most common Mycobacterium spp recovered from intraocular infections is M. chelonae and this occurs almost exclusively as a complication of surgical procedures. e Acid fast smears and mycobacterial cultures should be performed in all post-surgical infections of the eye. A 7H-11 agar or a Lowenstein-Jensen agar slant should be inoculated at the patient's bedside. If sufficient clinical sample remains, a smear should be prepared. Both the slant and the smear (if prepared) should be transported directly to the laboratory for further processing. If after inoculating a slant and preparing a smear at the bedside, there is still unused specimen remaining, it should be transported in a sterile container immediately to the laboratory at room temperature for inoculation into broth media and subsequent instrument-based processing. f Among the fungi listed, Candida albicans, C. glabrata, and other Candida spp cause endogenous endophthalmitis as a result of hematogenous seeding of the eye. The other fungi listed typically cause infection following traumatic inoculation of the eye. g At least one culture plate or slant containing a nonselective fungal growth medium should be inoculated directly at the patient's bedside at the time corneal scrapings are obtained. If sufficient sample is available, a smear on a glass slide may also be prepared at the patient's bedside after plates/slants have been inoculated. The inoculated plates/slants and slide (if prepared) are then transported directly to the microbiology laboratory. The smear is stained with Calcofluor-KOH in the laboratory and examined for fungal elements. more easily obtained. Sensitivities of NAATs ranging from 50% to 80% have been reported in patients with T. gondii retinitis depending on the sequence used and the specimen tested. It should be noted that the total numbers of specimens tested in these studies are small, so the diagnostic value of NAAT in T. gondii retinitis is not yet clear [bib_ref] Value of PCR for detection of Toxoplasma gondii in aqueous humor and..., Bou [/bib_ref] [bib_ref] Infectious uveitis in immunocompromised patients and the diagnostic value of polymerase chain..., Westeneng [/bib_ref].
Since the advent of highly active antiretroviral treatment (HAART), cytomegalovirus (CMV) retinitis has become much less frequent. Nevertheless, cases do occur in HIV patients who have either failed HIV therapy or as an AIDS-presenting diagnosis [bib_ref] HIV-associated retinopathy in the HAART era, Goldberg [/bib_ref]. In addition, CMV retinitis has been a well-recognized complication of bone marrow and solid organ transplantation, less frequent recently due to improvements in preemptive detection and therapy. CMV retinitis is frequently diagnosed clinically because of characteristic lesions seen on ophthalmologic examination. Quantitative CMV NAAT performed on peripheral blood is also a useful tool in the diagnosis and management of this infection. Patients with detectable CMV viral loads have a higher likelihood of retinal disease progression, and those with high CMV viral loads have increased mortality. Patients with undetectable CMV viral loads have a low likelihood of having virus that is resistant to antiviral agents [bib_ref] Cytomegalovirus (CMV) blood DNA load, CMV retinitis progression, and occurrence of resistant..., Jabs [/bib_ref]. Because of inter-laboratory variation in viral quantification, what represents a positive CMV viral load and a high CMV viral load will vary among laboratories [bib_ref] International consensus guidelines on the management of cytomegalovirus in solid organ transplantation, Kotton [/bib_ref]. Physicians should consult the laboratory performing the CMV viral load for assistance with test interpretation. As with CMV viral loads, persistent CMV antigenemia also predicts a higher likelihood of retinal disease progression and death [bib_ref] HIV and cytomegalovirus viral load and clinical outcomes in AIDS and cytomegalovirus..., Jabs [/bib_ref].
Patients with syphilitic uveitis frequently have central nervous system findings either associated with acute syphilitic meningitis or neurosyphilis. VDRL testing of cerebrospinal fluid is recommended in clinical settings where syphilitic uveitis is suspected [bib_ref] Syphilis: reemergence of an old adversary, Chao [/bib_ref] (see section II-A).
## Iv. soft tissue infections of the head and neck
Infection of various spaces and tissues that occur in the head and neck can be divided into those arising from odontogenic, oropharyngeal, or exogenous sources. Odontogenic infections are usually caused by endogenous periodontal or gingival flora. These infections include peritonsillar and pharyngeal abscesses, deep space abscesses, such as those of the retropharyngeal, parapharyngeal, submandibular, and sublingual spaces, and cervical lymphadenitis [bib_ref] Microbiology and management of peritonsillar, retropharyngeal, and parapharyngeal abscesses, Brook [/bib_ref] [bib_ref] Life-threatening infections of the peripharyngeal and deep fascial spaces of the head..., Reynolds [/bib_ref]. Complications of odontogenic infection can occur by hematogenous spread or by direct extension resulting in septic jugular vein thrombophlebitis (Lemierre syndrome), bacterial endocarditis, intracranial abscess, or acute mediastinitis [bib_ref] Oral infections and systemic disease-an emerging problem in medicine, Rautemaa [/bib_ref] [bib_ref] Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre's syndrome, Riordan [/bib_ref]. Accurate etiologic diagnosis depends on collection of an aspirate or biopsy of inflammatory material from affected tissues and tissue spaces while avoiding contamination with mucosal flora. The specimen should be placed into an anaerobic transport container to support the recovery of anaerobic bacteria (both aerobic and facultative bacteria survive in anaerobic transport). Requests for Gram-stained smears are standard for all anaerobic cultures because they allow the laboratorian to evaluate the adequacy of the specimen by identifying inflammatory cells, provide an early, presumptive etiologic diagnosis, and possibly identify mixed aerobic and anaerobic infections [bib_ref] The rapid laboratory diagnosis of anaerobic infection, Phillips [/bib_ref]. Additionally, spirochetes (often involved in odontogenic infection) cannot be recovered in routine anaerobic cultures but will be seen on the smear.
Infections caused by oropharyngeal flora include epiglottitis, mastoiditis, inflammation of salivary tissue, and suppurative parotitis [bib_ref] Atypical presentations of actinomycosis, Belmont [/bib_ref]. Because the epiglottis may swell dramatically during epiglottitis, there is a chance of sudden occlusion of the trachea if the epiglottis is disturbed, such as by an attempt to collect a swab specimen. Blood cultures are the preferred sample for the diagnosis of epiglottitis; if swabbing is attempted, it should be in a setting with available appropriate emergency response. Oropharyngeal flora also can extend into tissues of the middle ear, mastoid and nasal sinuses causing acute infection [bib_ref] Clinical experiences with acute mastoiditis-1988 through 1998, Lee [/bib_ref]. In addition, mycobacteria, staphylococci, and gram-negative bacilli occasionally are implicated. Aspirated material, saline lavage of a closed space, and tissue or tissue scrapings are preferred specimens and must be transported in a sterile container. Tissues should be transported under sterile conditions so that the specimen remains moist. Because anaerobic bacteria are infrequent pathogens in these infections, anaerobic transport is not needed routinely. Note that fungi are common causes of chronic sinusitis, and they may not be recovered on swabs, even those obtained endoscopically. Endoscopic sinus aspirates are the specimens of choice. For microbiology analysis, it is always best to submit the actual specimen, not a swab of the specimen.
Infections caused by exogenous pathogens (not part of the oral flora) include malignant otitis externa, mastoiditis, animal bites and trauma, irradiation burns, and complications of surgical procedures [bib_ref] Clinical experiences with acute mastoiditis-1988 through 1998, Lee [/bib_ref] [bib_ref] The changing face of malignant (necrotising) external otitis: clinical, radiological, and anatomic..., Grandis [/bib_ref]. Although oral flora may play an occasional etiologic role, gram-negative bacilli and staphylococci are most frequently associated with these conditions. Key points for the laboratory diagnosis of head and neck soft tissue infections:
- A swab is not the specimen of choice for these specimens. Submit tissue, fluid, or aspirate when possible.
- Resist swabbing in cases of epiglottitis.
- Use anaerobic transport containers if anaerobes are suspected.
- Keep tissue specimens moist during transport. The following tables include the most common soft tissue and tissue space infections of the head and neck that originate from odontogenic, oropharyngeal and exogenous sources. The optimum approach to establishing an etiologic diagnosis of each condition is provided.
A. Infections of the Oral Cavity, and Adjacent Spaces and Tissues Caused by Odontogenic and Oropharyngeal Flora (
## V. upper respiratory tract bacterial and fungal infections
Infections in the upper respiratory tract usually involve the ears, the mucus membranes lining the nose and throat above the epiglottis, and the sinuses. Most infections involving the c Note that nucleic acid tests are not usually available locally and must be sent to a reference laboratory with the resulting longer turnaround time.
d The laboratory should be alerted if Bartonella cultures will be requested so that appropriate media are available at the time the specimen arrives in the laboratory; even then, the yield of Bartonella culture is very low. When available, Bartonella nucleic acid testing is more sensitive. A portion of the specimen should be sent to the histopathology laboratory for H&E and Warthin-Starry stains.
nose and throat are caused by viruses (see XIV Viral Syndromes section for testing information). Inappropriate utilization of antibiotics for viral infections is a major driver of increasing antibiotic resistance. Proper diagnosis of infectious syndromes in this environment must involve laboratory tests to determine the etiology and thus inform the proper therapy.
Key points for the laboratory diagnosis of upper respiratory tract infections:
- Swabs are not recommended for otitis media or sinusitis. Submit an aspirate for culture.
- Most cases of otitis media can be diagnosed clinically and treated without culture support.
- Throat specimens require a firm, thorough sampling of the throat and tonsils, avoiding cheeks, gums, and teeth.
- Haemophilus influenzae, Staphylococcus aureus, Neisseria meningitidis, and Streptococcus pneumoniae are not etiologic agents of pharyngitis and should not be sought in throat cultures; nor can nasopharyngeal cultures accurately predict the etiologic agent of sinusitis.
## A. otitis media
Otitis media is the single most frequent condition causing pediatric patients to be taken to a healthcare provider. Acute otitis media with effusion (AOME) is the clinical variant of otitis media most likely to have a bacterial etiology and as a result, most likely to benefit from antimicrobial therapy [fig_ref] Table V - 1: [/fig_ref]. Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis are the most common bacterial causes of AOME, with S. aureus, Streptococcus pyogenes, and Pseudomonas aeruginosa occurring less commonly. Alloiococcus otitidis is also thought to cause AOME, but additional studies are needed to determine the true significance of this organism. A variety of respiratory viruses are known to cause AOME; however, there exists no pathogen specific therapy and as a result, there is little reason to attempt to establish an etiologic diagnosis in patients with a viral etiology. Efforts to determine the cause of AOME are best reserved for patients likely to have a bacterial etiology (recent onset, bulging tympanic membrane, pain, or exudate) who have not responded to prior courses of antimicrobial therapy, patients with immunological deficiencies, and acutely ill patients [bib_ref] Staphylococcus, Micrococcus, and other catalase-positive cocci, Bannerman [/bib_ref]. The only representative specimen is middle ear fluid obtained either by tympanocentesis or, in patients with otorrhoea or myringotomy tubes, by collecting drainage on minitipped swabs directly after cleaning the ear canal. Cultures of the pharynx, nasopharynx, anterior nares, or of nasal drainage material are of no value in attempting to establish an etiologic diagnosis of bacterial AOME.
Viruses are often the etiologic agent, but microbiologic studies do not help with treatment decisions.
## B. sinusitis
The etiological agents of sinusitis vary based upon the duration of symptoms and whether it is community-acquired or of nosocomial origin [fig_ref] Table V - 1: [/fig_ref]. Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis are the most common bacterial causes of acute maxillary sinusitis. The role of respiratory viruses in sinusitis needs further studies. Staphylococcus aureus, gram-negative bacilli, Streptococcus spp, and anaerobic bacteria are associated more frequently with subacute, chronic, or nosocomial sinusitis. The role of fungi as etiological agents is more controversial, possibly due to numerous publications that used poor sample collection methods and thus did not recover the fungal agents. In immunocompetent hosts, fungi are associated most often with chronic sinusitis. Sinusitis due to fungal infections in severely immunocompromised persons or uncontrolled diabetic patients is often severe and carries a high mortality rate. Attempts to establish an etiologic diagnosis of sinusitis are typically reserved for patients with complicated infections or chronic disease. Swabs are not recommended for collecting sinus specimens because an aspirate is much more productive of the true etiologic agent(s). Endoscopically obtained swabs can recover bacterial pathogens but rarely detect the causative fungi [bib_ref] Use of nebulized antibiotics for acute infections in chronic sinusitis, Vaughan [/bib_ref] [bib_ref] Acute community-acquired bacterial sinusitis: continuing challenges and current management, Sande [/bib_ref] [bib_ref] Biopsy and specimen collection in chronic rhinosinusitis, Orlandi [/bib_ref]. In maxillary sinusitis, antral puncture with sinus aspiration and, in adults, swabs of material draining from the middle meatus obtained under endoscopic guidance represent the only adequate specimens. Cultures of middle meatus drainage specimens are not recommended for pediatric patients due to potential colonization with respiratory tract pathogens. Examination of nasal drainage material is of no value in attempting to determine the cause of maxillary sinusitis. Surgical procedures are necessary to obtain specimens representative of infection of the frontal, sphenoid, or ethmoid sinuses. To establish a fungal etiology, an endoscopic sinus aspirate is recommended [bib_ref] Biopsy and specimen collection in chronic rhinosinusitis, Orlandi [/bib_ref].
## C. pharyngitis
Pharyngitis accounts for an estimated 40 million visits by adults to medical facilities annually in the United States. The condition occurs even more often in children. Differences between the epidemiology of various infectious agents related to the age of the patient, the season of the year, accompanying signs and symptoms, and the presence or absence of systemic disease are not sufficiently precise to permit establishing a definitive etiologic diagnosis on clinical and epidemiologic grounds alone [bib_ref] Role of the microbiology laboratory in diagnosis and management of pharyngitis, Bourbeau [/bib_ref]. Consequently, the results of laboratory tests play a central role in guiding therapeutic decisions [fig_ref] Table V - 1: [/fig_ref]. Antimicrobial therapy is only warranted in patients with pharyngitis with a proven bacterial etiology [bib_ref] Principles of appropriate antibiotic use for acute pharyngitis in adults: background, Cooper [/bib_ref].
Streptococcus pyogenes (Group A β-hemolytic Streptococcus) is the most common bacterial cause of pharyngitis and carries with it potentially serious sequelae, primarily in children, if left undiagnosed or inadequately treated. Several laboratory tests, including culture, rapid antigen tests, and molecular methods, have been used to establish an etiologic diagnosis of pharyngitis due to this organism [bib_ref] Role of the microbiology laboratory in diagnosis and management of pharyngitis, Bourbeau [/bib_ref]. During the past decade, rapid antigen tests for S. pyogenes, in particular, have been used extensively in the evaluation of patients with pharyngitis. Such tests are technically nondemanding, generally reliable and often performed at the point-of-care. For any of these methods, accuracy and clinical relevance depends on appropriate sampling technique.
There has been a general consensus among the professional societies that negative rapid antigen tests for S. pyogenes in children should be confirmed by culture or molecular assay. Although this is generally not necessary for negative test results in adults, new guidelines suggest that either conventional culture or confirmation of negative rapid antigen test results by culture should be used to achieve maximal sensitivity for diagnosis of S. pyogenes pharyngitis in adults [bib_ref] Clinical practice guideline for the diagnosis and management of group A streptococcal..., Shulman [/bib_ref]. Laboratories accredited by the College of American Pathologists are required to back up negative rapid antigen tests with culture.
The role of non-Group A β-hemolytic streptococci, in particular, Groups C and G, as causes of pharyngitis is controversial. However, many healthcare providers consider these organisms to be of significance and base therapeutic decisions on their detection. Rare cases of post-streptococcal glomerulonephritis after infection with these species have been reported. Therefore, we have included guidance for detecting Groups C and G βhemolytic streptococci (large colony producers, since S. anginosus group, characteristically yielding pinpoint colonies, does not cause pharyngitis) in pharyngeal swab specimens but indicate that this should be done only in settings in which these organisms are considered to be of significance, such as outbreaks of epidemiologically associated cases of pharyngitis. Recovery of the same organism from multiple patients during an outbreak should be investigated. Arcanobacterium haemolyticum also causes pharyngitis but less commonly. It occurs most often in teenagers and young adults and is often found to cause a highly suggestive scarlatina-form rash in some patients. Neisseria gonorrhoeae and Corynebacterium diphtheriae, in very specific epidemiologic settings, may also cause pharyngitis. Respiratory viruses are the most common cause of pharyngitis in both adult and pediatric populations; however, it is unnecessary to define a specific etiology in patients with pharyngitis due to respiratory viruses because there exists no pathogen-directed therapy for these agents. Herpes simplex virus (HSV), human immunodeficiency virus (HIV), and Epstein-Barr virus (EBV) may also cause pharyngitis. Because of the epidemiologic and clinical implications of infection due to HSV, HIV, and EBV, circumstances may arise in which it is important to attempt to determine if an individual patient's infection is caused by one of these 3 agents.
Recent studies have shown a relationship between Fusobacterium necrophorum and pharyngitis in some patients. In this case, throat infection could be a prelude to Lemierre syndrome. F. necrophorum is an anaerobic organism and as such, will require additional media and the use of anaerobic isolation and identification procedures, which most laboratories are not prepared to use with throat specimens. Notify the laboratory of the suspected diagnosis and the etiologic agent so appropriate procedures can be available. In the absence of anaerobic capability of the laboratory, this would be sent out to a reference laboratory [bib_ref] Real-time PCR investigation into the importance of Fusobacterium necrophorum as a cause..., Aliyu [/bib_ref] [bib_ref] A six-month audit of the isolation of Fusobacterium necrophorum from patients with..., Amess [/bib_ref] [bib_ref] Human infections with Fusobacterium necrophorum, Brazier [/bib_ref] [bib_ref] Lemierre's syndrome: a systematic review, Karkos [/bib_ref] [bib_ref] Prevalence of Fusobacterium necrophorum in persistent sore throat samples, Price [/bib_ref].
## Vi. lower respiratory tract infections
Respiratory tract infections are among the most common infectious diseases. The list of causative agents continues to expand as new pathogens and syndromes are recognized. This section describes the major etiologic agents and the microbiologic approaches to the diagnosis of bronchitis and bronchiolitis; community-acquired pneumonia; healthcare-associated and There are numerous commercially available direct antigen tests. These vary in terms of sensitivity and ease of use; the specific test employed will dictate the swab transport system used. In pediatric patients, if the direct antigen test is negative, and if the direct antigen test is known to have a sensitivity of <80%, a second throat swab should be examined by a more sensitive direct NAAT or by culture as a means of arbitrating possible false negative direct antigen test results [bib_ref] Principles of appropriate antibiotic use for acute pharyngitis in adults: background, Cooper [/bib_ref]. This secondary testing is usually unnecessary in adults [bib_ref] Clinical practice guideline for the diagnosis and management of group A streptococcal..., Shulman [/bib_ref]. A convenient means of facilitating this two-step algorithm of testing for Streptococcus pyogenes in pediatric patients is to collect a dual swab initially, recognizing that the second swab will be discarded if the direct antigen test is positive. b Direct NAATs for Streptococcus pyogenes are more sensitive than direct antigen tests and, as a result, negative direct NAAT results do not have to be arbitrated by a secondary test. The swab transport device should be compatible with the NAAT used. Nucleic acid probe tests are usually performed on enriched broth cultures, thus requiring longer turnaround times. c Detection of Groups C and G β-hemolytic streptococci is accomplished by throat culture in those patients in whom there exists a concern for an etiologic role for these organisms. Only large colony types are identified, as tiny colonies demonstrating groups C and G antigens are in the S. anginosus ("S. milleri") group. Check with the laboratory to determine if these are routinely looked for. d Arcanobacterium haemolyticum, Neisseria gonorrhoeae and Corynebacterium diphtheriae only cause pharyngitis in restricted epidemiologic settings. The laboratory will not routinely attempt to recover these organisms from throat swab specimens. If a clinical suspicion exists for one of these pathogens, the laboratory should be notified so that appropriate measures can be applied to aid in their detection. e If the Monospot test is positive, it may be considered diagnostic for EBV infection. Up to 10% of Monospot tests are, however, falsely negative. False negative Monospot tests are encountered most often in younger children. In a patient with a strong clinical suspicion for EBV infection and a negative Monospot test, a definitive diagnosis can be achieved with EBV-specific serologic testing. Such testing can be performed on the same sample that yielded a negative Monospot test. Alternatively, the Monospot test can be repeated on a serum specimen obtained 7-10 days later at which time, if the patient had EBV infection, the Monospot is more likely to be positive. f Probable cause of pharyngitis only in immumocompromised patients. Numerous rapid tests based on detecting HSV-specific antigen (by DFA) directly in clinical material have been developed; however the nonspecific stain Tzanck test is very insensitive and not recommended. A swab should be used to aggressively collect material from the base of multiple pharyngeal lesions and then placed in a swab transport device that is compatible with the test to be performed. Culture may be useful in immunocompromised patients. g The serologic test should distinguish between IgG and IgM. Depending on the age of the patient and the specific serologic assay used, in the face of a compatible illness, a single HSV-specific IgG level may be considered presumptive evidence of HSV infection. The presence of HSV-specific IgM may be considered diagnostic. c While approved for use with certain commercial products, throat specimens, especially swabs, are the least desirable and provide the poorest recovery.
d Rapid antigen tests for respiratory virus detection lack sensitivity and, depending upon the product, specificity. They should be considered as screening tests only. At a minimum a negative result should be verified by another method. Specimen quality is critical to optimize these tests. e Several FDA cleared NAAT platforms are currently available and vary in their approved specimen requirements and range of analytes detected. Readers should check with their laboratory regarding availability and performance characteristics including certain limitations. f Sensitivity in nonbacteremic patients with pneumococcal pneumonia is 52%-78%; sensitivity in bacteremic cases of pneumococcal pneumonia is 80%-86%; specificity in adults is >90%. However, studies have reported a 21%-54% false positive rate in children with NP carriage and no evidence of pneumoniaand adults with chronic obstructive pulmonary disease. ventilator-associated pneumonia; infections of the pleural space; bronchopulmonary infections in patients with cystic fibrosis; and pneumonia in the immunocompromised host. The reader is referred to various IDSA practice guidelines that have been written in recent years that describe the clinical features, diagnostic approaches, and patient management aspects of many of these syndromes.
The Key Points below summarize some important caveats when obtaining specimens for the diagnosis of respiratory infections. Abbreviations: BAL, bronchoalveolar lavage; BCYE, buffered charcoal yeast extract; CF, complement fixation; DFA, direct fluorescent antibody test; EIA, enzyme immunoassay; ID, immunodiffusion; KOH, potassium hydroxide; LA, latex agglutination; NAAT, nucleic acid amplification test; NP, nasopharyngeal; RT, room temperature. a Sensitivity in nonbacteremic patients with pneumococcal pneumonia is 52%-78%; sensitivity in bacteremic cases of pneumococcal pneumonia is 80%-86%; specificity in adults is > 90%. However, studies have reported a 21%-54% false positive rate in children with NP carriage and no evidence of pneumonia. b Currently there is one FDA approved platform (see text). Availability is laboratory specific. Provider needs to check with the laboratory for optimal specimen source, performance characteristics and turn around time. c Several FDA cleared NAAT platforms are currently available and vary in their approved specimen requirements and range of analytes detected. Readers should check with their laboratory regarding availability and performance characteristics including certain limitations. a Anaerobic culture should only be done if the specimen has been obtained with a protected brush or catheter and transported in an anaerobic transport container or by placing the brush in 1 mL of pre-reduced broth prior to transport. b Sensitivity in nonbacteremic patients with pneumococcal pneumonia is 52%-78%; sensitivity in bacteremic cases of pneumococcal pneumonia is 80%-86%; specificity in adults is >90%. However, studies have reported a 21%-54% false positive rate in children with NP carriage and no evidence of pneumonia. c No FDA cleared test is currently available. Availability is laboratory specific. Provider needs to check with the laboratory for optimal specimen source, performance characteristics and turnaround time. d Performance characteristics of these tests are reviewed in reference.
e Testing from this source is not offered in all microbiology laboratories.
f Several FDA cleared NAAT platforms are currently available and vary in their approved specimen requirements and range of analytes detected. Readers should check with their laboratories regarding availability and performance characteristics including certain limitations. Key points for the laboratory diagnosis of lower respiratory tract infections:
- First morning sputum is always best for culture.
- Calcium alginate swabs are not acceptable for nucleic acid amplification testing.
- Most negative rapid antigen test results should be confirmed by another method.
- Blood cultures that accompany sputum specimens may occasionally be helpful, particularly in high risk community acquired pneumonia patients.
- The laboratory should be contacted for specific instructions prior to collection of specimens for fastidious pathogens such as Bordetella pertussis.
- The range of pathogens causing exacerbations of lung disease in cystic fibrosis patients has expanded and specimens for mycobacterial and fungal cultures should be collected in some patients.
- In the immunocompromised host, a broad diagnostic approach based on invasively obtained specimens is suggested.
## A. bronchitis and bronchiolitis
Table VI-1 lists the etiologic agents and diagnostic approaches for acute bronchitis, acute exacerbation of chronic bronchitis and bronchiolitis, 3 clinical syndromes that involve inflammation of the tracheobronchial tree. Acute bronchitis is largely due to viral pathogens and is less frequently caused by Mycoplasma pneumoniae and Chlamydophila pneumoniae.
Bordetella pertussis should be considered in an adolescent or young adult with prominent cough. Direct fluorescent antibody testing has been replaced by nucleic acid amplification tests (NAATs) in combination with culture as the recommended tests of choice for B. pertussis detection. Currently, there is one FDA cleared platform for B. pertussis detection. Streptococcus pneumoniae and Haemophilus influenzae do not play an established role in acute bronchitis, but they, along with Moraxella catarrhalis, do figure prominently in cases of acute exacerbation of chronic bronchitis. Bronchiolitis is almost exclusively caused by viruses and M. pneumoniae. Several FDA-approved NAAT platforms are available for the detection of select respiratory viruses.
## B. community-acquired pneumonia
The diagnosis of community-acquired pneumonia is based on the presence of specific symptoms and suggestive radiographic features, such as pulmonary infiltrates and/or pleural effusion. Carefully obtained microbiological data can support the diagnosis but often fails to provide an etiologic agent. [fig_ref] Table I - 1: [/fig_ref] lists the more common causes of community-acquired pneumonia. Other less common etiologies may need to be considered depending upon recent travel history or exposure to vectors or animals that transmit zoonotic pathogens such as Sin Nombre virus (hantavirus pulmonary syndrome) or Yersinia pestis ( pneumonic plague, endemic in the western US).
The rationale for attempting to establish an etiology is that identification of a pathogen will focus the antibiotic management for a particular patient. In addition, identification of certain pathogens such as Legionella species, influenza viruses, and the agents of bioterrorism have important public health significance. Currently, IDSA/ATS practice guidelines consider diagnostic testing as optional for the patient who is not hospitalized [bib_ref] Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management..., Mandell [/bib_ref].
Those patients who require admission should have pretreatment blood cultures, culture and Gram stain of good-quality samples of expectorated sputum and, if disease is severe, urinary antigen tests for S. pneumoniae and Legionella pneumophila where available. Laboratories must have a mechanism in place for screening sputum samples for acceptability (to exclude those that are heavily contaminated with oropharyngeal flora and not representative of deeply expectorated samples) prior to setting up routine bacterial culture. Poor-quality specimens provide misleading results and should be rejected because interpretation would be compromised. Endotracheal aspirates or bronchoscopically obtained samples (including "mini BAL" using the Combicath [KOL Bio Medical Instruments, Chantilly, [fig_ref] Table I - 1: [/fig_ref]
## Respiratory viruses
See [fig_ref] Table I - 1: [/fig_ref] Mycobacterial infections should be in the differential diagnosis of community-acquired pneumonia (CAP) that fails to respond to therapy for the typical CAP pathogens. Mycobacterium tuberculosis, while declining in the United States in recent years, is still an important pathogen among immigrant populations. Mycobacterium avium complex is also important, not just among patients with HIV, but in patients with chronic lung disease, cystic fibrosis, and in middle-aged or elderly thin women [bib_ref] Nontuberculous mycobacterial pulmonary infections in Non-HIV patients, Parrish [/bib_ref].
C. Healthcare-Associated Pneumonia, Hospital-Acquired Pneumonia, and Ventilator-Associated Pneumonia
Healthcare-associated (HCAP), hospital-acquired pneumonia (HAP), and ventilator-associated (VAP) pneumonias are frequently caused by multidrug-resistant gram-negative bacteria or other bacterial pathogens. Aside from respiratory viruses that may be nosocomially transmitted, viruses and fungi are rare causes of HCAP, HA, and VAP in the immunocompetent patient. [fig_ref] Table I - 1: [/fig_ref] lists the organisms most commonly associated with pneumonia in the immunocompromised patient. Two diagnostic strategies have been recommended by the American Thoracic Society and the Infectious Diseases Society of America. The clinical strategy is based on the presence of a new lung infiltrate plus the presence of 2 of 3 clinical features (fever, leukocytosis or leucopenia, and purulent secretions). Determining the cause of the pneumonia relies on initial Gram stain and semiquantitative cultures of endotracheal aspirates or sputum. A smear lacking inflammatory cells and a culture absent of potential pathogens have a very high negative predictive value. Cultures of endotracheal aspirates, while likely to contain the true pathogen, also consistently grow more mixtures of species of bacteria than specimens obtained by bronchoscopic techniques. This may lead to additional unnecessary antibiotic therapy. The bacteriologic strategy uses quantitative cultures of lower respiratory tract secretions obtained either bronchoscopically or via endotracheal aspiration without a bronchoscope. Quantities of bacterial growth above a threshold are diagnostic of pneumonia and quantities below that threshold are more consistent with colonization. The generally accepted thresholds are as follows: Endotracheal aspirates, 10 6 CFU/mL; BAL, 10 4 CFU/mL; protected specimen brush samples (PSB), 10 3 CFU/mL. These values have significance only when the samples have been obtained >72 hours before the initiation or a change of antibiotic therapy. Quantitative studies require extensive laboratory work and special procedures that smaller laboratories may not accommodate. Bronchial washes are not appropriate for routine bacterial culture. Abbreviation: RT, room temperature. a Gram stain and culture of properly collected and transported stool specimens has a sensitivity of 95% as does histopathological examination. Culture may not be routinely available. b Agar-based or rapid urease tests have a slightly lower sensitivity of 90%-95% but offer the advantage of providing rapid results. They may be performed point-ofcare or in the laboratory. When these tests are performed on gastric fluid, orogastric brush or "string" specimens, they have lower sensitivity than when performed on biopsy specimens.
## D. infections of the pleural space
The infectious causes of pleural effusions have shifted from the traditional pneumonia pathogens of S. pneumoniae and S. pyogenes to polymicrobial infections in which anaerobic bacteria play a major role. Table VI-4 summarizes the major pathogens. Any significant accumulation of fluid in the pleural space should be sampled by thoracentesis. Specimens should be hand carried immediately to the laboratory or placed into appropriate anaerobic transport media for transport. In some institutions, bedside inoculation into blood culture bottles has become an established practice. This is acceptable providing that the manufacturer's guidelines are followed with respect to the volume inoculated and whether supplementation is required to enhance recovery of fastidious pathogens such as S. pneumoniae. If blood culture bottles are used, an additional sample should be sent to the microbiology laboratory for Gram stain and culture of nonbacterial pathogens when indicated. Fluid should be sent for cell count, pH, protein, glucose, and . These values assist with the determination of a transudative or exudative process and in the subsequent management of the syndrome. For example, the following parameters suggest the need for drainage: pH <7.28; glucose <40 mg/dL; LDH >1000 IU/L or the presence of polymorphonuclear leucocytes (PMNs) [bib_ref] Diagnosis and management of parapneumonic effusions and empyema, Sahn [/bib_ref]. Most infections result in an exudate or PMNs (empyema) within the pleural cavity. When tuberculosis or a fungal pathogen is thought to be the likely cause, a pleural biopsy sent for culture and histopathology increases the diagnostic sensitivity. Always notify the laboratory of a suspicion of tuberculosis so that appropriate safety precautions can be employed. An elevated adenosine deaminase level in the pleural fluid (>70 IU/L) in a patient with appropriate risk factors for tuberculosis has been shown to have a high sensitivity in high prevalence regions. A level <40 IU/L excludes the diagnosis. This marker of lymphocyte differentiation should be used in conjunction with hematologic and chemical parameters and other diagnostic tests such as NAAT, culture, and histology of a pleural biopsy. The performance of this assay in developed countries has been shown to be quite variable and is related to multiple factors including the type of method used, the likelihood of tuberculosis, and "false positive" results in patients with other causes of lymphocytic pleural effusion such as rheumatoid disease, mesothelioma, and histoplasmosis [bib_ref] Diagnosis and treatment of tuberculous pleural effusion in 2006, Gopi [/bib_ref].
## E. pulmonary infections in cystic fibrosis
Patients with cystic fibrosis (CF) suffer from chronic lung infections due to disruption of exocrine function that does not allow them to clear microorganisms that enter the distal airways of the lung. A limited number of organisms have been implicated in chronic infections [fig_ref] Table I - 1: [/fig_ref]. Early in childhood, infections are caused by organisms frequently seen in the non-CF pediatric population such as S. pneumoniae, H. influenzae, and S. aureus. At some point later in childhood or adolescence, P. aeruginosa becomes the most important pathogen involved in chronic lung infection and the concomitant lung destruction that follows. The P. aeruginosa strains adapt to the hypoxic stress of the retained mucoid secretions by converting to a biofilm mode of growth (mucoid colonies). Nosocomial pathogens such as S. maltophilia and Achromobacter xylosoxidans may be acquired during a hospital or clinic visit. Burkholderia cepacia complex is a very important pathogen in these patients. B. cepacia genomovar III (B. cenocepacia) is highly pathogenic and is responsible for rapid decline and death in a subset of patients who acquire the virulent clones. Special microbiological techniques are required to recover and differentiate B. cepacia complex from the mucoid P. aeruginosa strains. Less common gram-negative organisms that appear to be increasing in their frequency of recovery, but whose role in the pathogenesis of CF lung disease is still unclear, include B. gladioli, Ralstonia spp, Cupriavidus spp, and Pandorea [bib_ref] The changing microbial epidemiology in cystic fibrosis, Lipuma [/bib_ref]. As CF patients have survived into adulthood, opportunistic pathogens such as nontuberculous mycobacteria have been isolated with increasing frequency. There is evidence to suggest that both M. abscessus and M. avium complex contribute to lung destruction and should be treated when cultures are repeatedly positive. Mycobacterial culture should be added to the routine cultures obtained from patients older than 15 years of age who present with exacerbations, as the incidence of Mycobacterium species is likely underestimated due to failure to routinely assess patients for these organisms [bib_ref] The changing microbial epidemiology in cystic fibrosis, Lipuma [/bib_ref]. Aspergillus fumigatus is the most common fungus recovered from CF patients where it causes primarily allergic bronchopulmonary disease. Scedosporium apiospermum may cause a similar syndrome. Exophiala dermatitidis has been reported by some centers to cause chronic colonization of the CF airway [bib_ref] The changing microbial epidemiology in cystic fibrosis, Lipuma [/bib_ref]. Trichosporon mycotoxinivorans is a newly recognized pathogen that has a propensity to cause disease in patients with cystic fibrosis [bib_ref] Trichosporon mycotoxinivorans, a novel respiratory pathogen in patients with cystic fibrosis, Hickey [/bib_ref]. Table VI-5 summarizes the organisms most likely to cause exacerbation of pulmonary symptoms in CF patients [bib_ref] Nontuberculous mycobacterial pulmonary infections in Non-HIV patients, Parrish [/bib_ref] [bib_ref] The changing microbial epidemiology in cystic fibrosis, Lipuma [/bib_ref] [bib_ref] Occurrence and relevance of filamentous fungi in respiratory secretions of patients with..., Pihet [/bib_ref]. While a number of environmental nonfermenting gram-negative bacilli are frequently recovered from the sputum of these patients, their role in CF lung disease is either unknown at this time or unlikely to be of significance. These organisms have not been included in the table. Laboratories should spend resources on those pathogens proven or likely to play a significant role in pulmonary decline in these patients.
## F. pneumonia in the immunocompromised host
Advances in cancer treatments, transplantation immunology, and therapies for autoimmune diseases and HIV have expanded the population of severely immunocompromised patients. Pulmonary infections are the most common syndromes contributing to severe morbidity and mortality among these groups of patients.
Virtually any potential pathogen may result in significant illness, and the challenge for both clinicians and microbiologists is to rapidly differentiate infectious from noninfectious causes of pulmonary infiltrates. The likelihood of a specific infection may be affected by recently administered prophylaxis. Table VI-6 focuses on the major infectious etiologies likely to be of interest in most immunocompromised hosts. Patients are still vulnerable to the usual bacterial and viral causes of CAP and HAP. In addition, fungi, herpesviruses, and protozoa play a more significant role and should be considered.
When rapid and noninvasive tests such as urine or serum antigen tests and rapid viral diagnostics are not revealing, more definitive procedures to sample the lung are required. Several diagnostic procedures can be performed but usually the patient initially undergoes bronchoscopy with bronchoalveolar lavage with or without transbronchial biopsy. It is suggested that microbiology laboratories in collaboration with infectious diseases physicians and pulmonologists, develop an algorithm for processing samples that includes testing for all major categories of pathogens as summarized in the table. Cytologic analysis and/ or histopathology are often needed to interpret the significance of positive NAAT or culture for herpesviruses, for example, and to definitively diagnose filamentous fungi. It should be noted, however, that histopathology alone is not sensitive enough to diagnose fungal infections and should be accompanied by immunostain, culture, and, when available, NAAT [bib_ref] Challenges and pitfalls of morphologic identification of fungal infections in histologic and..., Sangoi [/bib_ref]. In addition, serum and BAL galactomannan and serum 1-3 β-Dglucan tests may be helpful. However, cytology and or histopathology are quite useful for distinguishing conditions such as pulmonary hemorrhage and rejection from infectious causes of infiltrates. Transthoracic needle aspiration, CT-guided biopsies of pleural-based lesions, and open lung likewise may be considered if less invasive diagnostics are unrevealing.
## Vii. infections of the gastrointestinal tract
Gastrointestinal (GI) infections include a wide variety of disease presentations as well as infectious agents. For many of these infections, particularly noninflammatory diarrhea and acute gastroenteritis of short duration, no laboratory testing is recommended. This section addresses the laboratory approach to establishing an etiologic diagnosis of esophagitis, gastritis, gastroenteritis and proctitis.
Key points for the laboratory diagnosis of gastrointestinal infections:
- The specimen of choice to diagnose diarrheal illness is the diarrheal stool, not a formed stool or a swab.
- Toxin or nucleic acid amplification testing for C. difficile should only be done on diarrheal stool, not formed stools, unless the physician notes that the patient has ileus.
## A. esophagitis
Esophagitis is most often caused by noninfectious conditions, such as gastroesophageal reflux disease. Infectious causes are often seen in patients with impaired immunity [fig_ref] Table I - 1: [/fig_ref]. Calcofluor, potassium hydroxide (KOH), or Gram stain of esophageal brushings with histopathological examination and viral culture of esophageal biopsies will establish the diagnosis in most cases.
## B. gastritis
Both invasive and noninvasive tests [fig_ref] Table I - 1: [/fig_ref] are available to aid in the diagnosis of H. pylori infection, the major infectious etiology of gastritis [bib_ref] Helicobacter pylori detection and antimicrobial susceptibility testing, Megraud [/bib_ref]. Invasive tests such as Gram stain and culture of endoscopy tissue, histopathologic staining, and direct tests for urease require the collection of biopsy samples obtained during endoscopy from patients that have not received antimicrobial agents or proton pump inhibitors in the 2 weeks prior to collection and as such pose greater risks to the patient. The advantage to the noninvasive assays such as the urea breath test and stool antigen determinations is that patients can avoid endoscopy and gastric biopsy. They are also useful to test for organism eradication after therapy. The urea breath test is performed in the clinic. The patient ingests a cocktail containing 13 C-labeled urea and 15-30 minutes later, a breath sample is obtained and analyzed for the presence of [bib_ref] Approach to diagnosis of meningitis. Cerebrospinal fluid evaluation, Greenlee [/bib_ref] C-labeled CO 2 as an indication of the presence of H. pylori in the stomach. This assay has a sensitivity of approximately 95%, comparable to the invasive assays. Stool antigen tests have a reported sensitivity of 88%-98% with sensitivity being higher in adults than in children. The noninvasive assays are also useful to test for organism eradication after therapy; the urea breath test having a somewhat higher sensitivity than stool antigen detection. Serodiagnosis has a lower sensitivity (<90%) and specificity (90%) and is not useful for test of cure after therapy.
[formula] X X X X X X Secondary Peritonits X X X X X X X X X Tertiary Peritonitis X X X X X X X X Peritoneal Dialysis- Associated Peritonitis X X X X X X X Lesions of the Liver X X X X X X X X Infections of Biliary Tree X X X X X X Splenic Abscess X X X X X X X X Secondary Pancreatic Infections X X X X Guide [/formula]
## C. gastroenteritis, infectious and toxin-induced diarrhea
GI infections encompass a wide variety of symptoms and recognized infectious agents [fig_ref] Table I - 1: [/fig_ref]. The appropriate diagnostic approach to diarrheal illness is determined by the patient's age, severity of disease, duration and type of illness, time of year, and geographic location. Fecal testing is indicated for severe, bloody, febrile, dysenteric, nosocomial, or persistent diarrheal illnesses. Communication with the laboratory is required to determine what organisms, methods, and screening parameters are included as part of the routine enteric pathogen culture. Most laboratories will have the ability to culture for Salmonella, Shigella, Campylobacter, and test for Clostridium difficile and Shiga toxin-producing Escherichia coli. Consult with the laboratory if other pathogens are suspected; special media may be required. The specimen of choice is the diarrheal stool (ie, takes the shape of the container). NAAT tests are being developed and will eventually be the first test of choice; currently only one commercial panel has received FDA clearance, although individual Shiga-toxin NAATs are available.
Stool Culture Stool culture is indicated for detection of invasive bacterial enteric pathogens. Most laboratories employ culture techniques to routinely detect Salmonella, Shigella, and Campylobacter and, more recently, Shiga toxin-producing E. coli in all stools submitted for culture. Salmonella spp can take 24-72 hours to recover and identify to genus alone with the specific serotyping usually performed at the State Public Health Laboratory level. It is recommended that tests for the detection of Shiga toxin, or tests to specifically detect Shiga toxin-producing E. coli O157: H7 or other Shiga toxin-producing serotypes be included as part of the routine test. However, in some settings, these tests may require a specific request. Tests that detect only E. coli O157:H7 will not detect the increasing number of non-O157 isolates being reported and may not detect all E. coli O157:H7. Screening algorithms that limit testing to bloody stools may also miss both O157 and non-O157 isolates. Detection of Vibrio and Yersinia in the United States is usually a special request and requires additional media or incubation conditions. Communication with the laboratory is necessary. Laboratory reports should indicate which of the enteric pathogens would be detected. Laboratories are encouraged to provide enteric pathogen isolates to their Public Health Laboratory and/or the Center for Disease Control and Prevention for pulsed-field gel analysis for national surveillance purposes.
Multiple stool specimens are rarely indicated for detection of stool pathogens. In studies of adult patients who submitted more than 1 specimen, the enteric pathogen was detected in the first sample 87%-94% of the time, with the second specimen bringing the positive rate up to 98% [bib_ref] Etiological agents of infectious diarrhea: implications for requests for microbial culture, Rohner [/bib_ref]. In pediatric patients, the first specimen detects 98% of the enteric pathogens [bib_ref] Practice guidelines for ordering stool cultures in a pediatric population, Church [/bib_ref]. Thus, 1 sample for children and a second for selected adult patients may be considered. Rectal swabs are less sensitive than stool specimens and are not recommended in adults but in symptomatic pediatric patients rectal swabs and stool culture are equivalent in the ability to detect fecal pathogens [bib_ref] Comparison of rectal swabs with fecal cultures for detection of Salmonella typhimurium..., Kotton [/bib_ref] [bib_ref] Survival of fastidious and nonfastidious aerobic bacteria in three bacterial transport swab..., Rishmawi [/bib_ref].
Clostridium botulinum Botulism is an intoxication in which a protein exotoxin, botulinum toxin, produced by Clostridium botulinum causes a life- threatening flaccid paralysis. Diagnosis, while not usually confirmed by the hospital microbiology laboratory, is made by clinical criteria, allowing prompt initiation of essential antitoxin therapy. The microbiologic diagnosis is dependent on detection of botulinum toxin in serum (in patients with wound, infant, and food-borne disease), stool (in patients with infant and food-borne disease), and gastric contents/vomitus (in patients with food-borne disease). Toxin detection is performed in many State Public Health Laboratories and at the Center for Disease Control and Prevention. Culture can be performed on both feces and wounds, but the yield is low and most laboratories lack the necessary expertise to isolate and identify this organism [bib_ref] Laboratory diagnostics of botulism, Lindstrom [/bib_ref]. Clostridium difficile Numerous methods have been employed for the laboratory diagnosis of infection caused by Clostridium difficile. Toxigenic culture is probably the most sensitive and specific of the assays for the detection of C. difficile. It is slow and labor intensive and not routinely performed in the community hospital setting. Compared to toxigenic culture, the cytotoxin assay has a sensitivity of 85%-90%. The cytotoxin assay requires 24-48 hours and is also labor intensive. Thus, toxin detection by either enzyme immunoassay (EIA) or immunochromatographic methods has been performed. These assays have reported sensitivity of 70%-85% but are significantly faster with results available in <2 hours. Utilization of an assay that detects both toxin A and toxin B improves the sensitivity. With the availability of NAAT assays, EIAs for toxin alone are no longer recommended as stand-alone assays.
Nucleic acid amplification assays for the detection of C. difficile are available and should be considered the test of choice for the diagnosis of enterocolitis due to C. difficile. They have reported sensitivity of 93%-100%. To reduce turnaround time and costs, some laboratories may employ an algorithm that uses a rapid screening test for glutamate dehydrogenase (GDH) antigen with or without toxin A and B detection followed by cytotoxin or NAAT confirmation where indicated. NAAT testing should be employed if GDH antigen and toxin screening results do not agree. This algorithm allows for both the rapid reporting of most negative specimens and the sensitivity of cytotoxin testing or NAAT but could result in delays in diagnosis that range from hours to days, depending on the laboratory testing platform employed [bib_ref] Yield of stool culture with isolate toxin testing versus a two-step algorithm..., Reller [/bib_ref] [bib_ref] Clostridium difficile testing: after 20 years, still challenging, Wilkins [/bib_ref].
Diarrheal stool specimens (not formed stools or rectal swabs) are required for the diagnosis of C.difficile disease (not colonization). The specimen should be loose enough to take the shape of the container. Formed stools should be appropriately rejected by the laboratory but with the proviso that formed stools from patients with ileus, or potential toxic megacolon, as noted by the physician, should be tested. Repeat testing of patients previously positive as a "test of cure" is not appropriate. Repeat testing of patients negative by NAATs should not be performed for at least 6 days [bib_ref] Is repeat PCR needed for diagnosis of Clostridium difficile infection?, Luo [/bib_ref].
Since 2000, an increase in C. difficile-associated disease with increased morbidity and mortality has been reported in the United States, Canada, and the United Kingdom. The epidemic strain is toxinotype III, North American PFGE type 1 (NAP1) and PCR-ribotype 027 (NAP1/027). It carries the binary toxin genes cdtA and cdtB and an 18 bp deletion in tcdC. It produces both toxin A and toxin B [bib_ref] An epidemic, toxin gene-variant strain of Clostridium difficile, Mcdonald [/bib_ref]. A commercially available FDAcleared NAAT for binary toxin and the tcdC deletion genes identifies this strain for epidemiological purposes. The severity of disease is believed to be due to toxin hyperproduction [bib_ref] Toxin production by an emerging strain of Clostridium difficile associated with outbreaks..., Warny [/bib_ref]. The association of binary toxin with disease severity is controversial.
Parasites
The number of specimens to be submitted for parasitologic examination may be a controversial subject [bib_ref] Utility of multiple-stool-specimen ova and parasite examinations in a high-prevalence setting, Cartwright [/bib_ref] [bib_ref] Clinical importance of adequately performed stool ova and parasite examinations, Rosenblatt [/bib_ref]. Historically, when using conventional microscopic procedures, it was recommended that 3 specimens collected over a 7-10 days period be submitted for ova and parasite (O&P) examination. Options for cost-effective testing today include examination of a second specimen only when the first is negative and the patient remains symptomatic, with a third specimen being submitted only if the patient continues to be O&P negative and symptomatic. Targeted use of immunoassay testing for the most common parasites based on geography, patient demographics, and physician request, can also be used as a screen with only negative patients with continued symptoms or patients with specific risk factors requiring full O&P examination. Immunoassays for Giardia are sensitive enough that only a single specimen may be needed.
The specimen preservative to be employed, often supplied by the laboratory, depends on the need to perform immunoassay procedures or special stains on the specimens and the manufacturer's recommendations for specimen fixative. Polyvinyl alcohol (PVA) is the gold standard; however, due to the presence of mercuric chloride, modifications that do not employ mercury have been developed. None of these modified preservatives allow stains to provide the same level of microscopic detail, although with experience, they are acceptable alternatives.
In routine procedures, pathogenic E. histolytica cannot be differentiated from nonpathogenic E. dispar using morphologic criteria, so the laboratory report may indicate E. histolytica/ dispar [bib_ref] Laboratory diagnosis of amebiasis, Tanyuksel [/bib_ref]. Only an immunoassay or NAAT can differentiate these organisms.
## D. proctitis
Proctitis is most commonly due to sexually transmitted agents, a result of anal-genital contact, although abscesses or perirectal wound infections may present with similar symptoms. One sample is usually sufficient for diagnosis [fig_ref] Table I - 1: [/fig_ref].
## Viii. intraabdominal infections
This section is designed to optimize the activities of the microbiology laboratory to achieve the best approach for the identification of microorganisms associated with peritonitis and intraperitoneal abscesses, hepatic and splenic abscesses, pancreatitis, and biliary tract infection. As molecular means begin to be used to define the microbiome of the gastrointestinal and genitourinary tract, contemporary culture protocols will surely evolve to accommodate new, emerging information. The future use of gene amplification and sequencing for identification of microorganisms in these infections will likely show that for every organism currently identified by culture there will be several times that number cannot be cultivated using current technologies. To remain focused on contemporary methods currently available in the diagnostic microbiology laboratory, the tables outline the most likely agents of each entity (Table VIII-1) and how best to evaluate the situation with existing techniques [fig_ref] Table I - 1: [/fig_ref].
Factors to consider when collecting specimens for laboratory diagnosis of intraabdominal infections:
Key points for the laboratory diagnosis of intraabdominal infections:
- The laboratory needs the specimen-not a swab of the specimen. Sufficient quantity of specimen must be collected to allow the Microbiology laboratory to perform all the necessary tests.
- The specimen of choice for an abscess is a sample of the contents plus a sample of the wall of the abscess.
- Pus alone may not reveal the etiologic agent since the PMNs may have destroyed morphological evidence of microbial invasion.
- While most molecular tests have excellent sensitivity, a Mycobacterium tuberculosis NAAT test should be an adjunct to a culture and never ordered alone. No current commercial methods are FDA-cleared for these specimens, so laboratories must have validated the test they use.
- If M. tuberculosis is present, it is usually a sign of disseminated disease that must be thoroughly investigated.
## A. spontaneous bacterial peritonitis and ascites
In cases of spontaneous bacterial peritonitis (SBP), the source of the invading organism(s) is unknown, and the syndrome can also be seen in patients with preexisting risk factors such as cirrhosis with ascites [bib_ref] Intra-abdominal infections: considerations for the use of the carbapenems, Kioumis [/bib_ref]. SBP tends to be monomicrobic and caused by aerobic organisms from the intestinal tract; therefore, anaerobic cultures are less valuable. Sufficient fluid (eg, 10-50 mL if available) should be obtained to allow for concentration by centrifugation and a cytospin Gram stain evaluation. At a minimum, at least 10 mL of peritoneal fluid (not swabs of the fluid) should be collected aseptically and transported to the laboratory prior to the administration of antimicrobial agents. Additional laboratory testing should include fluid analysis for protein, cell count and differential, lactate concentration and pH along with 2-3 sets of blood cultures for the identification of concomitant bacteremia [fig_ref] Table I - 1: [/fig_ref]. Alternatively, because SBP and infections of ascites fluid tend to be monomicrobic, an aerobic blood culture bottle can be inoculated with fluid (volume dependent on blood culture system) if the presence of a single organism is reasonably certain. A Gram stain may be used prior to broth inoculation to evaluate the morphology of the organism(s) present. Since the differentiation between SBP and secondary peritonitis may be uncertain, it may be beneficial to submit peritoneal fluid in a sterile container for conventional culture and stain as well as inoculate blood culture bottles at the bedside with the fluid. Sequencing and 16S PCR can be used to identify isolates present in these specimens if these techniques are available to the laboratory. In the next few years, next generation sequencing will be able to analyze such specimens to determine the total microbial load by species. If more than 1 morphologic type is noted in the Gram stain, a broth should not be inoculated. The caveat for use of blood culture bottles with fluid other than blood is that not all systems have been evaluated for this purpose. Further, broth cultures do not accurately reflect the bacterial burden or the variety of organisms at the time the specimen is obtained and the presence of a true pathogen may be obscured by the overgrowth of a more rapidly growing organism.
Negative culture results in the presence of other indicators of infection should prompt an evaluation for fastidious or slowly growing organisms such as Mycobacterium spp, fungi, Chlamydia trachomatis, or Neisseria gonorrhoeae.
## B. secondary peritonitis
The diagnosis of secondary peritonitis is dependent upon identifying a source for invading microorganisms-usually genitourinary or gastrointestinal flora [bib_ref] Spontaneous bacterial peritonitis: a therapeutic update, Strauss [/bib_ref]. There are numerous causes of secondary peritonitis including iatrogenic or accidental trauma, perforated appendix or diverticuli, typhlitis, or intra-abdominal abscess. Unlike SBP, however, secondary peritonitis tends to be polymicrobic and may include anaerobic flora. Organisms such as S. aureus, N. gonorrhoeae, and Mycobacterium spp are unusual in this setting. Common etiologies include aerobic and anaerobic gram-negative rods (Bacteroides spp, E. coli, Klebsiella spp), and gram-positive flora (Clostridium spp, Enterococcus spp, Bifidobacterium spp, Peptostreptococcus spp). If typhlitis is suspected, C. difficile toxin testing, stool cultures for enteric pathogens, and blood cultures should be requested. Additionally, C. septicum should be considered in neutropenic enterocolitis.
Peritoneal fluid should be sent to the laboratory in an anaerobic transport system for Gram stain and aerobic and anaerobic bacterial cultures. Inoculation of blood culture bottles alone with peritoneal fluid is not appropriate in this setting, as competitive bacterial growth in broth cultures could mask the recovery of clinically important pathogens [fig_ref] Table I - 1: [/fig_ref]. Because cytomegalovirus (CMV) is a possible cause of secondary peritonitis, the microbiology laboratory should be contacted to arrange for special processing if CMV is of concern. The microbiology laboratory should also be contacted if N. gonorrhoeae is of concern since special processing or NAAT (this specimen type has no FDA-cleared commercial platform for testing) will be necessary.
Because of the polymicrobic nature of secondary peritonitis, clinicians should not expect or request identification and susceptibility testing of all organisms isolated. Rather, the laboratory should provide a general description of the culture results (eg, mixed aerobic and anaerobic intestinal flora) and selective identification of certain organisms such as MRSA, β-hemolytic Streptococcus spp, multi-drug-resistant gram-negative bacilli, VRE, etc.) to guide empiric antimicrobial therapy [bib_ref] Intra-abdominal infections: considerations for the use of the carbapenems, Kioumis [/bib_ref] [bib_ref] Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections, Solomkin [/bib_ref]. Patients who do not respond to conventional therapy should have additional specimens collected to examine for resistant organisms or for the presence of intra-abdominal abscesses.
## C. tertiary peritonitis
This entity refers to persistent or recurrent peritonitis following unsuccessful treatment of secondary peritonitis. Tertiary peritonitis might also indicate the presence of an intra-abdominal abscess or organisms that are refractory to broad spectrum antimicrobial therapy such as vancomycin-resistant Enterococcus spp, Candida species, Pseudomonas aeruginosa, or biofilmproducing bacteria like coagulase-negative Staphylococcus spp. Fluid cultures from cases of tertiary peritonitis are commonly negative for bacteria [bib_ref] Intra-abdominal infections: considerations for the use of the carbapenems, Kioumis [/bib_ref]. In any case, cultures appropriate for spontaneous or secondary peritonitis may be helpful [fig_ref] Table I - 1: [/fig_ref] Abbreviations: AFB, acid-fast bacillus; KOH, potassium hydroxide; NAAT, nucleic acid amplification test; RT, room temperature. a Salmonella osteomyelitis occurs most often in patients with sickle cell trait or disease [bib_ref] Retrospective review of osteoarticular infections in a pediatric sickle cell age group, Chambers [/bib_ref].
b Streptococcus pneumoniae as a cause of osteomyelitis occurs most often in pediatric patients, not infrequently in the setting of spontaneous pneumococcal bacteremia [bib_ref] Review article: Paediatric bone and joint infection, Stott [/bib_ref]. c Brucella spp will be recovered in standard aerobic bacterial cultures, however, it is a slow growing bacterium and as a result, the laboratory should be notified when Brucella is considered to be a potential cause of osteomyelitis so that cultures can be held for examination over at least a one-week period and examined only in a biological safety cabinet. Concomitant blood cultures and serology testing are recommended (not necessary to hold blood cultures beyond standard incubation). d Hematogenous osteomyelitis caused by Pseudomonas aeruginosa and other Pseudomonas spp occurs most often in injection drug users [bib_ref] Bone and joint infections in intravenous drug abusers, Chandrasekar [/bib_ref]. e The most common site of osteomyelitis due to M. tuberculosis is the vertebral bodies. This organism can also seed the clavicles and in this setting represents one of the most common causes of clavicular osteomyelitis. Commercial NAATs are not FDA-cleared for nonrespiratory sites, so a laboratory-validated test method must be used if NAATs are requested. f Infections of skin and soft tissues, especially with extension of infection into deeper tissue spaces, pose a risk for the development of osteomyelitis of adjacent bone. While S. aureus is the most commonly incriminated organism, essentially any bacterium capable of causing deep soft tissue infection can also cause osteomyelitis. g Chronic endodontic infections such as apical abscesses may extend into surrounding bone resulting in osteomyelitis of the maxilla or mandible. These infections are caused by the aerobic and anaerobic bacterial flora of the oral cavity and may be either monomicrobic or polymicrobic. Actinomyces spp is a recognized pathogen in this setting. When Actinomyces is suspected, specimens should be transported to the laboratory and then processed within 15 minutes or there is little chance of recovering Actinomyces in culture. h Diabetic extremity infections with underlying osteomyelitis can be caused by a diverse group of bacteria including S. aureus, Group B β-hemolytic streptococci, Enterococcus spp, the Enterobacteriaceae, Pseudomonas spp, Stenotrophomonas maltophilia and a variety of anaerobes. This represents one of the few settings in which osteomyelitis can be polymicrobial. Superficial debridement followed by deep sampling at the advancing margin of the lesion is essential to avoid being misled by surface colonizing contaminants. i Mycetoma is a chronic soft tissue infection of the extremities which can also extend into contiguous bone and connective tissue. It occurs most often in tropical and subtropical climates and may be characterized by the development of draining sinuses. The etiologic agents (see are derived from the soil. Sinus tract drainage material, when present, may be representative of the etiology of underlying osteomyelitis. In addition to the stains and cultures noted in the table, sinus drainage should also be examined grossly and microscopically for the presence of "sulfur granules" characteristic of this disease. Further, the laboratory should be notified of the possibility of Nocardia as a pathogen so that appropriate media, eg Neisseria selective media and Legionella selective agar, can be inoculated which facilitate recovery of this organism. j Pseudomonas aeruginosa is the most common bacterial cause of calcaneal osteomyelitis in individuals who develop this infection after stepping on nails while wearing sneakers. k Direct trauma to bone such as may occur in open fractures with contamination of the site by soil, animal feces, water, etc, may lead to the development of osteomyelitis due to essentially any microorganism present in the contamination source. This includes the Enterobacteriaceae, Pseudomonas aeruginosa, unusual gram-negative bacilli, Bacillus spp, anaerobes such as Clostridium spp, Nocardia and other aerobic actinomycetes. This represents another form of osteomyelitis that can be polymicrobial.
or slowly growing organisms such as filamentous fungi and Mycobacterium spp should be entertained if bacterial cultures are negative for growth. If culture results in growth of Mycobacterium spp, it may represent disseminated disease. However, AFB and parasitic studies would only rarely be considered.
## D. peritoneal dialysis-associated peritonitis (pdap)
The evaluation of dialysis fluid from patients with suspected PDAP is essentially identical to that used for SBP. Infections tend to be monomicrobic and rarely anaerobic. In the case of PDAP, however, the list of likely suspect organisms is quite different from SBP. Gram-positive bacteria ( predominantly Staphylococcus spp and to a lesser extent, Streptococcus and Corynebacterium spp) account for >60% of cultured microorganisms. Gram-negative bacteria (mostly E. coli, Klebsiella, and Enterobacter spp) represent <30% of positive cultures while anaerobes comprise <3% of isolates [bib_ref] Treatment and outcome of CPD-associated peritonitis, Troidle [/bib_ref] [bib_ref] Microbiological aspects of peritonitis associated with continuous ambulatory peritoneal dialysis, Von Graevenitz [/bib_ref]. Fungi, especially Candida species contribute to the same number of identified infections as anaerobes [bib_ref] Treatment and outcome of CPD-associated peritonitis, Troidle [/bib_ref]. Cultures can remain negative in >20% of all cases of PDAP [bib_ref] Treatment and outcome of CPD-associated peritonitis, Troidle [/bib_ref]. Again, 10-50 mL of dialysate should be collected for concentration and culture, cytospin Gram stain evaluation, analysis for protein, cell count and differential [fig_ref] Table I - 1: [/fig_ref]. Blood cultures are rarely positive in cases of PDAP. Direct inoculation of dialysate or a concentrated dialysate into an aerobic blood culture bottle for automated detection has proven to be as effective as direct plating of centrifuged fluid [bib_ref] Microbiological aspects of peritonitis associated with continuous ambulatory peritoneal dialysis, Von Graevenitz [/bib_ref] [bib_ref] Use of the BacT/Alert blood culture system for culture of sterile body..., Bourbeau [/bib_ref]. Consult directly with the microbiology laboratory when primary cultures of fluid are negative and additional cultures for slowly growing or highly fastidious organisms such as Mycobacterium, Nocardia and filamentous fungi should be pursued. If Nocardia is of concern, primary culture plates require prolonged incubation or culture on fungal media or buffered charcoal yeast extract agar.
## E. space-occupying lesions of the liver
The primary diagnostic dilemma for cases of space-occupying lesions of the liver is distinguishing those caused by parasites (Entamoeba histolytica and Echinococcus) from pyogenic abscesses caused by bacteria or fungi. The location, size, and number of liver abscesses is often not helpful for differentiation purposes as the majority are in the right lobe and can be seen in single or multiple loci [bib_ref] Liver abscess in adults: ten years experience in a UK centre, Mohsen [/bib_ref] [bib_ref] Pyogenic liver abscess: retrospective analysis of 80 cases over a 10-year period, Wong [/bib_ref]. In regions where E. histolytica disease is endemic, the use of serology or serum antigen detection tests can be helpful to exclude amebic abscesswhereas examination of stool for cysts and trophozoites is generally not [fig_ref] Table I - 1: [/fig_ref]. Liver abscess aspirates can be tested for the presence of E.histolytica antigen as well as submitted for direct microscopic evaluation for parasites. When amebic disease is unlikely, the abscess should be aspirated and the contents submitted in anaerobic transport for aerobic and anaerobic bacterial cultures. Commonly recovered isolates include Klebsiella spp, E. coli, and other Enterobacteriaceae, Pseudomonas spp, Streptococcus spp including Streptococcus anginosus group spp, Enterococcus spp, viridans group Streptococcus, S. aureus, Bacteroides spp, Fusobacterium spp (especially with Lemierre's syndrome), Clostridium spp, and rarely Candida spp [bib_ref] Liver abscess in adults: ten years experience in a UK centre, Mohsen [/bib_ref] [bib_ref] Pyogenic liver abscess: retrospective analysis of 80 cases over a 10-year period, Wong [/bib_ref]. Aerobic and anaerobic bacterial culture should be requested [fig_ref] Table I - 1: [/fig_ref]. Blood cultures can also be helpful in establishing an etiology if collected prior to the institution of antimicrobial therapy [bib_ref] Liver abscess in adults: ten years experience in a UK centre, Mohsen [/bib_ref] [bib_ref] Pyogenic liver abscess: retrospective analysis of 80 cases over a 10-year period, Wong [/bib_ref]. Occasionally, patients with primary genital infections due to N. gonorrhoeae or C. trachomatis can have extension of the disease to involve the liver capsule or adjacent peritoneum (Fitz-Hugh-Curtis syndrome).
## F. infections of the biliary tree
Not unexpectedly, bacteria commonly associated in biliary tract infections ( primarily cholecystitis and cholangitis) are the same organisms recovered from cases of pyogenic liver abscess (see above and Table VIII-1). Parasitic causes include Ascaris and Clonorchis spp or any parasite that can inhabit the biliary tree leading to obstruction. At a minimum, cultures for aerobic bacteria (anaerobes if the aspirate is collected appropriately) and Gram stain should be requested. When signs of sepsis and peritonitis are present, blood and peritoneal cultures should be obtained as well.
For patients with HIV infection, the list of potential agents and subsequent microbiology evaluations needs to be expanded to include Cryptosporidium, microsporidia, Cystoisospora (Isospora) belli, CMV, and Mycobacterium avium complex. As the identification of these organisms requires special processing, it is important to communicate with the laboratory to determine test availability either on-site or at a reference laboratory.
## G. splenic abscess
Most cases of splenic abscess are the result of metastatic or contiguous infectious processes, trauma, splenic infarction, or immunosuppression [bib_ref] Splenic abscesses from 1987 to 1995, Ooi [/bib_ref]. Infection is most likely aerobic and monomicrobic with Staphylococcus spp, Streptococcus spp, Enterococcus spp, Salmonella spp and E. coli commonly isolated. Anaerobic bacteria have been recovered in 5%-17% of culture-positive cases [bib_ref] Splenic abscesses from 1987 to 1995, Ooi [/bib_ref]. Aspirates should be processed in a similar manner as pyogenic liver abscesses including aerobic and anaerobic culture, Gram stain, and concomitantly collected blood culture sets [fig_ref] Table I - 1: [/fig_ref]. Unusual causes of splenic abscess include Bartonella spp, Streptobacillus moniliformis, Nocardia spp, and Burkholderia pseudomallei (uncommon outside of Southeast Asia or without suggestive travel history). The laboratory should be notified if this agent is possible due to the need for increased biosafety precautions since B. pseudomallei is a potential bioterrorism agent. As in biliary disease, the spectrum of organisms to be considered needs to be expanded to include Mycobacterium spp, fungi (including Pneumocystis jirovecii), and parasites for immunocompromised patients.
## H. secondary pancreatic infection
Most cases of acute or chronic pancreatitis are produced by obstruction, autoimmunity or alcohol ingestion [bib_ref] AGA institute technical review on acute pancreatitis, Forsmark [/bib_ref]. Necrotic pancreatic tissue generated by one of these processes can serve as a nidus for infection [bib_ref] AGA institute technical review on acute pancreatitis, Forsmark [/bib_ref]. Infectious agents associated with acute pancreatitis are numerous and diverse, however, superinfection of the pancreas is most often caused by gastrointestinal flora such as E. coli, Klebsiella spp and other members of the Enterobacteriaceae, Enterococcus spp, Staphylococcus spp, Streptococcus spp, and Candida spp. Necrotic tissue or pancreatic aspirates should be sent for aerobic bacterial culture and Gram stain and accompanied by 2-3 sets of blood cultures [fig_ref] Table I - 1: [/fig_ref]. Antimicrobial susceptibility results from isolated organisms can be used to direct therapy to reduce the likelihood of pancreatic sepsis, further extension of infection to contiguous organs, and mortality. Sterile cultures of necrotic pancreatic tissue are not unusual but may trigger consideration of an expanded search for fastidious or slowly growing organisms, parasites, or viruses.
## Ix. bone and joint infections
Osteomyelitis may arise as a consequence of hematogenous seeding of bone from a distant site, extension into bone from a contiguous soft tissue infection, extension into bone from a biofilm on a contiguous prosthesis, or direct traumatic inoculation [bib_ref] Infection and musculoskeletal conditions: osteomyelitis, Sia [/bib_ref]. Similarly, joint infections may develop by any of these routes, but occur most often by hematogenous seeding. From the perspective of pathophysiology, specific nature of infection and to at least some extent, clinical course, it is useful to classify bone infections based on pathogenesis. With joint infections, a classification scheme based on specific site of involvement and tempo of disease is most instructive; ie, acute versus chronic arthritis and septic bursitis.
The potential list of causative agents of bone and joint infections is diverse and is largely predicated on the pathogenesis of infection, the nature of the infection and the host [bib_ref] Mycobacterial and fungal infections of bone and joints, Meier [/bib_ref]. With few exceptions, bone and joint infections are usually monomicrobic. Rarely, such infections are polymicrobic.
Key points for the laboratory diagnosis of bone and joint infections
- Swabs are not recommended for specimen collection; aspirates or 3-6 tissue biopsies are needed to provide sufficient sample for studies
- Concomitant blood cultures are indicated for detection of some systemic agents of osteomyelitis and joint infections, but not for prosthetic joint infection.
- Joint fluids should have an aliquot injected into an aerobic blood culture bottle, preferably at the bedside, in addition to placing fluid in a sterile container for direct processing.
- For prosthetic joint infection diagnosis, 3-6 separate tissue samples should be submitted. As an alternative, sonication or bead mill homogenizing of samples from the removed prosthesis are excellent methods to detect pathogens in biofilms.
- When anaerobic bacteria are suspected, anaerobic transport containers should be used.
- Some agents of joint infections are not culturable and require molecular methods and/or serology for detection.
## A. osteomyelitis
Establishing an etiologic diagnosis of osteomyelitis nearly always requires obtaining bone biopsy material for microbiologic evaluation [bib_ref] Laboratory diagnosis of bone, joint, soft-tissue, and skin infections, Wilson [/bib_ref]. As much specimen as possible is desirable; specimens may include pieces of intact bone, shavings, scrapings and excised necrotic material. In true osteomyelitis, the bone tissue is often so necrotic that it can be easily obtained with a curette. Swab cultures of sinus tracts are not diagnostic and are not recommended. Similarly, determining the etiology of joint infections usually requires sampling the joint space directly with aspiration of synovial fluid and/or biopsy of the synovium. Concomitant or secondary bacteremia or fungemia occurs sporadically in patients with both osteomyelitis and infections of joints, although patients with contiguous spread osteomyelitis rarely develop bacteremia and blood cultures are rarely appropriate for that population. Thus, blood cultures collected during febrile episodes are recommended for the evaluation of patients suspected of having secondary bacteremia or fungemia. Assessment of acute phase reactants or nonspecific markers of inflammation such as procalcitonin, C-reactive protein, and erythrocyte sedimentation rates are not diagnostic in patients with these infections, but they may yield helpful information during therapy. Some less common agents may require molecular detection methods, which will often need to be sent to a reference laboratory with ensuing longer turnaround time for results (Table IX-1) [bib_ref] The polymerase chain reaction in infectious and post-infectious arthritis. A review, Louie [/bib_ref].
## B. joint infections
In addition to spontaneous and hematogenously seeded joint infections [fig_ref] Table I - 1: [/fig_ref] , a special category exists for prosthetic joint infections, especially infections of knee and hip prostheses, which are most often caused by coagulase-negative staphylococci [bib_ref] Clinical practice. Infection associated with prosthetic joints, Pozo [/bib_ref] [bib_ref] Guiding empirical antibiotic therapy in orthopaedics: the microbiology of prosthetic joint infection..., Moran [/bib_ref]. Laboratory diagnosis of prosthetic joint infections based on peri-surgical cultures is difficult since contamination with skin organisms is not uncommon in surgical samples. It is important to change to a fresh sterile scalpel after making the initial incision. One recommendation to differentiate true coagulase-negative staphylococcal infection from contamination occurring during surgical removal of tissue surrounding a prosthetic joint is to obtain 3-6 separate small tissue biopsies or curettings during the surgical procedure. If the same species is recovered from 3 or more of the samples, this is strong evidence of its pathogenicity [bib_ref] Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection at revision..., Atkins [/bib_ref].
Pre-surgical sampling of joint fluids from any suspected infection should be performed in the same manner as for acute arthritis [fig_ref] Table I - 1: [/fig_ref]. A European publication documented rapid (1-2 hour) pre-and perisurgical identification of S. aureus, MRSA, and putative methicillin-resistant coagulase negative staphylococci from joint fluids using a rapid NAAT assay [bib_ref] Direct detection of Staphylococcus osteoarticular infections by use of Xpert MRSA/SA SSTI..., Dubouix-Bourandy [/bib_ref]. Intra-operative Gram stains have poor yield (33%-50%) but if positive, may be helpful. Shoulder joints, whether natural or prosthetic, are preferentially infected with Propionibacterium acnes, a normally commensal skin organism [bib_ref] Microbiologic diagnosis of prosthetic shoulder infection by use of implant sonication, Piper [/bib_ref]. Anaerobic cultures of shoulder tissue biopsies should be incubated in anaerobic broth for up to 14 days before discarding as negative. Recent work, primarily from Mayo Clinic, recommends sonication of prosthetic joint biopsy samples and culture of the post-sonication fluid [bib_ref] Sonication of explanted prosthetic components in bags for diagnosis of prosthetic joint..., Trampuz [/bib_ref]. Another recent technique that was found to increase yield of bacteria and perhaps yeast from joint tissue and bone removed during prosthetic revision surgery was bead mill processing using 1 mm glass beads [bib_ref] Diagnosis of prosthetic joint infection by beadmill processing of a periprosthetic specimen, Roux [/bib_ref]. Since fungi and mycobacteria are extremely rare in this setting, they should not be sought without special communication with the laboratory [bib_ref] Use and cost-effectiveness of intraoperative acid-fast bacilli and fungal cultures in assessing..., Wadey [/bib_ref] [bib_ref] Current concepts review. Tuberculosis of bones and joints (78-A:288-298, Feb. 1996) by..., St Clair Strange [/bib_ref]. If fungi are suspected, the bead mill method would likely destroy hyphal elements, so mincing bone and tissue and direct inoculation onto fungal agar is still recommended. Both sonication and bead mill processing are not available in most laboratories.
## X. urinary tract infections
Clinical microbiology tests of value in establishing an etiologic diagnosis of infections of the urinary tract are covered in this section, including specimens and laboratory procedures for the diagnosis of cystitis, pyelonephritis, prostatitis, epididymitis and orchitis. Some special tests not available in smaller laboratories may be sent to a reference laboratory, but expect longer turnaround times for results.
Key points for the laboratory diagnosis of urinary tract infections:
- Urine should not sit at room temperature for more than 30 minutes. Hold at refrigerator temperatures if not cultured within 30 minutes.
- Reflexing to culture after a positive pyuria screen should be a locally approved policy.
- Three or more species of bacteria in a urine specimen usually indicates contamination at the time of collection and interpretation is fraught with error.
- Do not ask the laboratory to report "everything that grows" without first consulting with the laboratory and providing documentation for interpretive criteria for culture that is not in the laboratory procedure manual.
IDSA guidelines for diagnosis and treatment of urinary tract infections are published [bib_ref] Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis..., Warren [/bib_ref] [bib_ref] Bone and joint infections in intravenous drug abusers, Chandrasekar [/bib_ref] as are ASM recommendations. These provide diagnostic recommendations that are similar to those presented here (Table X-1). The differentiation of cystitis and pyelonephritis requires clinical information and physical findings as well as laboratory information, and from the laboratory perspective the spectrum of pathogens is similar for the two syndromes. Culturing only urines that have tested positive for pyuria, either with a dipstick test for leukocyte esterase or other indicators of PMNs may increase the likelihood of a positive culture, but occasionally samples yielding positive screening tests yield negative culture results and vice versa [bib_ref] The usefulness of screening tests for pyuria in combination with culture in..., Pfaller [/bib_ref]. The Gram stain is not the appropriate method to detect PMNs in urine but it can be ordered as an option for detection of high numbers of gram-negative rods when a patient is suspected of suffering from urosepsis. Because urine is so easily contaminated with commensal flora, specimens for culture of bacterial urinary tract pathogens should be collected with attention to minimizing contamination from the perineal and superficial mucosal microbiota. Although some literature suggests that traditional skin cleansing in preparation for the collection of midstream or "clean catch" specimens is not of benefit, many laboratories find that such specimens obtained without skin cleansing routinely contain mixed flora and if not stored properly and transported within one hour to the laboratory, yield high numbers of one or more potential pathogens on culture. Interpretation of such cultures is difficult, so skin cleansing is still recommended. The use of urine transport media in vacuum-fill tubes or refrigeration immediately after collection may decrease the proliferation of small numbers of contaminating organisms and increase the numbers of interpretable results. Straight or "in-and-out" catheterization of a properly prepared patient usually provides a less contaminated specimen. If mixed enteric bacteria in high numbers are recovered from a second, well- Or submit the removed prosthesis in sterile container for sonication protocol. Enterobacteriaceae
## Pseudomonas aeruginosa
Corynebacterium spp collected straight-catheterized sample from the same patient, a rectal-urinary fistula should be considered. Laboratory actions should be based on decisions arrived at by dialogue between clinician and laboratory.
Specimens from urinary catheters in place for more than a few hours frequently contain colonizing flora due to rapid biofilm formation on the catheter surface, which may not represent infection. Culture from indwelling catheters is therefore strongly discouraged, but if required, the specimen should be taken from the sampling port of a newly inserted device. Cultures of Foley catheter tips are of no clinical value and will be rejected. Collection of specimens from urinary diversions such as ileal loops is also discouraged because of the propensity of these locations to be chronically colonized. Chronic nephrostomy collections and bagged urine collections are also of questionable value. Multiple organisms or coagulase-negative staphylococci may be recovered in patients with urinary stents, and may be pathogenic. It is important that Urologists and Nephrologists who care for patients with complicated infections discuss any special needs or requests with the microbiology director or supervisor. Specimens from these patients may contain a mixed flora and if specific interpretive criteria are documented for these specimen types, the laboratory must be aware of the documentation and the special interpretive standards. Laboratories routinely provide antimicrobial susceptibility tests on potential pathogens in significant numbers. Specimens obtained by more invasive means, such as cystoscope or suprapubic aspirations should be clearly identified and the workup discussed in advance with the laboratory, especially if the clinician is interested in recovery of bacteria in concentrations less than 1000 colony forming units (cfu) per milliliter. Identification of a single potential pathogen in numbers as low as 200 cfu/mL may be significant, such as in acute urethral syndrome, but requests for culture results reports of <10 000 cfu/mL should be coordinated with the laboratory so that an appropriate volume of urine can be procesed.
Recovery of yeast, usually Candida spp, even in high cfu/mL is not infrequent from patients who do not actually have yeast UTI, thus interpretation of cultures yielding yeast is not as standardized as that for bacterial pathogens. Yeast in urine may rarely indicate systemic infection, for which additional tests must be conducted for confirmation (eg, blood cultures and β-glucan levels). Recovery of Mycobacterium tuberculosis is best accomplished with first-voided morning specimens of >20 mL, and requires a specific request to the laboratory so that appropriate processing and media are employed. Recovery of adenovirus in cases of cystitis requires a specific request for viral culture. A nucleic acid amplification test (NAAT) may also be available at reference laboratories for detection of adenovirus. Polyoma BK virus nephropathy is best diagnosed by quantitative molecular determination of circulating virus in blood rather than detection of virus in urine. Such tests are usually performed in reference laboratories.
Acute bacterial prostatitis is defined by clinical signs and physical findings combined with positive urine or prostate
## Polymicrobial infections also consider submitting prosthesis (if removed) for sonication
Abbreviations: AFB, acid-fast bacillus; KOH, potassium hydroxide; NAAT, nucleic acid amplification test; RT, room temperature. a When sufficient synovial fluid specimen has been obtained, up to 10 mL should be transferred aseptically into an aerobic blood culture bottle and processed in a manner similar to routine blood cultures [bib_ref] Culture with BACTEC Peds Plus/ F bottle compared with conventional methods for..., Hughes [/bib_ref] [bib_ref] Culture of joint specimens in bacterial arthritis. Impact of blood culture bottle..., Von Essen [/bib_ref]. This practice, however, does not obviate the value of direct specimen Gram stains and direct solid agar culture of synovial fluid specimens. These procedures should always be done in addition to inoculation of a blood culture bottle with up to 10 mL of the fluid. Dilution of active PMNs and other factors in the blood culture broth may allow recovery of the organism when direct culture yields no growth. b Kingella kingae is most often observed as a cause of septic joint infections in children and usually involves the knee [bib_ref] Review article: Paediatric bone and joint infection, Stott [/bib_ref] [bib_ref] Kingella kingae: an emerging cause of invasive infections in young children, Yagupsky [/bib_ref].
c Neisseria gonorrhoeae may yield aberrant morphologic forms on Gram stain of synovial fluid in patients with joint infections due to this organism. Synovial fluid and synovium biopsy specimens should be processed expeditiously for culture and even then, cultures are often negative [bib_ref] Spectrum of gonococcal arthritis: evidence for sequential stages and clinical subgroups, Gelfand [/bib_ref]. d In a patient with a compatible illness, especially with a history of recent vaccination with the live attenuated rubella virus vaccine, a negative serologic test for rubella may be considered suggestive evidence for joint infection due to rubella virus [bib_ref] Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative..., Tingle [/bib_ref]. e Culture of synovial fluid for B. burgdorferi requires use of specialized media and even with expeditious processing of specimens in an experienced laboratory, rarely results in recovery of the organism. Most laboratories will need to send the sample to a reference laboratory, further delaying and compromising possible cultures. Culture is rarely done except in research settings. f Detection of M. tuberculosis or other Mycobacterium species by microscopy or in culture is very uncommon from synovial fluid specimens in patients with joint infections due to these organisms [bib_ref] Current concepts review. Tuberculosis of bones and joints (78-A:288-298, Feb. 1996) by..., St Clair Strange [/bib_ref]. Synovium tissue enhances the likelihood of detection.
secretion cultures yielding usual urinary tract pathogens [bib_ref] Prostatitis revisited: new definitions, new approaches, Krieger [/bib_ref] [bib_ref] Acute and chronic prostatitis: diagnosis and treatment, Meares [/bib_ref] [bib_ref] Clinical practice. Chronic prostatitis and the chronic pelvic pain syndrome, Schaeffer [/bib_ref]. The diagnosis of chronic prostatitis is much more problematic, and the percentage of cases in which a positive culture is obtained is much lower [bib_ref] New paradigms in understanding chronic pelvic pain syndrome, Konkle [/bib_ref]. The traditional Meares-Stamey four glass specimen obtained by collecting the first 10 mL void, a mid-stream specimen, expressed prostate secretions (EPS) and a 10 mL post-prostate-massage urine is positive if there is a ten fold higher bacterial count in the EPS than the mid-stream urine. A two-specimen variant, involving only the mid-stream and the EPS specimens, is also used. A positive test is infrequent, and chronic pelvic pain syndrome is not frequently caused by a culturable infectious agent. It should be remembered that prostatic massage in a patient with acute bacterial prostatitis may precipitate bacteremia and/or shock. [fig_ref] Table X - 1: [/fig_ref] summarizes the approach to laboratory diagnosis of prostatitis. Epididymitis in men under 35 years of age is most frequently associated with the sexually transmitted pathogens Chlamydia trachomatis and Neisseria gonorrhoeae. NAATs are the most sensitive and rapid diagnostic procedures for these agents and each commercially available system has its own collection kit. Culture of N. gonorrhoeae is recommended when antibiotic resistance is a concern, and special media are required for antimicrobial susceptibility testing (AST), which may be referred to a public health laboratory. In men over 35 years of age, gram-negative and gram-positive pathogens similar to the organisms causing UTI and prostatitis may cause invasive infections of the epididymis and testis. Surgically obtained tissue may be cultured for bacterial pathogens, and AST will be performed. Fungal and mycobacterial disease are both uncommon, and laboratory diagnosis requires communication from the clinician to the laboratory to ensure proper medium selection and processing, particularly if tissue is to be cultured for these organisms.
Bacterial orchitis may be caused by both gram-negative and gram-positive pathogens, frequently by extension from a contiguous infection of the epididymis. Viral orchitis is most frequently ascribed to Mumps virus. The diagnosis is made by IgM serology for Mumps antibodies, or by acute and convalescent IgG serology. Other viral causes of epididymo-orchitis are Coxsackie virus, rubella virus, Epstein-Barr virus and Varicella-Zoster virus. Systemic fungal diseases can involve the epididymis or testis, including blastomycosis, histoplasmosis and coccidioidomycosis. Mycobacterium tuberculosis may also involve these sites [bib_ref] Epididymo-orchitis and epididymitis: a review of causes and management of unusual forms, Hagley [/bib_ref]. Table X-3 summarizes the approaches to specimen management for cases of epididymitis and orchitis.
## Xi. genital infections
Both point of care and laboratory tests to identify the microbiological etiology of genital infections are described below. In addition, because recommendations exist for screening of genital infections for specific risk groups, these are also presented. In this section infections are categorized as follows: cutaneous genital lesions, vaginitis and vaginosis, urethritis and cervicitis, and infections of the female pelvis, including endometritis and pelvic inflammatory disease (PID). Testing in special populations, such as pregnant patients, children and men who have sex with men (MSM) are noted where applicable but readers are referred to the more comprehensive guidelines referenced. There is considerable overlap in symptoms and signs for many genital infections and clinical diagnosis alone is neither sensitive nor specific. Thus, diagnostic testing is recommended for the following reasons: appropriate treatment can be focused, specific diagnosis has the benefit of increasing therapeutic compliance by the patient and the patient is more likely to comply with partner notification. Providers should also recognize that despite diagnostic testing, 25%-40% of the causes of genital infections or symptoms may not be specifically identified, and that many infections are acquired from an asymptomatic partner unaware of their infection. In fact, patients who seem to "fail" therapy and continue to exhibit symptoms and/or have positive tests for sexually transmitted infections (STIs), are most likely to have been re-infected by their sexual partner [bib_ref] Methods for detection of Trichomonas vaginalis in the male partners of infected..., Hobbs [/bib_ref]. Thus referral for partners for specific testing and treatment is essential to prevent re-infection and is especially true for patients who may be pregnant. Finally, because the vast majority of genital infections are STIs and communicable, they are a public health concern and patients and providers should note that positive tests for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (GC), syphilis, chancroid, and human immunodeficiency virus (HIV) require reporting in accordance with state and local statutory requirements by the laboratory and/or the provider. Reporting of additional STIs varies by state.
## Key points for the laboratory diagnosis of genital infections:
- For vaginosis (altered vaginal flora) a Gram stain is more specific than culture or probe testing and culture is not recommended.
- Distinguishing between HSV-1 and HSV-2 antibodies requires testing with type-specific glycoprotein G (gG)-based assays.
- Testing simultaneously for CT, GC and Trichomonas is optimal for detection of the most common treatable STIs in female patients.
- Screen for Group B streptococcus at 35-37 weeks of pregnancy using both vaginal and rectal swabs.
- Screen for HIV early in each new pregnancy and in sexually active patients age 13-64 seeking evaluation for STIs.
- Undertake partner testing and/or treatment of positive index cases to prevent re-infection.
## A. genital lesions
Genital lesions may have multiple simultaneous infectious etiologies that make them a challenge to diagnose and treat properly. Centers for Disease Control and Prevention (CDC) guidelines recommend that all patients presenting with a genital lesion should be evaluated with a serological test for syphilis, as well as diagnostic tests for genital herpes and for H. ducreyi where chancroid is prevalent. Because many of the genital lesions exhibit inflammatory epithelium that enhances the transmission of HIV, screening with an EIA (enzymeimmunoassay) HIV antibody test is recommended in these patients as well. [fig_ref] Table I - 1: [/fig_ref] shows the diagnostic tests for identifying the etiology of the most common genital lesions. For suspected cases of HSV genital lesions, viral culture, direct fluorescent antibody (DFA) and/or nucleic acid amplification tests (NAATs) are commonly used for diagnosis. Since methods for specific testing for vesicles varies among laboratories, consultation with the laboratory before specimen collection is appropriate. For instance, while NAATs are the most sensitive, especially where suboptimal collection, or nonulcerative or vesicular lesions may be present, there may be limitations as to specimen source acceptable and patient age depending on the NAAT used. Culture is more likely to be positive in patients that have vesicular versus ulcerative lesions, specimens obtained from a first episodic lesion versus a recurrent lesion, and specimens from immunosuppressed patients rather than immunocompetent. DFA allows assessment of an adequate specimen and can be a rapid test if performed on-site; isolates should be typed to determine if they are HSV-1 or 2 since 12-month recurrence rates are more common with HSV-2 (90%) than HSV-1 (55%). Serology cannot distinguish between HSV-1 and HSV-2 unless a type-specific glycoprotein G (gG) -based assay is requested.
Point of care tests (POCT) for HSV-2 may yield false positive results in patient populations with a low likelihood of HSV infection or in early stages of infection as well as false negative results in primary lesions that are due to HSV-1.
In children presenting with genital lesions, providers should not assume HSV only but should consider potential atypical presentation of Varicella zoster virus (VZV). DFA is best for detection of VZV as culture is less sensitive. Pregnant patients with a history of genital herpes should be assessed for active lesions at the time of delivery.
New consensus guidelines for the management of women with abnormal cervical cytologic lesions and human papilloma virus (HPV) as well as the use of genotyping tests are pending publication. The 2006 consensus guidelines are discussed in the American Journal of Obstetrics and Gynecology by Wright et al. regarding routine high-risk HPV testing and available at the website www.asccp.org/consensus/histological.shtml (accessed 2-3-13) [bib_ref] consensus guidelines for the management of women with abnormal cervical cancer screening..., Wright [/bib_ref]. A more recent American Society for Colposcopy and Cervical Pathology (ASCCP) HPV genotyping update discusses the testing specifically for HPV 16/18 genotype in women over 30. Basically, HPV testing is recommended for the purposes of triaging women >20 years of age with atypical squamous cells of undetermined significance (ASC-US) or ASC-H (atypical squamous cells cannot exclude high grade squamous intraepithelial lesion [HSIL]). Only testing for those high-risk HPV types that are associated with cervical cancer is appropriate. Follow-up testing for abnormal cytology and/or positive HPV is complicated and readers are referred to the ASCCP guidelines for management decisions. In addition, recommendations for testing for genotypes 16/18 HPV for women over 30, where high risk HPV testing can be ordered in conjunction with cytology, should be considered. In general, results of cytology negative but HPV high risk positive warrant HPV 16/18 genotype determination for identification of patients at higher risk for progression to invasive cervical cancer. Endocervical specimens in liquid cytology medium have a higher sensitivity for detecting significant lesions (eg squamous intraepithelial lesions (SIL) and can facilitate subsequent HPV testing in patients since it can be done from the same specimen. Patients with a cervix remaining after hysterectomy, HIV positive patients, and patients that have received the quadrivalent recombinant HPV vaccine (Gardasil from Merck and Co.) should undergo routine Papanicolaou (Pap) and HPV screening and management. Pap and/or HPV testing should be postponed when a woman is menstruating [bib_ref] consensus guidelines for the management of women with abnormal cervical cancer screening..., Wright [/bib_ref] [bib_ref] American Cancer Society guideline for the early detection of cervical neoplasia and..., Saslow [/bib_ref].
In the United States, testing for syphilis traditionally has consisted of initial screening with an inexpensive nontreponemal test (rapid plasma reagin, RPR), then retesting reactive specimens with a more specific, and more expensive, treponemal test (eg T. pallidum particle agglutination [TP-PA]). If a nontreponemal test is being used as the screening test, it should be confirmed, as a high percentage of false positive results occur in many medical conditions unrelated to syphilis. When both test results are reactive, they indicate present or past infection. However, for economic reasons, some high-volume clinical laboratories have begun using automated treponemal tests, such as automated EIAs or immunochemoluminescence tests, and have reversed the testing sequence: first screening with a treponemal test and then retesting reactive results with a nontreponemal test. This approach has introduced complexities in test interpretation that did not exist with the traditional sequence. Specifically, screening with a treponemal test sometimes identifies persons who are reactive to the treponemal test but nonreactive to the nontreponemal test. No formal recommendations exist regarding how such results derived from this new testing sequence should be interpreted, or how patients with such results should be managed. To begin an assessment of how clinical laboratories are addressing this concern, CDC reviewed the testing algorithms used and the test interpretations provided in four laboratories in New York City. Substantial variation was found in the testing strategies used, which might lead to confusion about appropriate patient management. A total of 3664 (3%) of 116 822 specimens had test results (ie, reactive treponemal test result and nonreactive nontreponemal test result) that would not have been identified by the traditional testing algorithms, which obviate additional testing if the nontreponemal test result is nonreactive. If they have not been previously treated, patients with reactive results from treponemal tests and nonreactive results from nontreponemal tests should be treated for late latent syphilis.
Treponema pallidum cannot be seen on Gram stain and cannot be cultured in the routine laboratory. Darkfield exam for motile spirochetes is unavailable in the majority of laboratories.
Chancroid, caused by the gram-negative organism Haemophilus ducreyi, is the one genital lesion where a Gram stain may be helpful in diagnosis. Communication with the laboratory about the presumed diagnosis and specimen transport may enhance recognition of organisms in the Gram stain and facilitate the appropriate culture technique. Samples must be obtained after surface debridement and should be sent to a referral laboratory familiar with this testing as many microbiologists have rarely seen chancroid. Lymphogranuloma venereum (LGV) is caused by the intracellular pathogen Chlamydia trachomatis (CT), specifically serovars L1, L2a, L2b and L3.
LGV is a diagnosis of exclusion of more common entities in context with epidemiological information.
## B. vaginosis/vaginitis
The diagnoses of bacterial vaginosis (BV), or altered vaginal flora, and vaginitis caused by fungal organisms (vulvovaginal candidiasis [VVC]) or Trichomonas vaginalis (TV), are often considered clinically and diagnostically as a group because of their overlapping nature. However, the mode of transmission and/or acquisition is not necessarily that of an STI for BV or VVC, but it is for TV. A number of point-of-care tests (POCTs) can be performed from a vaginal discharge specimen while the patient is in the healthcare setting. Although POCTs are popular, the sensitivity and specificity of POCTs for making a specific diagnosis varies widely and these assays, while rapid, are often diagnostically poor. Some of the tests include a pH strip test, scored Gram stain for BV, wet mount for TV, and 10% KOH microscopic examinations for VVC. For BV, use of clinical criteria (Amsel's diagnostic criteria) is equal to a scored Gram stain of vaginal discharge. However, a scored Gram stain is more specific than probe hybridization and POCT tests (that only detect the presence of G. vaginalis as the hallmark organisms for altered vaginal flora). For VVC and TV the presence of pseudohyphae and motile trichomonads, respectively, allows a diagnosis. However, proficiency in microscopic examination is essential given that infections may be mixed and/or present with atypical manifestations. Unfortunately consistent microscopic exam of vaginal specimens and interpretation are difficult for many laboratories to perform and wide variation of sensitivities (40%-70%) for both TV and CVV using smear exam exists relative to NAAT and culture, respectively. It should be noted that recent publications utilizing NAATs highlight the prevalence of Trichomonas as equal to or greater than CT and GC and point to a growing trend toward screening for TV, CT and GC simultaneously. Tests for the entities of vaginosis/vaginitis are shown in [fig_ref] Table I - 1: [/fig_ref] [bib_ref] Comparison of APTIMA® Trichomonas vaginalis transcription-mediated amplification assay and BD Affirm VPIII..., Andrea [/bib_ref] [bib_ref] Rapid antigen testing compares favorably with transcription-mediated amplification assay for the detection..., Huppert [/bib_ref].
## C. urethritis/cervicitis
Urethritis and cervicitis share common signs and symptoms and infectious etiologies in male and female patients, respectively. Table XI-3 combines the diagnostic tests used to identify the pathogens common to both. In addition, because screening for CT and GC has reduced the repercussions related to infections and subsequent PID, the following guidelines for screening women for CT and GC have been presented by the U.S. Preventive Services Task Force [bib_ref] Acute and chronic prostatitis: diagnosis and treatment, Meares [/bib_ref].
Annual CT screening For laboratory diagnosis of CT and GC, many methods exist but nucleic amplification tests (NAATs) are the preferred assays for detection because of increased sensitivity while retaining specificity in low prevalence populations (pregnant patients) and the ability to screen with a noninvasive urine specimen [bib_ref] Molecular tests for detection of the sexually-transmitted pathogens Neisseria gonorrhoeae and Chlamydia..., Chapin [/bib_ref]. Specifically, EIA tests for CT should not be used due to lack of sensitivity. In general, retesting patients with a follow-up test for CT or GC (test of cure) is not recommended unless special circumstances exist (pregnancy, continuing symptoms). However, patients that are at higher risk for STIs should be screened within 3-12 months from the initial positive test for possible re-infection because those patients with repeat infections are at higher risk for PID. Requirements for testing practices and/or need for confirmatory testing in pediatric patients may vary from state to state. Appropriate providers or laboratories that perform testing in children should be consulted. NAATs on samples other than genital are currently not FDAcleared and require in-house laboratory validation.
Recently, prevalence studies using NAATs have shown that Trichomonas is as common as CT and more common that GC q NAATs for CT will detect L1-L3 but do not distinguish these from the other CT serovars.
r Place a drop of mineral oil on a sterile scalpel blade. Allow some of the oil to flow onto the papule. Scrape vigorously six or seven times to remove the top of the papule. (Tiny flecks of blood should be seen in the oil.) Use the flat side of the scalpel to add pressure to the side of the papule to push the mite out of the burrow. Transfer the oil and scrapings onto a glass slide (an applicator stick can be used). Do not use a swab, which will absort the material and not release it onto the slide. For best results, scrape 20 papules.
in most clinical and geographic settings, with a uniquely high presence in women over 40 and incarcerated populations. In addition, the ulcerative nature of the infection leads to sequelae similar to those of CT and GC, including perinatal complications as well as susceptibility to HIV and HSV acquisition and transmission. An FDA-cleared NAAT allows testing from the same screening specimens used for CT and GC testing with significantly improved sensitivity over wet mount. Standardized tests for M. genitalium are not available or recommended. However, in patients with nonchlamydial, NGU (nongonococcal) urethritis, 15%-25% infections may be due to this organism. A NAAT may be the best option for detection of M. genitalium, due to issues with culture and cross-reactivity with serologic tests, but that test is neither FDA-cleared nor widely available. Culture for Ureaplasma is not recommended because of the high prevalence of colonization in asymptomatic, sexually active people [bib_ref] Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure, Bradshaw [/bib_ref].
## D. infections of the female pelvis
Pelvic inflammatory disease (PID) is a spectrum of disorders of the upper female genital tract and includes any single or combination of endometritis, tubo-ovarian abscess, and salpingitis. PID can be clinically difficult to identify when patients present with mild or nonspecific symptoms. Finding symptoms on physical exam (cervical motion tenderness) as well as other criteria (elevated temperature or mucopurulent discharge) increases the specificity and positive predictive value of laboratory tests. Diagnostic tests are dependent on the clinical severity of disease, epidemiological risk assessment, and whether invasive procedures, such as laparoscopy and/or endometrial biopsy, are used. Bacterial tests performed on nonaseptically collected specimens (endocervical or dilatation and curettage [D and C] have limited utility in diagnosing PID. Actinomyces spp can cause infections associated with intrauterine devices; if suspected, the laboratory should be notified to culture such samples anaerobically, including an anaerobic broth that is held for 7 days. Patients with suspected PID should be tested for CT, GC, TV and HIV. Both difficulty in diagnosis as well as significant potential sequelae should make the threshold for therapy low. Postpartum endometritis should be suspected when the patient presents with high fever (≥101°F or >100.4°F (38.0°C) on more than two occasions >6 hours apart after the first 24 hours of delivery and up to 10 days post delivery).) after the first 24 hours post-delivery, abdominal pain, uterine tenderness and foul lochia. Usually a multi-organism syndrome, the infection is most commonly seen in patients with unplanned ceaserean section because of the inability to introduce antibiotics quickly. Postpartum endometritis can be reduced by testing and treating for symptomatic BV late in pregnancy, which has been associated with preterm labor and prolonged delivery. Screening for colonization with group B streptococci (both vaginal and anal swabs) at 35-37 weeks gestation and prophylaxis during labor and delivery can reduce the incidence of neonatal disease [bib_ref] Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal..., Verani [/bib_ref]. Although the role of culture in the setting of endometritis is controversial, diagnostic tests to consider in the diagnosis of PID and postpartum endometritis are shown in [fig_ref] Table I - 1: [/fig_ref].
## E. special populations
Children for whom sexual assault is a consideration should be referred to a setting or clinic that specifically deals with this situation. Readers are referred to the references by Jenny, Kellogg, Girardet, and Black where NAAT and noninvasive specimens have yielded excellent results [bib_ref] Comparison of nucleic acid amplification tests and culture techniques in the detection..., Kellogg [/bib_ref] [bib_ref] Multicenter study of nucleic acid amplification tests for detection of Chlamydia trachomatis..., Black [/bib_ref].
In MSM, the typical genital sites are not always infected, eg the urethra or urine. Recommendations from the CDC now include screening in this population at a number of sites for GC and CT, including rectum, pharynx and urethra. Readers are referred to the CDC Treatment Guidelines for further recommendations.
In pregnant patients, screening for HIV, syphilis, hepatitis B surface antigen (HBsAg), CT, GC (if in high risk group or high GC prevalence area) is routine. Symptomatic patients with vaginosis/vaginitis should be tested for BV and Trichomonas. Screening for Group B streptococci should occur at 35-37 weeks with both rectal and vaginal swab specimens submitted to optimize identification of carriers. Laboratories typically use an enrichment broth and selective media to enhance recovery for both Trichomonas and Group B streptococci. While NAATs are available for Group B streptococci, the sensitivity is optimal only when performed from an enrichment broth specimen. Group A streptococci are not detected by Group B PCR tests. Past history of STIs, those in higher risk groups, and/or clinical presentation consistent with infection, should be assessed for other pathogens as warranted, eg HSV if vesicular lesions are present. Although rare, Listeria infection in the pregnant woman (usually acquired via ingestion of unpasteurized cheese or other food) can be passed to the fetus, leading to disease or death of the neonate. Due to nonspecific symptoms, diagnosis is difficult, but blood cultures from a bacteremic mother may allow detection of this pathogen in time for antibiotic prophylaxis [bib_ref] Invasive listeriosis in the Foodborne Diseases Active Surveillance Network (FoodNet), 2004-2009: further..., Silk [/bib_ref]. Screening tests (serology, stool cultures) in pregnant women are not appropriate.
## Xii. skin and soft tissue infections
Cutaneous infections, often referred to as skin and soft tissue infections (SSTIs), occur when the skin's protective mechanisms fail, especially following trauma, inflammation, maceration from excessive moisture, poor blood perfusion, or other factors that disrupt the stratum corneum. Thus, any compromise of skin and skin structure provides a point of entry for a myriad of exogenous and endogenous microbial flora that can produce a variety of infections. Infections of the skin and soft tissue are often classified as primary pyodermas, infections associated with underlying conditions of the skin, and necrotizing infections. Representative primary cutaneous infections of the skin include cellulitis, ecthyma, impetigo, folliculitis, furunculosis, and erysipelas and are commonly caused by a narrow spectrum of pyogenic bacteria (Staphylococcus aureus and/or Streptococcus pyogenes [Group A streptococcus]). Secondary infections are often extensions of pre-existing lesions (traumatic or surgical wounds, ulcers) which serve as the primary portal of entry for microbial pathogens and are often polymicrobial (mixed aerobic and anaerobic microorganisms) involving subcutaneous tissue. Diabetic foot infections (DFI) typically originate in a wound, secondary to a neuropathic ulceration. Anaerobic bacteria are important and predominant pathogens in DFI and should always be considered in choosing therapeutic options. The majority of DFIs are polymicrobial but grampositive cocci, specifically staphylococci, are the most common infectious agents. Pseudomonas aeruginosa is involved in the majority of chronic DFIs but its relevance related to treatment decisions is not clear. Surface cultures of such wounds, including decubitus ulcers, are not valuable, as they usually represent colonizing microbes, which cannot be differentiated from the underlying etiologic agent. Tissue biopsies after thorough debridement, or bone biopsies through a debrided site, are most valuable. Necrotizing cutaneous infections, such as necrotizing fasciitis, are usually caused by streptococci (and less often by MRSA or Klebsiella species), but can also be polymcrobial. The infection usually occurs following a penetrating wound to the extremities, is often life-threatening, and requires immediate recognition and intervention. On rare occasions, necrotizing fasciitis occurs in the absence of identifiable trauma.
For the common forms of SSTIs, cultures are not indicated for uncomplicated infections (cellulitis, subcutaneous abscesses) treated in the outpatient setting. Whether cultures are beneficial in managing cellulitis in the hospitalized patient is uncertain and the sensitivity of blood cultures in this setting is low. Cultures are indicated for the patient who requires operative incision and drainage because of risk for deep structure and underlying tissue involvement [bib_ref] Practice guidelines for the diagnosis and management of skin and soft-tissue infections, Stevens [/bib_ref]. In this section, cutaneous infections, involving skin and soft tissue, have been expanded and categorized as follows: traumaassociated, surgical site, burn wounds, fungal, human and animal bites, and device-related. Although the majority of these infections are commonly caused by S. aureus and S. pyogenes, other microorganisms, including fungi and viruses, are important and require appropriate medical and therapeutic management. It is important that the clinician be familiar with the extent or limitation of services provided by the supporting laboratory. For example, not all laboratories provide quantitative cultures for the assessment of wounds, especially burn wounds. If a desired service or procedure is not available in the local microbiology laboratory, consult with the laboratory so that arrangements can be made to transfer the specimen to a qualified reference laboratory with the understanding that turnaround times (TAT) are likely to be longer, thus extending the time to receipt of results.
A major factor in acquiring clinically relevant culture and associated diagnostic testing results is the acquisition of appropriate specimens that represent the group of diseases discussed in this section. Guidelines for obtaining representative specimens are summarized as follows:
Key points for the laboratory diagnosis of skin and soft tissue infections:
- Do not use the label "wound" alone. Be specific about body site and type of wound (for example "human bite wound, knuckle").
- The specimen of choice is a biopsied sample of the advancing margin of the lesion. Pus alone or a cursory surface swab is inadequate and does not represent the disease process.
- Do not ask the laboratory to report everything that grows.
## A. burn wound infections
Reliance on clinical signs and symptoms alone in the diagnosis of burn wound infections is challenging and unreliable. Sampling of the burn wound by either surface swab or tissue biopsy for culture is recommended for monitoring the presence and extent of infection [fig_ref] Table I - 1: [/fig_ref]. Quantitative culture of either specimen is recommended; optimal utilization of quantitative surface swabs requires twice weekly sampling of the same site to accurately monitor the trend of bacterial colonization. A major limitation of surface swab quantitative culture is that microbial growth reflects the microbial flora on the surface of the wound rather than the advancing margin of the subcutaneous or deep, underlying damaged tissue. Quantitative bacterial culture of tissue biopsy should be supplemented with histopathological examination to better ascertain the extent of microbial invasion. Be advised that quantitative bacterial cultures may not be offered in all laboratories; quantitative biopsy cultures should be considered for patients in which grafting is necessary. Prior to any sampling or biopsy, the wound should be thoroughly cleansed and devoid of topical antimicrobials that can affect culture results. Blood cultures should be collected for detection of systemic disease secondary to the wound. The application of nucleic acid amplification tests (NAAT) for detection of listed viruses is commonly restricted to blood and/or body fluids. It is advisable that the clinician determine if the local supporting laboratory has validated such assays and if the laboratory has assessed the performance with tissue specimens. This precaution would also apply to the molecular detection of MRSA (except for one FDA-cleared test for S. aureus and MRSA from SSTIs) and VRE [bib_ref] Burn wound infections, Church [/bib_ref].
## B. human bite wound infections
The human oral cavity contains many potential aerobic and anaerobic pathogens and is the primary source of pathogens that cause infections following human bites. The most common of these are Staphylococcus spp, Streptococcus spp, Clostridium spp, pigmenting anaerobic gram-negative rods, and Fusobacterium spp. Such infections are common in the pediatric age group and are often inflicted during play or by abusive adults. Bite wounds can vary from superficial abrasions to more severe manifestations including lymphangitis, local abscesses, septic arthritis, tenosynovitis, and osteomyelitis. Rare complications include endocarditis, meningitis, brain abscess, and sepsis with accompanying disseminated intravascular coagulation, especially in immunocompromised patients.
In addition to the challenge of acquiring a representative wound specimen for aerobic and anaerobic culture, a major limitation of culture is the potential for misleading information as a result of the polymicrobial nature of the wound. It is important that a Gram stain be performed on the specimen to assess the presence of indicators of inflammation (eg neutrophils), superficial contamination (squamous epithelial cells), and microorganisms. Swabs are not the specimen of choice in many cases [fig_ref] Table I - 1: [/fig_ref] tissue biopsy or aspirates include: 1) greater risk of contamination with surface/colonizing flora; 2) limited quantity of specimen that can be acquired; 3) drying unless placed in appropriate transport media, which in itself dilutes out rare microbes and further limits the yield of the culture [bib_ref] Bacteriology of human bite wound infections, Merriam [/bib_ref] [bib_ref] Microbiology and management of human and animal bite wound infections, Brook [/bib_ref].
## 2). major limitations of swabs versus
## C. animal bite wound infections
As with human bite wounds, the oral cavity of animals is the primary source of potential pathogens and thus the anticipated etiological agent(s) is highly dependant upon the type of animal that inflicted the bite [fig_ref] Table I - 1: [/fig_ref]. Since dogs and cats account for the majority of animal-inflicted bite wounds, the two most prominent groups of microorganisms initially considered in the evaluation of patients are Pasteurella spp, namely P. canis (dogs) and P. multocida subspecies multocida and subspecies septica (cats) or Capnocytophaga canimorsus. Other common aerobes include streptococci, staphylococci, Moraxella spp and saprophytic Neisseria spp. Animal bite wounds are often polymicrobial in nature and include a variety of anaerobes. Due to the complexity of the microbial flora in animals, examination of cultures for organisms other than those listed in [fig_ref] Table I - 1: [/fig_ref] is of little benefit since these organisms are not included in most of the commercial identification systems (conventional and automated) data bases [bib_ref] Prolonged incubation and extensive subculturing do not increase recovery of clinically significant..., Baron [/bib_ref] [bib_ref] Fusobacterium canifelinum sp. nov., from the oral cavity of cats and dogs, Conrads [/bib_ref] [bib_ref] Migdalis I. Pseudomonas fluorescens cutaneous abscess and recurrent bacteremia following a dog..., Dalamaga [/bib_ref] [bib_ref] Capnocytophaga canimorsus sepsis with purpura fulminans and symmetrical gangrene following a dog..., Deshmukh [/bib_ref] [bib_ref] Clinical significance and epidemiology of NO-1, an unusual bacterium associated with dog..., Kaiser [/bib_ref] [bib_ref] Description of Kingella potus sp. nov., an organism isolated from a wound..., Lawson [/bib_ref] [bib_ref] Mycobacterium fortuitum infection after a brown bear bite, Lehtinen [/bib_ref] [bib_ref] Mycobacterium fortuitum infection caused by a cat bite, Ngan [/bib_ref] [bib_ref] Tenosynovitis caused by Mycobacterium kansasii associated with a dog bite, Southern [/bib_ref] [bib_ref] Bacteriologic analysis of infected dog and cat bites, Talan [/bib_ref] [bib_ref] Human infection with Halomonas venusta following fish bite, Von Graevenitz [/bib_ref].
## D. trauma-associated cutaneous infections
Infections from trauma are usually caused by exogenous or environmental microbial flora but can be due to the individual's endogenous (normal) flora [fig_ref] Table I - 1: [/fig_ref]. It is strongly recommended that specimens not be submitted for culture within the first 48 hours post-trauma since growth from specimens collected within this time frame most likely represents environmental flora acquired at the time of the trauma episode (motor vehicle accident, stabbings, gunshot wounds, etc). The optimal time to acquire cultures is immediately post-debridement of the trauma site [bib_ref] Enterobacter taylorae") infections associated with severe trauma or crush injuries, Abbott [/bib_ref] [bib_ref] Cutaneous infections: microbiologic and epidemiologic considerations, Bisno [/bib_ref] [bib_ref] Isolation and identification of Clostridium spp. from infections associated with the injection..., Brazier [/bib_ref] [bib_ref] Targeting lurking pathogens in acute traumatic and chronic wounds, Eron [/bib_ref]. It is recommended that initial cultures focus on common pathogens with additional testing being reserved for uncommon or rare infections associated with special circumstances (ex: detection of Vibrio spp following salt-water exposure) or patients with chronic manifestations of infection or who do not respond to an initial course of therapy.
Although not considered in quite the same manner as external trauma, intravenous drug users (IVDU) inject themselves with exogenous substances that may include spores from soil and other contaminants that cause skin and soft tissue infections, ranging from abscesses to necrotizing fasciitis. Agents are similar to those in [fig_ref] Table I - 1: [/fig_ref] , with the addition of Clostridium sordellii, C. botulinum (causing wound botulism), and the agents of human bite wounds [fig_ref] Table I - 1: [/fig_ref] among skin poppers who use saliva as a drug diluent.
## E. surgical site infections
Surgical site infections (SSIs) may be caused by endogenous flora or originate from exogenous sources such as healthcare providers, the environment, or materials manipulated during an "incisional" or "organ/space" surgical procedure. Incisional infections are further divided into superficial (skin and subcutaneous tissue) and deep (tissue, muscle, fascia). Deep incisional and organ/space infections are the SSIs associated with the highest morbidity. The reader is referred to the Centers for Disease Control and Prevention Guidelines for Prevention of Surgical Site infections, 1999, for specific definitions of SSIs (http://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf ). Of the microbial agents listed below [fig_ref] Table I - 1: [/fig_ref] , Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), coagulase-negative staphylococci, and enterococci are isolated from nearly 50% of these infections. Although nterococcal species are commonly isolated from superficial cultures, they are seldom true pathogens; regimens that do not include coverage for enterococci are successful for surgical site infections. The recommended IDSA therapeutic regimens for surgical site infections are not reliably active against these organisms [bib_ref] Practice guidelines for the diagnosis and management of skin and soft-tissue infections, Stevens [/bib_ref]. To optimize clinically relevant laboratory results, resist the use of swabs during surgical procedures, and instead submit tissue, fluids, or aspirates.
## F. interventional radiology and drain devices
Common interventional devices that are used for diagnostic or therapeutic purposes include interventional radiology and surgical drains. The former consists of minimally invasive procedures (angiography, balloon angioplasty/stent, chemoembolization, drain insertions, embolizations, thrombolysis, biopsy, radiofrequency ablation, cryoablation, line insertion, inferior vena cava filters, vertebroplasty, nephrostomy placement, radiologically inserted gastrostomy, dialysis access and related intervention, transjugular intrahepatic porto-systemic shunt, biliary intervention, and endovenous laser ablation of varicose veins) performed using image guidance. Procedures are regarded as either diagnostic, (eg angiogram) or performed for treatment purposes, (eg angioplasty). Images are used to direct procedures that are performed with needles or other tiny instruments (eg catheters). Infections as a result of such procedures are rare but should be considered when evaluating a patient who has undergone interventional radiology which constitutes a risk factor for infection due to the invasive nature of the procedure. A variety of drainage devices are used to remove blood, serum, lymph, urine, pus and other fluids that accumulate in the wound bed following a procedure, (eg, fluids from deep wounds, intracorporeal cavities, or intraabdominal postoperative abscess). They are commonly used following abdominal, cardiothoracic, neurosurgery, orthopedic and breast surgery. Chest and abdominal drains are also used in trauma patients. The removal of fluid accumulations helps to prevent seromas and their subsequent infection. The routine use of postoperative surgical drains is diminishing, although their use in certain situations is quite necessary.
The type of drain to be used is selected according to quality and quantity of drainage fluid, the amount of suction required, the anatomical location, and the anticipated amount of time the drain will be needed. Tubing may also be tailored according to the aforementioned specifications. Some types of tubing include: round or flat silicone, rubber, Blake/Channel, and Triple-Lumen sump. The mechanism for drainage may depend on gravity or bulb suction, or it may require hospital wall suction or a portable suction device. Drains may be left in place from one day to weeks, but should be removed if an infection is suspected. The infectious organisms that may colonize a drain or its tubing typically depend on the anatomical location and position of the drain (superficial, intraperitoneal, or within an organ, duct or fistula) and the indication for its use. Intrepretation of culture results from drains that have been in place for more than 3 days may be difficult due to the presence of colonizing bacteria and yeast.
Drains are characterized as Gravity, Low-Pressure Bulb Evacuators, Spring Reservoir, Low Pressure or High Pressure. Fluids from drains are optimal specimens for collection and submission to the microbiology laboratory. All fluids should be collected aseptically and transported to the laboratory in an appropriate device such as blood culture bottle (aerobic), sterile, leak proof container (ie, urine cup), or a citrate-containing blood collection tube to prevent clotting in the event that blood is present. Expected pathogens from gravity drains originate from the skin or GI tract; for the remaining drain types, skin flora represent the predominate pathogens.
## G. cutaneous fungal infections
The presence of fungi (moulds or yeasts) on the skin poses a challenge to the clinician in determining if this represents contamination, saprophytic colonization, or is a true clinical infection. For convenience, the fungi have been listed by the type of mycosis they produce [fig_ref] Table I - 1: [/fig_ref] , eg dermatophytes typically produce tinea (ringworm)-type infections; dematiaceous (darkly pigmented moulds and yeast-like fungi) cause both cutaneous and subcutaneous forms of mycosis; dimorphic fungi generally cause systemic mycosis and the presence of cutaneous lesions signifies either disseminated or primary (direct inoculation) infection; yeast-like fungi are usually agents of opportunistic-types of mycoses but can also manifest as primary or disseminated disease as is true for the opportunistic moulds (eg Aspergillus spp, Fusarium spp). In addition to the recommended optimal specimens and associated cultures, fungal serology testing (complement fixation and immunodiffusion performed in parallel, not independent of the other) is often beneficial in diagnosing agents of systemic mycosis, specifically those caused by Histoplasma and Coccidioides. In cases of active histoplasmosis and blastomycosis, the urine antigen test may be of value in identifying disseminated disease.
The clinician should be aware that dematiaceous fungi (named so because they appear darkly pigmented on laboratory media), do not always appear pigmented in tissue but rather hyaline in nature. To help differentiate the dematiaceous species, a Fontana Mason stain (histopathology) should be performed to detect small quantities of melanin produced by these fungi. It is not uncommon for this group of fungi to be mistakenly misidentified by histology as a hyaline mould such as Aspergillus spp. This highlights the importance of correlating culture results with histological observations in determining the clinical relevance since the observation of fungal elements in histopathology specimens is most likely indicative of active fungal invasion [bib_ref] Diagnostic dilemmas: cutaneous fungal Bipolaris infection, Shafii [/bib_ref] [bib_ref] Cutaneous infections due to opportunistic molds: uncommon presentations, Vennewald [/bib_ref].
## Xiii. tickborne infections
The clinical microbiology tests of value in establishing an etiology of various tickborne diseases are presented below [fig_ref] Table I - 1: [/fig_ref]. Borrelia species are responsible for relapsing fever and Lyme borreliosis; both diseases are transmitted by ticks to humans. Lyme borreliosis is a multisystem disease that can affect the skin, nervous system, the joints, and heart; this infection is the most frequently reported tickborne disease in the northern hemisphere. For the most part, early Lyme disease is diagnosed on clinical grounds including the presence of erythema migrans while early/disseminated and late/persistent Lyme disease are diagnosed by two-tiered serological testing (EIA followed by Western blot). Western blot should not be performed except as a reflex test after an initial EIA has returned positive or equivocal. The IgM Western blot is not clinically interpretable after a patient has had 6-8 weeks of symptoms. Western blot IgG and IgM are based on testing 10 IgG bands and 3 IgM bands. Criteria for positivity are at least 5 IgG bands or at least 2 IgM bands (plus a positive or equivocal EIA) [bib_ref] Final report of the Lyme disease review panel of the Infectious Diseases..., Lantos [/bib_ref]. A 'post-treatment' Lyme disease syndrome may occur after appropriate antibiotic therapy for laboratory documented B. burgdorferi infection. Persistent symptoms lasting more than six months such as fatigue, musculoskeletal pains, and neurocognitive dysfunction do not permanently respond to long-term antibiotic therapy based on randomized-controlled trial data."
Rickettsial diseases that are transmitted by ticks include Rocky Mountain spotted fever, human granulocytotropic anaplasmosis, human monocytotropic ehrlichiosis, and others including those caused by Ehrlichia ewingii [bib_ref] Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses,..., Chapman [/bib_ref] [bib_ref] Ehrlichioses in humans: epidemiology, clinical presentation, diagnosis, and treatment, Dumler [/bib_ref]. Although clinically similar, these diseases are epidemiologically and etiologically distinct illnesses. The diagnosis of patients with these infections is challenging early in the course of their clinical infection since signs and symptoms are often nonspecific or mimic benign viral illnesses. In addition to Lyme borreliosis and rickettsial diseases, babesiosis and Colorado tick fever virus are also transmitted by ticks.
Since the organisms transmitted by ticks are infrequently encountered in clinical specimens, most clinical microbiology laboratories do not provide all of the services listed in the table below. Of significance, tick borne relapsing fever, ehrlichiosis, anaplasmosis, and babesiosis can all be rapidly diagnosed by examining peripheral blood smears. However, a negative smear result does not necessarily rule out a tick borne disease due to the often low and variable sensitivity of peripheral blood smear examination for these organisms. Therefore, clinical specimens for culture, molecular analysis and the majority of serologic assays are, for the most part, sent to reference laboratories. In addition, because most NAATs for the diseases listed are not FDA-cleared, such tests are not universally available. With these limitations in the availability of and performance of various testing formats (ie culture, molecular analysis, and the majority of serologic assays), the provider needs to check with the laboratory for availability of testing, the optimum testing approach, appropriate specimen source, and turn-around time.
Key points for the laboratory diagnosis of tickborne infections:
- Tick-borne diseases are difficult to diagnose because symptoms are nonspecific, including fever, chills, aches, pains, and rashes.
- Patient travel history, recent locations, and potential for tick bite are important.
- Consultation with the microbiology laboratory is normally required to determine the specimens accepted, the location of the testing laboratory, and the turnaround time for results. adenovirus, rabies virus and lymphocytic choriomeningitis virus are specifically highlighted. Not all clinical microbiology laboratories provide all of the services outlined in the tables, especially in the case of serologic and molecular tests. When the recommended testing is not available in a local laboratory, it can usually be referred to a reference laboratory with an ensuing possible increase in the time necessary to obtain results. Specific IgM assays for a variety of viral agents may be associated with false positive results, especially with high titers of IgG antibodies. Therefore, if the pretest probability of acute infection is low to moderate, it is good practice to measure IgG (or total -IgG plus IgM) antibodies at disease presentation ("acute phase") and two to three weeks later ("convalescent phase") to assess for a four-fold or greater rise in antibody titer.
Many molecular diagnostic tests for viral pathogens are laboratory developed tests, offered by Clinical Laboratory Improvement Amendments (CLIA)-certified reference laboratories. Although such tests require establishment of performance characteristics prior to clinical use and appropriate quality systems, performance may vary between laboratories. Throughout this section, the term NAAT generally refers to polymerase chain reaction (PCR) or reverse transcriptase PCR. Other specific techniques may be substituted with appropriate validation. [bib_ref] Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses,..., Chapman [/bib_ref]. Of note, tick-borne disease caused by Rickettsia parkeri is emerging; this organism has a similar clinical presentation as ATBF and MSF with fever, headache, eschars, and regional lymphadenopathy [bib_ref] Tick-and flea-borne rickettsial emerging zoonoses, Parola [/bib_ref]. b Organisms are best detected in blood while a patient is febrile. With subsequent febrile epidsodes, the number of circulating spirochetes decreases. Even during initial episodes, organisms are seen only 70% of the time. c Special media and technical expertise is required for culture of Borrelia species that cause relapsing fever. A centrifugation-based enrichment method followed by Giemsa staining is a rapid and viable approach [bib_ref] Epidemiology of relapsing fever borreliosis in Europe, Rebaudet [/bib_ref]. d Not valuable for an immediate diagnosis, however, serologic testing is available through public health and some private laboratories. An acute serum (obtained within 7 days of the onset of symptoms) and convalescent serum (obtained at least 21 days after the onset of symptoms) should be submitted for testing. Of significance, early antibiotic treatment can blunt the antibody response and antibody levels may fall quickly during the months after exposure. e To date, 18 genomic species are reported in the literature, three are confirmed agents of localized, disseminated and late manifestations of Lyme disease and are listed in the table. Another 9 species have been described with possible pathogenic potential. A "chronic" or "post" Lyme disease syndrome after initial short-course antibiotic treatment has not been supported in a rigorous scientific study. Treatment of "chronic Lyme disease" is a controversial issue that has been addressed by IDSA in a guideline available on its website (http://cid.oxfordjournals.org/content/43/9/1089.full#sec-36). f Erythema migrans (EM) is the only manifestation of Lyme disease in the United States that is sufficiently distinctive to allow clinical diagnosis in the absence of laboratory confirmation. Positive culture rates for secondary EM lesions, primary EM lesions, and large volume (≥9 mL) blood or plasma specimens are 90%, 60%, and 48%, respectively [bib_ref] Laboratory testing for Lyme disease: possibilities and practicalities, Reed [/bib_ref]. If skin is biopsied, more than 1 biopsy sample should be taken for culture due to uneven distribution of spirochetes; disinfect the skin prior to collection and submit tissues in sterile saline. Culture is rarely performed outside of research settings. [bib_ref] Diagnosis of lyme borreliosis, Aguero-Rosenfeld [/bib_ref]. Although Borrelia can be detected by NAAT in blood, biopsy specimens of infected skin, synovial tissue or fluid, or CSF, its usefulness for the diagnosis of Lyme disease is limited at this time. For example, Borrelia DNA is detected in the blood of fewer than half of patients in the early acute stage of disease when the erythema migrans rash is present, and if symptoms of Lyme disease have been present for a month or more, spirochetes can no longer be found in blood. Similarly, NAAT testing of CSF specimens is positive in only about one-third of US patients with early neuroborreliosis, and is even less sensitive in patients with late neurologic disease. The utility of testing synovial fluid and other specimen types is not well established and should be considered only under special circumstances and skin biopsy is not generally recommended because patients with erythema migrans can be reasonably diagnosed and treated on the basis of history and clinical signs alone. j Communication with the laboratory is of paramount importance when ehrlichiosis is suspected to ensure that Wright-stained peripheral blood smears will be carefully examined for intracytoplasmic inclusions (morulae) in either monocytes or neutrophils or bands. k A newly discovered Ehrlichia species was reported to cause ehrlichiosis in Minnesota and Wisconsin; this Ehrlichia is closely related to Ehrlichia muris [bib_ref] Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, Pritt [/bib_ref].
l Sensitivity of IFA antibody titers for tick-borne rickettsial diseases (RMSF, ehrlichiosis and anaplasmosis) is dependent on the timing of specimen collection; the IFA is estimated to be 94% to 100% sensitive after 14 days of onset of symptoms and sensitivity is increased if paired samples are tested. m Treatment decisions for tick-borne rickettsial diseases for acutely ill patients should not be delayed while waiting for laboratory confirmation of a diagnosis. Fundamental understanding of signs, symptoms, and epidemiology of the disease is crucial in guiding requests for tests and interpretation of test results for ehrlichiosis, anaplasmosis and Rocky Mountain spotted fever (RMSF). Misuse of specialized tests for patients with low probability of disease and in areas with a low prevalence of disease might result in confusion. n Antibiotic therapy may diminish the development of convalescent antibodies in RMSF.
o IgM antibodies develop 2 weeks after symptom onset.
p Laboratory assays for the diagnosis of neuroborreliosis are of limited clinical value.
Key points for the laboratory diagnosis of viral syndromes:
- Viral syndromes should be considered based on the patient's age, immune status, history, and many other variables.
- Samples can be obtained and tested for the most likely agents, with additional samples held frozen in the laboratory for additional testing if necessary; it is not cost-effective to test initial samples broadly for numerous viruses.
- Sample collection and handling are essential components of obtaining a reliable viral test result; consult the microbiology laboratory to determine which specimens should be obtained and how to transport them to the laboratory.
- Many laboratories will not have virology capabilities and tests will be sent out, resulting in longer turnaround times for results.
- Cross-reactivity among some agents will result in nonspecific serologic results.
- Tests for immunity, previous virus infection (eg, tissue donors), and new infection may have different formats, even when the same virus is being considered.
## A. human immunodeficiency virus (hiv)
HIV-1 is an RNA virus with a genome consisting of three major genes encoding capsid proteins (gag -p55, p24, p17); reverse transcriptase, protease, and integrase ( pol -p66, p51, p31); and envelope glycoproteins (env -pg160, gp120, gp41). HIV viruses are classified based on relatedness of genomic sequence into types 1 and 2, groups, and clades. HIV-1 and HIV-2 proteins differ in molecular weight. HIV-1 is categorized into groups M, O, non-M, non-O (N) and P, with M being most common [bib_ref] HIV testing-the perspective from across the pond, Murphy [/bib_ref]. HIV-1 is more common than HIV-2 in the U.S.; the latter should be considered in persons who were born in, have traveled to, have received blood products from, or have had a sexual partner from West Africa, as well as those who have been similarly exposed to HIV-2-infected persons in any geographic area.
Antibodies are detectable in acute HIV infection, usually within the first four weeks following exposure, preceded in positivity by p24 antigen, which is in turn preceded (by three to five days) by HIV RNA positivity. Performing an HIV RNA test after a negative initial antibody and/or antigen test in persons suspected of acute infection may therefore be helpful. Because of the time course of test positivity and the possibility of seronegativity, the laboratory diagnosis of primary (acute) HIV-1 infection is usually based on a high quantitative HIV-1 RNA (viral load) result (typically >10 5 copies/mL), or qualitative detection of HIV-1 RNA and/or proviral DNA; (Table XIV-1) [bib_ref] Diagnosis and management of acute HIV infection, Zetola [/bib_ref]. Outside of the setting of acute HIV infection however, HIV viral load assays should be used with caution for diagnosis of HIV infection because of the possibility of false positive results. False positive results are generally of low copy number (<5000 copies/mL); therefore, low copy number results should prompt retesting of a second specimen. Notably, because there is a 10-to 14-day period after infection when no markers are detectable, testing another specimen two to four weeks later should be considered if initial antibody, antigen or RNA tests are negative. NAAT is not 100% sensitive in individuals with established HIV infection due to viral suppression, either naturally or therapeutically, or improper specimen collection/handling. If NAAT is used to make a diagnosis of acute HIV-1 infection, it may be helpful to document subsequent HIV-1 seroconversion by conventional serologic testing.
In the neonate, serologic testing is unreliable due to persistence of maternal antibodies; quantitative HIV-1 RNA (viral load) testing is as sensitive as qualitative HIV-1 RNA and/or proviral DNA testing for the diagnosis of HIV-1 infection [bib_ref] Diagnosis of HIV-1 infection in children younger than 18 months in the..., Read [/bib_ref]. Serologic diagnosis has evolved since the 1980s. First and second generation assays were indirect EIAs that used viral lysate and recombinant/synthetic peptide antigens, respectively. Third generation assays allowed detection of HIV IgM (in addition to IgG), enabling earlier diagnosis of infection. The most recent-fourth generation-assays incorporate HIV p24 antigen detection, allowing even earlier diagnosis of infection. Third and fourth generation assays are generally positive seven to 14 and four to seven days, respectively, after detectable virus by NAAT.
HIV p24 antigen may be detected in serum or plasma between 14 and 22 days after infection (before antibody becomes detectable); it typically decreases below detection limits thereafter, limiting utility of p24 antigen testing alone. Combined HIV antibody plus p24 assays (ie, fourth generation assays) are in widespread use as initial screening assays and the Association of Public Health Laboratories and the Centers for Disease Control and Prevention now recommend them as initial screening tests for diagnosis of HIV infection [bib_ref] HIV testing-the perspective from across the pond, Murphy [/bib_ref]. The testing algorithm associated with their use does not require Western Blot. Instead, individuals with reactive results are further tested with an antibody immunoassay that distinguishes HIV-1 from HIV-2 antibodies. If the differentiation assay is negative, further testing with a qualitative or quantitative NAAT is recommended to rule out acute HIV-1 infection. If the differentiation assay is positive, viral load testing (and usually also CD4 determination) is recommended to direct management. An alternate approach is an initial HIV antigen/ antibody combination assay that discriminates detection of antigen from antibody; p24 reactivity is subsequently confirmed by NAAT and antibody reactivity by an HIV-1/HIV-2 differentiation assay. The traditional laboratory diagnosis of nonacute HIV-1 infection [fig_ref] Table I - 1: [/fig_ref] begins with screening for HIV-1/-2 antibodies. When testing by the screening assay shows reactive results, confirmatory testing by Western blot is performed. (As an alternative, NAAT testing or a second antibody immunoassay-using different antigenic constituents or based on different principles-may be considered.) An initial positive HIV antibody immunoassay using an oral fluid specimen is followed by an immunoassay performed on blood, serum or plasma, a positive result of which is followed by NAAT or supplemental antibody testing to corroborate infection. A negative blood, serum or plasma result requires follow-up testing as previously described [bib_ref] HIV testing-the perspective from across the pond, Murphy [/bib_ref]. Using the traditional algorithm, if the Western blot result is positive, the patient is considered to be infected with HIV-1. If negative, testing for HIV-2 antibodies is recommended to rule out the possibility of HIV-2 infection causing the reactive combined HIV-1/-2 antibody result. If the Western blot test is unreadable (ie, due to high background reactivity of the strip), testing with an HIV-1 antibodyspecific indirect immunofluorescence assay or qualitative or quantitative testing for HIV-1 RNA or for proviral DNA should be considered. According to Association of Public Health Laboratories and the Centers for Disease Control and Prevention, an HIV-1 antibody Western blot result is interpreted as positive when at least 2 of the 3 following bands are present: p24, gp41, and gp120/gp160. If only one of these bands is present, the result is indeterminate, and additional supplemental testing with an HIV-1 antibody-specific indirect immunofluorescence assay, an EIA for HIV-2 antibodies alone, and a qualitative HIV-1 RNA and/or proviral DNA assay should be considered. Causes of indeterminate Western blots include evolving antibody profiles, specimen contamination, antibody decline with immune system failure (late stage infection), nonspecific reactivity due to viral or cellular protein components, other infections (eg, syphilis, other retroviruses, some parasites), immune-modulating conditions (eg, pregnancy), and infection with groups N, O, or P HIV-1, or HIV-2. High-risk patients with reactive serologic screening test results and indeterminate Western blots but negative supplemental tests should be considered for retesting two to four weeks later. If this does not resolve the issue, additional supplemental testing (eg, NAAT) may be considered. Western blot assay is less sensitive than third or fourth generation EIAs during seroconversion with up to three weeks following a positive fourth generation assay before a positive Western blot assay. Since as many as a third of healthy HIV-uninfected blood donors have indeterminate HIV-1 Western blot assays, they should not be ordered as the first test for HIV. Line immunoassays incorporating HIV-1 and HIV-2-specific recombinant proteins and/or synthetic peptides (compared to purified proteins separated by electrophoresis used in Western blotting) are alternatives to Western blot assays.
Resistance testing is recommended for patients with acute or chronic HIV infection prior to initiating therapy (including treatment-naïve pregnant HIV-1-infected women), virologic failure during combination drug therapy, and suboptimal suppression of viral load after initiating therapy.
## B. epstein-barr virus
Epstein-Barr virus is a cause of mononucleosis and lymphoproliferative disease in immunocompromised patients. An elevated white blood cell count with an increased percentage of atypical lymphocytes is common in EBV-associated mononucleosis. Heterophile antibodies usually become detectable between the sixth and tenth day following symptom onset, increase through the second or third week of the illness and, thereafter, gradually decline over a year or longer. False-positive results may be found in patients with leukemia, pancreatic carcinoma, viral hepatitis, CMV infection, etc. False-negative results are obtained in approximately 10% of patients, and are especially common in children younger than 10 years.
When rapid Monospot or heterophile test results are negative, additional laboratory testing [fig_ref] Table I - 1: [/fig_ref] may be considered to differentiate EBV infection from a mononucleosis-like illness caused by CMV, adenovirus, HIV, Toxoplasma gondii, etc. In this situation, EBV antibody testing for IgG and IgM to viral capsid antigen (VCA) and Epstein-Barr nuclear antigen (EBNA) are recommended. The presence of VCA IgM (with or without VCA IgG) antibodies in the absence of antibodies to EBNA indicates recent primary infection with EBV. The presence of EBNA antibodies indicates infection more than 6 weeks from the time of the sample and therefore not likely implicating EBV as a cause. Antibodies to EBNA develop one to two or more months after primary infection and are detectable for life. Over 90% of the normal adult population has IgG class antibodies to VCA and EBNA antigens, although approximately 5%-10% of patients who have been infected with EBV fail to develop antibodies to the EBNA antigen.
EBV is associated with lymphoproliferative disease in patients with congenital or acquired immunodeficiency, including patients with severe combined immunodeficiency, recipients of organ or peripheral blood stem cell transplants, and patients infected with HIV. Increases in EBV viral load detected by NAAT in peripheral blood may be present in patients before the development of EBV-associated lymphoproliferative disease; these levels typically decrease with effective therapy. Tissues from patients with EBV-associated lymphoproliferative disease may show monoclonal, oligoclonal, or polyclonal lesions. The diagnosis of EBV-associated lymphoproliferative disease requires demonstration of EBV DNA, RNA or protein in biopsy tissue.
NAAT may be used to detect EBV DNA in CSF of patients with acquired immunodeficiency syndrome-related central nervous system lymphoma, however EBV DNA may also be present in cerebrospinal fluid with other abnormalities (eg, central nervous system toxoplasmosis, pyogenic brain abscesses) and therefore positivity is nonspecific. Detection of antibody in CSF may indicate central nervous system infection, blood contamination, or transfer of antibodies across the blood-brain barrier. Calculation of the CSF to serum antibody index may be helpful.
## C. cytomegalovirus
In immunocompetent individuals suspected of having acute CMV infection, testing for CMV-specific antibodies is recommended as the first line laboratory diagnostic test [fig_ref] Table I - 1: [/fig_ref]. In the immunocompetent host, the presence of IgM class antibodies indicates recent infection; however, false positive CMV IgM results may occur in patients infected with EBV or with activated immune systems due to other causes. The presence of IgG antibodies alone indicates past exposure to CMV. In recipients of organ or peripheral blood stem cell transplants, CMV viral load by NAAT or antigenemia ( performed by fewer laboratories as NAATs gain favor) is used as a marker for preemptive therapy, to diagnose CMV-associated signs and symptoms, and to monitor response to antiviral therapy. Standard Reference Material (SRM) is available from the National Institute of Standards and Technology (NIST) for CMV viral load measurement. SRM 2366, which consists of a bacterial artificial chromosome that contains the genome of the Towne strain of CMV, is used for assignment of the number of amplifiable genome copies of CMV/volume (eg, copies/microliter).
Cytomegalovirus can be cultured from peripheral blood mononuclear cells (and other clinical specimens). However, isolation is labor-intensive and can take up to 14 days; the waiting time can be shortened to 1-2 days with the use of the shell vial assay. In addition to a long turnaround time, culturebased assays have poor sensitivity. Because viral load is typically high and CMV is shed in the urine of newborns, urine culture for CMV continues to be used at some institutions for the diagnosis of congenital CMV infection.
Cytomegalovirus antigens can be demonstrated by immunohistochemical or in situ hybridization tests of formalin-fixed, paraffin-embedded tissues. Cytomegalovirus DNA, detected using NAAT in a variety of clinical specimens, may be useful in diagnosing CMV disease.
Among immunocompromised patients with CMV infection, the potential exists for the emergence of resistance to antiviral agents. A variety of assays can be used to assess antiviral resistance; most commonly sequencing of UL97 ( phosphotransferase gene) with or without UL54 (DNA polymerase gene) is utilized in such situations. Sequencing-based assays are performed on DNA amplified directly from clinical specimens, provided they contain a sufficient quantity of CMV DNA. Alternatively, the virus can first be isolated in cell culture. Ganciclovir resistance most commonly emerges due to point mutations or deletions in UL97 (with foscarnet and cidofovir unaffected) with mutations at three codons (460, 594, 595) being most common. UL54 point mutations or deletions occur less frequently. If UL54 mutations are selected by ganciclovir or cidofovir, there is typically cross-resistance to both ganciclovir and cidofovir but not foscarnet; but if mutations are selected by foscarnet, there is usually no cross-resistance to ganciclovir or cidofovir.
NAATs may be used to detect CMV DNA in CSF of patients with suspected CMV-central nervous system infection, but false positive results may occur (eg, in patients with bacterial meningitis in whom CMV DNA in blood crosses the inflamed blood-brain barrier and contaminates cerebrospinal fluid). Detection of antibody in cerebrospinal fluid may indicate central nervous system infection, blood contamination, or transfer of antibodies across the blood-brain barrier. Calculation of the CSF to serum CMV antibody index may be helpful.
## D. varicella-zoster virus
The presence of VZV IgG and IgM typically indicates recent infection with VZV; however, these results may also be observed in patients with recent immunization to VZV. A positive VZV IgG with a negative VZV IgM result indicates previous exposure to VZV and/or response to vaccination. A negative IgG result coupled with a negative IgM result indicates the absence of prior exposure to VZV and no immunity, but does not rule out VZV infection, as the specimen may have been drawn before the appearance of detectable antibodies. Negative results in suspected early VZV infection should be followed by testing a new serum specimen in two to three weeks.
The most sensitive and specific test for diagnosis of VZVassociated skin lesions is NAAT [fig_ref] Table I - 1: [/fig_ref]. A culture transport swab is vigorously rubbed on the base of the suspect skin lesion; the vesicle may be unroofed to expose the base. A less sensitive method for diagnosis is detection of viral antigens by direct fluorescent antibody stain of lesion scrapings. VZV culture is not recommended since this virus is difficult to grow in routine cell lines and may take two weeks to isolate (unless using shell vial assay). Suspected VZV-associated skin lesions must be clinically differentiated from smallpox as described in the algorithm developed by the Centers for Disease Control and Prevention (http://www.bt.cdc.gov/agent/smallpox/diagnosis/ riskalgorithm/index.asp); information about laboratory testing for smallpox is available at http://www.bt.cdc.gov/agent/smallpox/ lab-testing.
VZV NAATs can be performed on CSF as an aid to the diagnosis of VZV central nervous system infection. CSF IgM or intrathecal antibody synthesis distinguishes meningoencephalitis from a post-infectious immune-mediated process.
## E. herpes simplex virus
The presence of IgG antibodies specific to the glycoprotein G antigen from HSV type 1 or 2 indicates previous exposure to NAAT is the most sensitive, specific and rapid test for diagnosis of HSV-associated skin or mucosal lesions and should detect and distinguish HSV types 1 and 2 [fig_ref] Table I - 1: [/fig_ref]. A viral culture transport swab is vigorously rubbed over the base of the suspect skin or mucosal lesion; the vesicle may be unroofed to expose the base. Older, dried and scabbed lesions are less likely to yield positive results. Culture and direct fluorescent antibody testing are less sensitive than NAATs.
HSV NAATs performed on CSF are used to diagnose HSV central nervous system disease [bib_ref] Diagnosis of herpes simplex virus in the era of polymerase chain reaction, Kimberlin [/bib_ref]. The assay should detect and distinguish HSV types 1 and 2; type 1 is most commonly associated with encephalitis and type 2 with meningitis. Viral culture of cerebrospinal fluid is insensitive for diagnosis of HSV central nervous system disease.
## F. human herpes virus-6
Human herpes virus-6 causes roseola infantum in children and can cause primary or reactivation infection in immunocompromised patients. IgG seroconversion, the demonstration of anti-HHV-6 IgM, or a four-fold rise in IgG antibodies from paired sera may indicate recent infection with HHV-6. Commercial assays do not typically distinguish between variants A and B. Because of the ubiquitous nature of HHV-6, most people have been exposed to the virus by two years of age. Therefore, a single HHV-6 IgG serologic test result may not be clinically relevant. Five percent of asymptomatic adults may be IgM positive at any given time.
The most commonly used molecular test for the laboratory diagnosis of HHV-6 is NAAT (none FDA-cleared), some formats of which differentiate variants A and B [fig_ref] Table I - 1: [/fig_ref]. NAAT does not differentiate replicating from latent virus. HHV-6 DNA quantification may be useful in this regard, as well as in monitoring response to antiviral therapy. HHV-6 may be shed intermittently by healthy and immunocompromised hosts. Therefore detection of HHV-6 in blood, body fluids or even tissue does not definitively establish a diagnosis of disease caused by HHV-6. Chromosomally integrated HHV-6, which results in high HHV-6 levels in whole blood, may lead to an erroneous diagnosis of active infection. HHV-6 can be cultured from peripheral blood mononuclear cells (and other clinical specimens) . However, viral isolation is laborintensive, taking up to 21 days; the detection time can be shortened to 1-3 days with the shell vial culture assay. In addition to a long processing time, culture-based assays suffer from poor sensitivity and do not differentiate between variants A and B. HHV-6 antigens can be demonstrated by immunohistochemical or in situ hybridization tests in formalin-fixed, paraffin-embedded tissues.
## G. parvovirus (erythrovirus) b19
In immunocompetent individuals with erythema infectiosum or arthralgia/arthritis, testing for parvovirus (erythrovirus) B19-specific antibodies is recommended as the first line laboratory diagnostic method for parvovirus B19 infection [fig_ref] Table I - 1: [/fig_ref]. The presence of IgM class antibodies suggests recent infection. IgM antibodies can be detected 10 to 14 days post infection and may persist for five months, and occasionally even longer [bib_ref] Diagnosis and management of human parvovirus B19 infection, Ramirez [/bib_ref]. IgG and IgM reach peak titers within one NAAT is the most sensitive noninvasive technique for the laboratory diagnosis of parvovirus B19-related anemia in solid organ transplant recipients, although current tests are laboratory-validated and not FDA-cleared. A caveat regarding NAAT for diagnosis of parvovirus B19-related anemia is that parvovirus B19 DNA has been anecdotally detected for extended periods in serum, even in healthy individuals. The presence of giant pronormoblasts in bone marrow is suggestive of parvovirus B19 infection, although such cells are not always detected.
## H. measles (rubeola) virus
Individuals who are immune to measles should yield a positive result for IgG antibody to the virus. Those who are not immune have negative IgG and IgM results. Recent infection with measles virus is typically indicated by a positive IgM antibody result in the absence of IgG. IgM is often positive on the day of onset of rash; however, in the first 72 hours after rash onset, up to 20% of tests for IgM may be falsely negative. Therefore, if the acute IgM is negative, a second serum specimen, collected 72 hours after rash onset, should be tested for IgM. IgM is detectable for a month or longer after rash onset. IgM may be positive in individuals with recent immunization to measles virus. A serologic diagnosis of acute measles requires demonstration of a four-fold rise in IgG antibody titer [fig_ref] Table I - 1: [/fig_ref]. Two serum specimens are collected, with the first specimen being obtained as soon as possible after rash onset, and the second specimen being collected 10 to 30 days later; both should then be tested concurrently by the same method. Criteria for documenting an increase in titer depend on the specific test used.
Measurement of measles-specific antibodies in CSF is used in the diagnosis of subacute sclerosing panencephalitis (SSPE); levels of rubeola antibody are highly elevated in the cerebrospinal fluid of SSPE patients compared to those without the disease.
Measles virus can be isolated from throat or nasopharyngeal swabs or urine. Specimens should be collected soon after rash onset. NAAT also can be considered as a diagnostic test option [bib_ref] Evaluation of serological and virological tests in the diagnosis of clinical and..., Van Binnendijk [/bib_ref].Place the swab in viral transport medium, cell culture medium or other sterile isotonic solution (eg, saline).
## I. mumps virus
Several types of tests are used for mumps diagnosis [fig_ref] Table I - 1: [/fig_ref]. Laboratory criteria for the diagnosis of mumps include a positive serologic test for mumps IgM antibody, a four-fold rise in serum mumps IgG antibody levels between acute-and convalescent-phase paired sera, isolation of mumps virus from clinical samples, or detection of mumps RNA in a clinical specimen.
Sera for acute phase IgG testing should be collected within 5 days after symptom onset (ie, at the time of diagnosis); convalescent sera should be collected approximately two weeks after symptom onset. IgM antibodies typically become detectable during the first few days of illness and reach a peak about a week after onset. Receipt of one or more doses of the mumps vaccine may result in an absent, delayed or transient IgM response. If the acute IgM is negative, a second specimen should be collected for IgM testing 2-3 weeks after onset of symptoms. Among previously immunized suspected cases, mumps virus detection is a particularly important method of confirming the case. The preferred sample for viral isolation is a swab from the parotid duct, or from the duct of another affected salivary gland. Mumps virus can also be detected by molecular techniques (no FDA-cleared tests) [bib_ref] Real-time PCR for mumps diagnosis on clinical specimens-comparison with results of conventional..., Krause [/bib_ref]. Mumps viral RNA may be detected prior to onset of parotitis until five to nine days after onset.
Detection of antibody in CSF may indicate central nervous system infection, blood contamination, or transfer of antibodies across the blood brain barrier. Calculation of the CSF to serum antibody index to mumps virus may be helpful.
## J. rubella virus
Serology is the most common method of confirming the diagnosis of rubella [fig_ref] Table I - 1: [/fig_ref] [bib_ref] A semiquantitative culture method for identifying intravenous-catheter-related infection, Maki [/bib_ref]. The presence of antibodies to rubella virus in a single serum specimen is evidence of immunity. Acute rubella infection can be serologically confirmed by a four-fold rise in rubella IgG antibody titer between acute and convalescent serum specimens or by the presence of serum rubella IgM. If testing is performed, serum should be collected as early as possible (within 7 to 10 days) after onset of illness, and again 14 to 21 days (minimum of 7) days later. Caution should be taken in interpreting positive rubella IgM results, as false positive results can occur. Rubella is no longer endemic in the United States; therefore, IgM testing should only be performed in patients with a clinical presentation suggestive of acute rubella. Prenatal screening for rubella immunity should only be performed using an IgG-based assay.
## K. bk virus
BK virus causes allograft nephropathy in renal transplant recipients, a definitive diagnosis of which requires renal allograft biopsy with in situ hybridization for BK virus. BK virus may also cause hemorrhagic cystitis, especially in stem cell transplant recipients.
Detection of certain levels of BK viral load by NAAT in plasma may provide an early indication of allograft nephropathy, although there are no FDA-cleared NAATs [fig_ref] Table I - 1: [/fig_ref] [bib_ref] Current recommendations for diagnosis and management of polyoma BK virus nephropathy in..., Blanckaert [/bib_ref]. Urine cytology or quantitative NAAT may be used as a screening test, followed by BK viral load testing by NAAT, if positive. Urine NAAT for BK virus may be more sensitive than urine decoy cell (virus-infected cells shed from the tubules or urinary tract epithelium) detection; BK virus DNA may be present earlier in the urine than are decoy cells. However, urinary shedding of BK virus is a common occurrence; if used as a screening test, only high levels (ie, above a laboratory established threshold that correlates with disease) should be considered significant. Urine testing for BK virus places the laboratory at risk for specimen cross-contamination as extremely high levels of virus in the urine may lead to carryover between specimens and false positive results.
## L. jc virus
JC virus is the etiologic agent of progressive multifocal leukoencephalopathy (PML), an often fatal demyelinating disease of the central nervous system that occurs in immunocompromised hosts. Histologic examination of brain biopsy tissue reveals characteristic pathologic changes. In situ hybridization for JC virus may be performed on brain tissue. Detection of JC virus DNA by NAAT in CSF specimens of patients with suspected progressive multifocal leukoencephalopathy has largely replaced the need for tissue biopsy for laboratory diagnosis [fig_ref] Table I - 1: [/fig_ref].
## M. dengue virus
Dengue is a mosquito-borne febrile illness. In travelers from certain areas, Chikungunya and yellow fever should be considered in the differential diagnosis, along with malaria. Dengue diagnosis requires laboratory confirmation by culture, NAAT or testing for dengue specific antibodies [fig_ref] Table I - 1: [/fig_ref]
## O. hepatitis b, d, and c viruses
Hepatitis B surface antigen may be detected in the presence of acute or chronic hepatitis B virus infection [bib_ref] Chronic hepatitis B: current testing strategies, Gish [/bib_ref] ; it indicates that the person is infectious. In acute infection, its appearance predates clinical symptoms by four weeks and it remains detectable for one to six weeks. The tests for hepatitis B and D disease detection are primarily serologic and molecular [fig_ref] Table I - 1: [/fig_ref] [bib_ref] A systematic review of rapid diagnostic tests for the detection of tuberculosis..., Dinnes [/bib_ref]. Check with the laboratory about minimum volumes of blood needed, as some molecular platforms require more blood than others. The presence of hepatitis B surface antibodies indicates recovery from and immunity to hepatitis B infection, as a result of either natural infection or vaccination. In most patients with self-limited acute hepatitis B infection, hepatitis B surface antigen and antibodies are not detectable simultaneously in serum or plasma.
Hepatitis B core IgM antibodies appear during acute or recent hepatitis B virus infection and remain detectable for about six months. A serologic "window" occurs when hepatitis B surface antigen disappears and hepatitis B surface antibody is undetectable. During this "window" period, infection can be diagnosed by detecting hepatitis B core IgM antibodies, which can remain detectable for up to six months.
Hepatitis B core total antibodies appear at the onset of symptoms of acute hepatitis B infection and persist for life; their presence indicates acute (mainly virus-specific IgM antibodies), recent (both hepatitis B core-specific IgM and IgG antibodies), or previous (hepatitis B core-specific IgG antibodies) hepatitis B infection. A chronic hepatitis B virus carrier state is defined by persistence of hepatitis B surface antigen for at least 20 weeks. In patients with chronic hepatitis B infection, the presence of hepatitis B e antigen in serum or plasma is a marker of high viral replication levels in the liver. Loss of hepatitis B e antigen and emergence of antibody to hepatitis B e antigen is usually associated with improvement of underlying hepatitis and a reduction in the risk of hepatocellular carcinoma and cirrhosis. Alternatively, disappearance of hepatitis B e antigen may denote the emergence of a precore mutant virus; high concentrations of HBsAg and HBV DNA, in the absence of hepatitis B e antigen and presence of antibody to hepatitis B e antigen suggest the presence of a precore mutant virus. Hepatitis B viral DNA is present in serum or plasma in acute and chronic hepatitis B infection [bib_ref] Molecular testing in the diagnosis and management of chronic hepatitis B, Valsamakis [/bib_ref]. Quantification of hepatitis B viral DNA (by PCR or branched-DNA assay methods) may be included in the initial evaluation and management of chronic hepatitis B infection, especially when deciding treatment initiation and monitoring patient's response to therapy. Other molecular laboratory tests used in the diagnosis and management of hepatitis B infection have been reviewed and include assays for determining viral genotype, detection of genotypic drug resistance mutations, and core promoter/precore mutations [bib_ref] Molecular testing in the diagnosis and management of chronic hepatitis B, Valsamakis [/bib_ref].
Detection of hepatitis B surface antibodies in the absence of hepatitis B core total antibodies distinguishes vaccine-mediated immunity from immunity acquired by natural infection (in which hepatitis B surface and hepatitis B core total antibodies are both present). Current commercially available assays for detecting hepatitis B surface antibody yield positive results (qualitative) for antibody levels of ≥10 mIU/mL in serum or plasma, indicating post-vaccination immunity ( protective antibody level). Quantitative hepatitis B surface antibody results are used to monitor adequacy of hepatitis B immune globulin therapy in liver transplant recipients receiving such therapy during the post-transplant period.
In acute hepatitis D superinfection of a patient with known chronic hepatitis B, hepatitis D antigen, hepatitis D-specific IgM and total antibodies are present [fig_ref] Table I - 1: [/fig_ref] [bib_ref] A systematic review of rapid diagnostic tests for the detection of tuberculosis..., Dinnes [/bib_ref]. In acute hepatitis B and D co-infection, the same serologic markers (ie, hepatitis D antigen, hepatitis D-specific IgM and total antibodies) are present, along with hepatitis B core IgM antibodies.
The diagnosis of HCV usually begins with a screening test for HCV-specific IgG antibodies using EIA or chemiluminescent immunoassay (CIA). Antibodies may not be detectable, however, until six to ten weeks after the onset of clinical illness. Individuals with negative screening test results do not need further testing for HCV [fig_ref] Table I - 1: [/fig_ref] [bib_ref] Tuberculosis of the central nervous system, Garg [/bib_ref]. Those with positive screening test results should undergo confirmatory or supplemental testing for HCV RNA by molecular test methods. Signal-to-cut-off ratios (calculated by dividing the optical density value of the sample tested by the optical density value of the assay cut-off for that run) are an alternative to supplemental testing (http://www.cdc.gov/hepatitis/HCV/LabTesting. htm). Hepatitis C virus RNA can be detected by NAATs soon after infection as well as in chronic infection. NAAT for HCV can be performed qualitatively (by reverse-transcription PCR or transcription-mediated amplification) or quantitatively (by reverse-transcription PCR or branched DNA). Prior to and during treatment, quantification of HCV RNA (by PCR or branched-DNA assay methods) is necessary to monitor rapid and early virologic response to antiviral therapy, while qualitative or quantitative HCV RNA detection is used to determine end-of-therapy and sustained virologic response to therapy.
The recombinant immunoblot assay (RIBA) has similar sensitivity to, but higher specificity than, screening tests, and was formerly used as a confirmatory test in patients with a positive screening antibody test for HCV. Patients with a positive screening test but negative RIBA results are considered not to have HCV infection (ie, falsely reactive screening test). Positive RIBA results (≥ two bands present) are indicative of chronic or resolved HCV infection, whereas those with a single band detected are considered indeterminate. Hepatitis C virus genotyping is used to guide the choice and duration of antiviral therapy and predict the likelihood of response to therapy, as different genotypes have varying susceptibilities to current treatment regimens. A human genomic polymorphism interleukin-28B (IL-28B) genotype CC (within an interferon gamma promoter region), is associated with increased likelihood of sustained viral response in individuals with chronic hepatitis C virus infection undergoing treatment with pegylated interferon and ribavirin, and has strong predictive value for spontaneous resolution of infection.
The Centers for Disease Control and Prevention has recently recommended that adults born during 1945 and 1965 receive one-time testing for hepatitis C virus.
## P. enterovirus and parechovirus
The enteroviruses that most often cause meningitis include certain echovirus and coxsackievirus serotypes and enteroviruses 70 and 71. NAAT of CSF is more sensitive than culture for the diagnosis of enteroviral central nervous system infection [fig_ref] Table I - 1: [/fig_ref] [bib_ref] Beyond viruses: clinical profiles and etiologies associated with encephalitis, Glaser [/bib_ref]. Plasma or serum is useful for diagnosis of sepsis syndrome of the newborn due to enterovirus, but testing is less reliable outside of the newborn period. In the right clinical scenario, recovery of enterovirus from throat or stool may provide circumstantial etiologic evidence of central nervous system infection.
Serologic evaluation involves assessment of acute and convalescent titers, and is not typically useful in real-time clinical practice.
Parechoviruses have clinical presentations similar to enteroviruses, but are classified as a different genus and require a specific NAAT (laboratory validated only, no FDA-cleared tests) for detection.A commercial FDA-cleared product is available for rapid PCR testing for enteroviruses in CSF.
## Q. respiratory syncytial virus
Respiratory syncytial virus causes bronchiolitis and/or pneumonia and is most common in infants and young children, although it can present in older individuals and cause severe disease in the immunocompromised. It is ideally detected by NAAT testing of secretions obtained by washing, suctioning, or swabbing the nasopharynx [fig_ref] Table I - 1: [/fig_ref] [bib_ref] The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society..., Tunkel [/bib_ref]. Several FDAcleared NAAT platforms exist. Culture is more time-consuming and less sensitive.
The presence of IgG generally indicates past exposure and immunity. The presence of IgM class antibodies or a 4-fold or greater rise in IgG titer between acute and convalescent sera suggests recent infection.
## R. influenza virus infection
Rapid diagnosis of influenza virus infection (≤48 hours following the onset of symptoms) is needed to facilitate early administration of antiviral therapy. The virus may be rapidly detected by NAAT or direct antigen detection from nasopharyngeal swabs [fig_ref] Table I - 1: [/fig_ref] [bib_ref] Molecular methods for diagnosis of viral encephalitis, Debiasi [/bib_ref]. Sensitivity is higher for NAAT than rapid antigen detection. Rapid screening tests may perform poorly during influenza season (especially for detection of pandemic H1N1 and swine-associated H3N2 strains) and negative tests may need to be confirmed by NAAT or culture. During seasons of low prevalence of influenza, false positive tests are more likely to occur with rapid screening procedures. Performance of influenza assays varies depending on the assay and the circulating strains. NAAT is now considered the gold standard for detection of influenza virus in clinical samples. Several FDA-cleared NAAT platforms exist. Serologic evaluation involves assessment of acute and convalescent titers, but is not typically useful in real-time clinical practice.
## S. west nile virus
West Nile virus (and Eastern equine, Western equine, Saint Louis and California encephalitis viruses) cause central nervous system infections.
The laboratory diagnosis of West Nile virus is typically accomplished by detecting virus-specific IgM antibodies in serum [fig_ref] Table I - 1: [/fig_ref] [bib_ref] Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain..., Weil [/bib_ref]. West Nile virus IgM antibodies may persist in serum for ≥6 months and false positive results may occur following recent yellow fever immunization or natural infection with other flaviviruses (eg, dengue, Saint Louis encephalitis). Acute (3-10 days after symptom onset) and convalescent (2-3 weeks later) serum for IgG serology may also be helpful. Positive antibody titers to West Nile virus are commonly present in older individuals, especially those from the Indian subcontinent (who presumably have been exposed to flaviviruses during their lifetimes). Therefore in patients where the pretest probability of infection with West Nile virus is low, the presence of West Nile virus antibodies in plasma or serum should be interpreted cautiously.
Serologic diagnosis of West Nile virus central nervous system infection is based on assessing the CSF to serum antibody index or the detection of West Nile virus IgM in cerebrospinal fluid. However, detection of antibody in cerebrospinal fluid may indicate central nervous system infection, blood contamination, or transfer of antibodies across the blood-brain barrier.
West Nile virus NAAT is insensitive in immunocompetent hosts, but more sensitive in immunocompromised hosts. Viremia typically drops to levels that may be undetectable by NAAT at the time of symptom onset. West Nile Virus NAAT testing is insensitive for central nervous system disease. Viral culture may be available in specialized laboratories but is also insensitive.
Eastern and Western equine, Saint Louis and California encephalitis virus infection may be diagnosed serologically following the same strategy used for West Nile virus.
## T. adenovirus
In otherwise healthy individuals, adenoviruses usually cause mild, self-limiting respiratory illnesses with most cases being [fig_ref] Table I - 1: [/fig_ref] [bib_ref] West Nile virus: a primer for the clinician, Petersen [/bib_ref]. Viral culture has a long turnaround time but is reduced if using shell vial technology. Plasma viral load (assessed by quantitative NAAT) may be useful as a marker for preemptive therapy, to diagnose adenovirus-associated signs and symptoms, and to monitor response to antiviral therapy in some immunocompromised populations.
Serologic testing relies on demonstration of antibodies to group-specific antigens, and often requires analysis of acute and convalescent sera. Serologic diagnosis of central nervous system infection is based on CSF to serum antibody index, four-fold rise in acute to convalescent IgG titer, or a single positive IgM. Detection of antibody in CSF may indicate central nervous system infection, blood contamination, or transfer of antibodies across the blood-brain barrier.
## U. rabies virus
Rabies virus infects the central nervous system and is most often transmitted through the bite of a rabid animal. State Health Departments should be consulted immediately in cases of suspected rabies.
No single test is sufficient to diagnose rabies ante-mortem [fig_ref] Table I - 1: [/fig_ref]. Testing is performed on samples of saliva, serum, spinal fluid and skin biopsies of hair follicles at the nape of the neck. Saliva and CSF may be tested by culture and NAAT (laboratory-validated). Serum and CSF may be tested for antibodies to rabies virus. Skin biopsy specimens may be examined for rabies antigen in the cutaneous nerves at the base of hair follicles. Histopathologic evaluation and direct fluorescent antibody testing of brain biopsy material are helpful, if available.
Serologic testing may be used to document post-vaccination seroconversion in the immunocompromised, if there is significant deviation from a prophylaxis schedule or if an individual initiated treatment internationally with a non-cell culture vaccine.
## V. lymphocytic choriomeningitis virus
Lymphocytic choriomeningitis virus is a rodent-borne virus that can cause meningoencephalitis and may be life-threatening in immunosuppressed persons. Serologic diagnosis is based on a four-fold rise in acute to convalescent IgG titer, or a single positive IgM [fig_ref] Table I - 1: [/fig_ref]. Detection of antibody in CSF may indicate central nervous system infection, blood contamination, or transfer of antibodies across blood-brain barrier; CSF to serum antibody index may be helpful in interpreting CSF antibody results.
## Xv. blood and tissue parasite infections
Blood and tissue parasites comprise a large number of protozoa and helminths found in tropical and temperate climates worldwide. Certain parasites cause infections with associated high morbidity and mortality (eg malaria, amebic encephalitis) while others may cause mild or asymptomatic disease (eg filariasis due to Mansonella spp, toxoplasmosis in immunocompetent adults). As expected, the most commonly submitted specimens for laboratory identification of these parasites are whole blood, tissue aspirates/biopsies, and serum for serologic studies. Microscopy remains the cornerstone of laboratory testing for the diagnosis of most blood and tissue parasitic infections. Expert microscopic examination of Giemsa stained thick and thin peripheral blood films is used for detection and identification of the protozoan blood parasites Plasmodium, Babesia, and Trypanosoma, and the filarial nematodes, Brugia, Wuchereria, and Mansonella, whereas microscopic examination and/or culture of ulcer samples, bone marrow, tissue aspirates, and biopsies are useful in the diagnosis of African trypanosomiasis, onchocerciasis, trichinosis, toxoplasmosis, and leishmaniasis. Although requiring a minimal amount of reagents and equipment, the accuracy of microscopic methods requires well-trained and experienced technologists. Even in the best hands, diagnosis may be hampered by sparseness of organisms on the slide and the subjective nature of differentiating similar appearing organisms (Plasmodium vs. Babesia; various microfilariae) or in identifying the species of Plasmodium present. The laboratory can enhance the sensitivity of these methods by employing a number of concentration procedures such as buffy coat examination, centrifugation, and filtration. In all of these procedures, samples must be properly obtained, transported to the laboratory as quickly as possible and processed in a timely fashion to preserve organism viability and/or morphology.
Serologic assays for detection of antibodies are available as adjunctive methods for the diagnosis of a number of blood and tissue parasite infections. Unfortunately, none are sensitive or specific enough to be used to establish the diagnosis on their own. In particular, assays for infection with one helminth will often cross-react with antibodies to a different helminth. When available, antibody titers may be used to determine the strength of the immune response or detect a trend in antibody levels over time. Indirect fluorescent antibody assays (IFA) can provide quantitative titer results but reading the slides is subjective and inherently prone to varying results. In contrast, EIAs typically provide only qualitative positive or negative results determined by an arbitrarily set breakpoint. Thus, clinicians will not be able to determine if a positive result was a very strong positive or a very weak one without calling the laboratory for more information. This can have important implications for interpretation of results which are not entirely consistent with the clinical picture.
Laboratory methods that detect parasite antigens and/or DNA provide an attractive alternative to traditional morphologic and serologic techniques. For example, a simple rapid immunochromatographic card assay for the detection of Plasmodium has recently been approved by the FDA [bib_ref] Rapid diagnostic tests for malaria parasites, Moody [/bib_ref] [bib_ref] Diagnostic performance of rapid diagnostic tests versus blood smears for malaria in..., Stauffer [/bib_ref]. It may find use in acute care settings such as emergency departments (EDs) or out-patient clinics to establish a diagnosis of malaria quickly while awaiting results of confirmatory blood films. This assay is adequately sensitive in typical patients with symptomatic malaria ("fever and chills") but loses sensitivity if the parasitemia is very low or infection is due to non-falciparum species [bib_ref] Rapid diagnostic tests for malaria parasites, Moody [/bib_ref]. This is especially important in nonendemic settings such as the U.S. where patients often present with low parasitemia.
Finally, the Centers for Disease Control and Prevention (CDC) and a number of reference laboratories in the U. S. and Canada perform extremely sensitive nucleic acid detection methods such as real-time PCR assays for certain blood and tissue parasites, including Plasmodium, Babesia, Toxoplasma, and the agents of amebic encephalitis. Clinicians should consult their microbiology laboratory to determine if their reference laboratory or other entity offers the desired testing. Molecular assays may be of particular use in patients with very low parasitemias or in specifically identifying organisms that cannot be differentiated microscopically. However, DNA may persist for days or weeks after successful treatment and detection does not necessarily correlate with the presence of viable organisms. In addition, the current restriction to the reference laboratory setting means that the time from specimen collection to receipt of result may be longer than desired for optimal patient care. In situations where infection is potentially life threatening, empiric treatment should be considered while awaiting results from the outside laboratory.
Key points for the laboratory diagnosis of blood and tissue parasites:
- Microscopy is the cornerstone of laboratory identification but is highly subjective and dependent on technologist experience and training.
- Proper specimen collection and transport are essential components of morphology and culture based techniques.
- Serology shows significant cross-reactivity among helminths, including filaria.
- There are a limited number of antigen detection methods available for blood and tissue parasites in the United States.
- Automated hematology analyzers may fail to detect malaria or babesiosis parasites; request manual evaluation if either agent is suspected. Microscopy and culture of CSF or brain tissue Specimens for culture should not be refrigerated. Balamuthia mandrillaris does not grow on standard agar (requires specialized cell-culture).
PCR from unfixed tissue or CSF is available from the CDC. Stained and unstained tissue slides may also be sent.
## Angiostrongyliasis and gnathostomiasis
Serology from CDC or Faculty of Tropical Medicine, Mahidol University, Bangkok Thailand (http://www.tm.mahidol.ac.th/en/ special)
In eosinophilic meningitis, larvae may be rarely seen in CSF. Larvae may also be seen in tissue sections with associated eosinophils and/or necrosis. Larvae may be seen on histopathologic sections of brain tissue Cysticercosis and Echinococcosis Serology from the CDC or referral laboratories. Cross-reactivity may be observed between tests for either organism.
Serology is confirmatory to radiologic and scan studies.
Encysted larvae and/or hooklets can be seen in tissue biopsies or aspirates of cysts (echinococcosis).
Filariasis due to species of Wuchereria, Brugia, and Mansonella
Microscopy of Giemsa stained thick and thin blood films. Examination of concentrated blood specimens (Knott's, Nuclepore filtered blood or buffy coat) increases sensitivity. Antibody and/or antigen detection EIA (Wuchereria bancrofti and Brugia malayi) in blood by the CDC or reference lab
Blood films for W. bancrofti and B. malayi should be collected at night when microfilariae are circulating. Repeat exams may be necessary due to low parasitemia. Serology does not differentiate between filaria.
## Filariasis, onchocerciasis due to onchocerca volvulus
Microscopy of "skin snip" after incubation in saline at 37°C"Skin snips" should be from areas near nodules and should be "razor thin" with no visible blood. Histopathologic examination of skin biopsy or resected nodule (onchocercoma) can identify microfilariae and/ or adults. Serology available from reference laboratories; does not differentiate between filariae.
Leishmaniasis, cutaneous due to various Leishmania species
Microscopic exam of Giemsa stained smears of biopsy touch impressions or aspirate from leading edge of ulcer; culture may be available using special media (NNN and others)
Histopathology of leading edge ulcer biopsies is less sensitive than impression smears.
PCR and isoenzyme analysis are available at the CDC for speciation, which may be important for treatment considerations [bib_ref] Advances in leishmaniasis, Murray [/bib_ref] Serology is not useful for cutaneous disease.
Leishmaniasis, visceral, due to various Leishmania species
Microscopic exam of Giemsa stained bone marrow aspirate/biopsy, splenic aspirate; culture may be available using special media (NNN and others). Contact laboratory for availability of special media.
Positive rK39 serology reported to be both sensitive and specific for the diagnosis of visceral leishmaniasis in various endemic areas of the world.
Serology from the CDC or reference laboratory [bib_ref] Advances in leishmaniasis, Murray [/bib_ref] Malaria due to Plasmodium falciparum, P. ovale, P. vivax, P. malariae, P. knowlesi
Microscopy of Giemsa stained thick and thin blood films (3 sets obtained during febrile episodes); antigen (HR-2, aldolase, pLDH) detection tests (BinaxNow is FDA approved in US)
Antigen strip tests lack sensitivity in low parasitemia and non-falciparum malaria and do not differentiate all species.
NAAT from some reference laboratories will detect and differentiate all species.
Toxocariasis (visceral larva migrans)
Serology from CDC or referral laboratories Larvae may be seen in histopathologic sections of biopsies of liver or other infected tissues. Histopathology - NAATs are useful for detection of low parasitemia or in specifically identifying organisms which cannot be differentiated microscopically.
- NAATs should not be used to monitor response to therapy, since DNA may be detectable for days to weeks after successful treatment.
- Nucleic acid detection of blood and tissue parasites is currently available only from specialized laboratories and turnaround time may be prolonged.
Table XV-1 presents an inclusive overview of the approach to the diagnosis of blood and tissue parasitic infections. Important points are bolded. Subsequent sections A and B provide more detailed information on the diagnosis of parasitic infections which are of particular concern to practitioners in North America (babesiosis and American trypanosomiasis) or in which rapid and accurate diagnosis is crucial because of the life-threatening nature of the infection (malaria and babesiosis). With all testing, it is important to note that results are only as reliable as the experience, resources, and expertise of the laboratory performing the tests. In general, large public health laboratories such as those of the CDC and World Health Organization (WHO) are more likely than commercial laboratories to have the experience and volume of specimens to properly validate the more esoteric tests, while turnaround time for results is often faster with commercial reference labs. Direct communication by phone or e-mail will sometimes hasten specimen processing and result reporting from public health Cysts and tachyzoites can be seen in specimens from immunocompromised patients (eg bronchoalveolar lavage, brain biopsy).
NAAT is available from some reference labs. Animal inoculation may be available from the CDC.
Trichinosis due to Trichinella spiralis and other species Serology (EIA) from the CDC or reference laboratoryEncysted larvae can be seen in histopathologic sections of muscle biopsies.
## Histopathology
Trypanosomiasis, African (Sleeping Sickness) due to Trypanosoma brucei gambiense (West African) or T. b. rhodesiense (East African)
Microscopy of Giemsa stained thick and thin blood films or buffy coat preps. Parasitemia is often low, requiring repeated exams. Centrifuged CSF may be examined but organisms are rarely seen. Aspirates of chancres and lymph nodes may also be examined. There is an infection hazard from live organisms in blood specimens. [bib_ref] The trypanosomiases, Barrett [/bib_ref] [bib_ref] Options for field diagnosis of human african trypanosomiasis, Chappuis [/bib_ref] Morula cells of Mott (plasma cells with large eosinophilic antibody globules) may be seen in CSF and brain biopsy. Microscopy of Giemsa stained thick and thin blood films or buffy coat preps.
## Parasitemia is very low in chronic infection.
IgG antibody may persist for decades and its presence is considered evidence of chronic infection.
Serology available for donor and diagnostic testing.
An FDA-approved test is available for screening blood donors and is different from the test used for diagnostic purposes. Culture of blood may be available using special media (NNN and others). Contact the laboratory for availability of special media.
There is an infection hazard from live organism in blood specimens [bib_ref] The trypanosomiases, Barrett [/bib_ref] [bib_ref] Evaluation and treatment of chagas disease in the United States: a systematic..., Bern [/bib_ref].
laboratories, especially when there is an urgent clinical situation. The DPDx website at CDC (http://www.dpd.cdc.gov/ dpdx/HTML/DiagnosticProcedures.htm) provides a list of currently available diagnostic tests for parasitic infections available from the CDC. The CDC also provides a valuable consultation service that can be accessed through the DPDx website for both the laboratorian and clinician. The availability of rapid shipping methods (FedEx, UPS, etc.) and e-mail or other electronic communication allow reporting of results from specialty laboratories, including those in Europe and Asia, in surprisingly short periods of time. It is useful to obtain shipping information from such laboratories to avoid unnecessary delays because of customs or airline regulations or other delivery problems.
## A. babesia and malaria
Babesiosis is caused primarily by Babesia microti in the U.S. and B. divergens in Europe. More recently, a small number of infections occurring in California and Washington have been attributed to B. duncani, while an unnamed species (MO-1 strain) has been detected from a fatal case in Missouri. Malaria is caused by Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi; the latter is primarily a simian parasite in Southeast Asia which has recently been recognized in an increasing number of human patients. Table XV-2 summarizes the laboratory tests available for these agents. The standard method for diagnosis of both parasites is microscopic examination of Giemsa stained thick and thin blood films. Although this method requires a minimum amount of resources (staining materials and high quality microscopes), well trained and experienced technologists must be available to obtain maximum accuracy and efficiency [bib_ref] The reliability of diagnostic techniques in the diagnosis and management of malaria..., Ochola [/bib_ref]. Because both babesiosis and malaria are serious infections which can progress to fatal outcomes if not diagnosed and treated accurately, it is necessary for health care facilities to have ready access to rapid accurate laboratory testing. Ideally, samples are obtained from fresh capillary (or venous) blood and slides are prepared immediately. However, it is typically more practical to obtain EDTA ( preferred) or heparin anticoagulated blood and transport the sample to the laboratory for slide preparation.
Thick blood films are essentially lysed concentrates which allow rapid detection of the presence of parasites consistent with either Plasmodium or Babesia but generally do not allow definitive identification. The thick film is made using 2-3 drops of blood that have been "laked" (lysed) by placement into a hypotonic staining solution. This releases the intracellular parasites and allows for examination of multiple (20-30) layers of blood simultaneously. For this reason, it is the most sensitive method for microscopic screening and allows detection of very low levels of parasitemia (less than 0.001% of RBCs infected). In contrast, the thin films are prepared like a hematology peripheral smear and are fixed in ethanol before staining. Fixation retains the structure of the RBCs and intraerythrocytic parasites and provides ideal morphology for Plasmodium speciation. It also allows for optimal evaluation and differentiation of malaria from Babesia parasites, although the different Babesia species cannot be distinguished from one another by morphology alone. Staining is best performed with Giemsa at a pH of 7.2 to highlight the microscopic features of the parasites. Wright-Giemsa and rapid field stains are also acceptable.
Both thick and thin films should be screened manually, since automated hematology analyzers may fail to detect Plasmodium and Babesia species parasites. The slides should first be screened at low power (100 times final magnification) for identification of larger microfilariae, followed by examination under oil immersion. The laboratorian should examine a minimum of 300 microscopic fields at 500 to 1000 times total magnification on the thick and thin films before reporting a specimen as negative. It is important to remember that Babesia and Plasmodium may at times be indistinguishable on blood films and that both can be transmitted by transfusion so each can occur in atypical clinical settings. Clinical and epidemiologic information must be considered and additional testing may be required.
If parasites are identified and the laboratory does not have expertise for species identification, then a preliminary diagnosis of "Plasmodium or Babesia parasites" should be made, followed by confirmatory testing at a reference lab. In this situation, the primary laboratory should relay the message to the clinical team that the deadly parasite, P. falciparum, cannot be excluded from consideration. Repeat blood samples (3 or more specimens drawn during febrile episodes) are indicated if the initial film is negative, and malaria or babesiosis is strongly suspected.
When Plasmodium species are identified, one can enumerate the number of infected RBCs and divide by the total number of RBCs counted to arrive at the percent parasitemia. This is best determined by using the thin film. Quantification can also be performed using the thick film, but this method is less precise. Quantification may be used to guide initial treatment decisions and to follow a patient's progress during treatment.
An alternative to Giemsa-stained blood films for morphologic examination is the Quantitative Buffy Coat (QBC) method. This test detects fluorescently stained parasites within RBCs and requires specialized equipment. It acquires maximum efficiency for the laboratory if multiple specimens are being processed at the same time which is seldom the case in U. S. laboratories. In addition it requires preparation of a thin blood smear if a QBC sample is positive, since specific identification and rate of parasitemia will still need to be determined by the latter method. For these reasons, the QBC method is seldom used in the U.S. at this time.
Although morphologic examination is the conventional method for diagnosis of malaria, it requires considerable time and expertise. Rapid antigen detection tests (RDTs) for malaria provide cost effective, rapid alternatives and can be used for screening when qualified technologists are not available. The Bi-naxNow rapid diagnostic test has recently been approved by the FDA. It is a rapid immunochromatographic card (or "dipstick") assay which requires no specialized equipment or special training for qualified technologists. This RDT uses monoclonal antibodies to detect the HRP-2 antigen of P. falciparum and an aldolase common to all species of Plasmodium. Positive RDTs should be confirmed by examination of thick and thin blood films which are also necessary to determine which species other than P. falciparum (if the assay is aldolase positive but HRP-2 negative) is present and to determine the rate of parasitemia.
This RDT is somewhat less sensitive than a thick blood film and may be falsely negative in cases with very low rates of parasitemia. However, the sensitivity is comparable to blood smear in symptomatic malaria patients with P. falciparum infection. In addition, RDTs may be falsely positive for several days after eradication of intact parasites, since antigens may still be detected. Therefore, the assay should not be used to follow patients after adequate therapy has been given. The RDT should not be viewed as a replacement for blood films but rather as a substitute in situations where reliable blood films will not be readily available (off hours in the laboratory when skilled personnel are not available) or when the clinical situation is critical and an immediate diagnosis is required (stat laboratory in the emergency department). Such RDT testing should be followed as soon as possible by good quality thick and thin blood films.
Serology plays little role in diagnosis of acute babesiosis and malaria, since antibodies may not appear early in infection and titers may be too low to determine the status of infection. The primary use of antibody detection is for epidemiologic studies and as evidence of previous or relapsing infection. Indirect immunofluorescent antibody (IFA) is the most readily available commercial assay for Babesia (Focus Diagnostics, Cypress CA, Rapid NAAT assays have recently been developed for malaria and babesiosis and are available from some commercial reference laboratories and the CDC although none are FDAcleared. These methods are comparable in sensitivity to the thick blood film and require no specialized parasitologic expertise. NAATs may be useful in accurate diagnosis of acute infection if blood films are negative or difficult to obtain and in the differentiation of malaria parasites from Babesia or nonparasitic artifacts. Finally, NAAT may provide diagnostic confirmation in cases empirically treated without prior laboratory diagnosis by detection of remnant nucleic acid. Because residual DNA can be detected days (or even weeks to months in asplenic persons) after intact parasites have been eradicated, NAATs should not be used to monitor response to therapy. When a NAAT is positive for Plasmodium or Babesia parasites, thin blood films must still be examined to determine the percent parasitemia.
It is important to stress that requests for malaria and babesiosis diagnosis should be considered "STAT" and testing performed as rapidly as possible. NAAT assays may be rapid but are limited to the reference laboratory setting, and the total turnaround time will be too long to enable rapid institution of antimalarial therapy. In such cases, the primary use of NAATs is for confirmation of infection, assistance in species identification, and differentiation of malaria from Babesia.
## B. american trypanosomiasis or chagas disease caused by trypanosoma cruzi
American trypanosomiasis may consist of acute, latent, and chronic phases, and the optimal diagnostic method differs with each stage. The standard method for diagnosis of American trypanosomiasis during the acute phase of infection (4-8 weeks in length) is microscopy of Giemsa stained thick and thin blood or buffy coat films, since extracellular trypanosomes will be present at this time [fig_ref] Table V - 1: [/fig_ref]. As with blood films for malaria and Babesia, a minimum amount of resources (staining materials and high quality microscopes), as well as proficient Serum or plasma should be separated from blood within several hours. Store serum refrigerated or frozen if not tested within 4-6 h to preserve antibody and prevent bacterial growth. Avoid use of hyperlipemic or hemolyzed blood. and experienced technologists, must be available to obtain maximum accuracy and efficiency. On stained preparations, the motile trypomastigote forms typically adopt a "C" shape and can be differentiated from the similar appearing trypomastigotes of T. brucei by the presence in T. cruzi of a large posterior kinetoplast. In comparison, the kinetoplast of T. brucei trypomastigotes is much smaller. Of course, these infections can also be likely differentiated on epidemiologic grounds. Motile organisms can also be observed in fresh wet preparations of anticoagulated blood or buffy coat although most U.S. labs are unfamiliar with this method. Unfortunately, infection is rarely diagnosed in the acute stage since only 1%-2% of infected individuals present with symptoms during this time period. Microscopy is less useful during the latent and chronic stages of infection when rates of parasitemia are very low. The diagnosis in these stages may be established serologically or by microscopic examination of tissue aspirates or biopsies. The nonmotile (amastigote) intracellular form of T. cruzi predominates during this phase of the infection. Culture in easily prepared Novy-MacNeal-Nicolle medium (NNN) or similar media of any appropriate blood or tissue specimen during the acute and chronic stages will add to the sensitivity of laboratory diagnosis. The laboratory should be contacted to assure the availability of special media. It must be emphasized that live trypanosomes are highly infectious and specimens must be handled with care using "standard precautions." for the handling of blood and body fluids.
Serology by commercially available enzyme-linked immunoassay (ELISA) kits is of greatest use during the latent and chronic stages of disease when parasites are no longer easily detected in peripheral blood preparations by microscopy. Positive ELISA results are considered evidence of active infection and would exclude potential blood/tissue donors who test positive from acting as donors, since the infection has been shown to be transmitted by transfusion and transplantation. A somewhat unusual situation has developed for serologic testing for American trypanosomiasis where the FDA has approved two commercial assays for blood or organ donor screening and a different commercial assay for patient diagnostic testing. Each assay cannot be used for the nonapproved purpose even though they are supposed to be detecting the same antibodies. An ELISA (Ortho-Clinical Diagnostics, Raritan, NJ) and an automated method (Abbott Prism Chagas, Abbott Park, IL) have been approved for blood, organ, cell, and tissue donor screening whereas a different ELISA test (Hemagen Diagnostics, Columbia, Md) is approved for diagnostic testing. Donor screening test positives may be tested by an FDA approved supplemental test (ABBOTT ESA Chagas) and/or submitted to a reference laboratory for confirmatory testing by a radioimmunoprecipitation assay (RIPA). The Hemagen assay measures IgG and does not require confirmatory testing. Both ELISAs provide only qualitative positive or negative results without information regarding antibody titer.
## Notes
[table] Table Introduction: -1. Transport Issues (General Guide) a [/table]
[table] Table I -: 1. Blood Culture Laboratory Diagnosis Organized by Etiologic Agent [/table]
[table] Table II: -1. Laboratory Diagnosis of Meningitis [/table]
[table] Table IV - 1: B. Mastoiditis and Malignant Otitis Externa Caused by Oropharyngeal and Exogenous Pathogens(Table IV-2) [/table]
[table] Table IV -: 2. Laboratory Diagnosis of Mastoiditis and Malignant Otitis Externa Caused by Oropharyngeal and Exogenous Pathogens [/table]
[table] Table V -: 1. Laboratory Diagnosis of Otitis Media [/table]
[table] Table V: Abbreviations: IgG, immunoglobulin G; IgM, immunoglobulin M; NAAT, nucleic acid amplification test; RT, room temperature. a A rapid antigen test for Streptococcus pyogenes may be performed at the point-of-care by healthcare personnel or transported to the laboratory for performance of the test. [/table]
[table] Table IX -: 1. Laboratory Diagnosis of Osteomyelitis [/table]
[table] Table X -: 1. Laboratory Diagnosis of Cystitis and Pyelonephritis [/table]
[table] Table XI -: 1. Laboratory Diagnosis of Genital Lesions [/table]
[table] Table XII: Abbreviations: AST, antimicrobial susceptibility tests; MRSA, methicillin-resistant Staphylococcus aureus; NAAT, nucleic acid amplification test; RT, room temperature. a Electrical burns; potential for transmission from leaches. [/table]
[table] Table XIV -: 2. Laboratory Diagnosis of Epstein-Barr Virus [/table]
[table] Table XIV: Abbreviations: NAAT, nucleic acid amplification test; RT, room temperature. month. IgG antibodies may persist for years. The presence of IgG antibodies alone is indicative of past exposure and suggests immunity; this test may be helpful for women in the first trimester of pregnancy. Serologic tests may be negative in the immunocompromised host despite prior exposure to the virus.Parvovirus B19 DNA-based assays may be used for the diagnosis of parvovirus B19 infection presenting as transient aplastic crisis or chronic anemia in immunosuppressed patients. [/table]
[table] Table XV: -1. Laboratory Diagnosis of Blood and Tissue Parasitic Infections a,b [/table]
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Abstract The critical role of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician and the microbiologists who provide enormous value to the health care team. This document, developed by both laboratory and clinical experts, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. Sections are divided into anatomic systems, including Bloodstream Infections and Infections of the Cardiovascular System, Central Nervous System Infections, Ocular Infections, Soft Tissue Infections of the Head and Neck, Upper Respiratory Infections, Lower Respiratory Tract infections, Infections of the Gastrointestinal Tract, Intraabdominal Infections, Bone and Joint Infections, Urinary Tract Infections, Genital Infections, and Skin and Soft Tissue Infections; or into etiologic agent groups, including Tickborne Infections, Viral Syndromes, and Blood and Tissue Parasite Infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. There is redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a reference to guide physicians in choosing tests that will aid them to diagnose infectious diseases in their patients.
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Diagnosis and treatment of early breast cancer, including locally advanced disease—summary of NICE guidance
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Diagnosis and treatment of early breast cancer, including locally advanced disease—summary of NICE guidance
This is one of a series of BMJ summaries of new guidelines, which are based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.Why read this summary?Breast cancer is the commonest cancer in women, with over 40 500 new cases diagnosed each year in England and Wales. 1 2 Despite a steady decline in age standardised mortality rates owing to screening and better management, the disease still causes 10 900 deaths each year in England and Wales, 1 2 with a huge social and emotional impact. This article outlines the most important recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the diagnosis and treatment of early and locally advanced breast cancer. 3RecommendationsNICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the Guideline Development Group's opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.This new guideline covers women presenting with breast cancer in whom the primary tumour may have been non-palpable and detected by screening mammography through to women with cancers over 5 cm but in whom there is no evidence of spread beyond the breast and axillary lymph nodes. The guideline includes a large spectrum of disease, ranging from ductal carcinoma in situ (DCIS) to inflammatory breast cancer, and also includes breast cancer in men, which is rare. Advanced breast cancer is the subject of another guideline. 4Diagnosis and preoperative assessment- Magnetic resonance imaging (MRI) of the breast is not recommended as a routine preoperative assessment of patients with invasive breast cancer or DCIS but can help when a discrepancy exists between the clinical and radiological assessment, when breast density prevents mammographic assessment, or when breast conservation surgery to assess tumour size is being considered in lobular cancer. [Based on moderate quality evidence from case-control and case series studies and on the experience of the Guideline Development Group] - Ensure that pretreatment ultrasonography of the axilla is carried out and ultrasound guided needle biopsy also if abnormal lymph nodes are detected. [Based on moderate quality clinical evidence from case series studies that informed an economic analysis of cost effectiveness] Psychological support - Members of the breast cancer clinical team should have completed an approved communication skills training programme.- Allocate patients to a named breast care nurse specialist to support them throughout their care and follow-up.- Ensure that specialist psychological support, including psychiatric services, is readily available when necessary.
This is one of a series of BMJ summaries of new guidelines, which are based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.
## Why read this summary?
Breast cancer is the commonest cancer in women, with over 40 500 new cases diagnosed each year in England and Wales. 1 2 Despite a steady decline in age standardised mortality rates owing to screening and better management, the disease still causes 10 900 deaths each year in England and Wales, 1 2 with a huge social and emotional impact. This article outlines the most important recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the diagnosis and treatment of early and locally advanced breast cancer. 3
Recommendations NICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the Guideline Development Group's opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.
This new guideline covers women presenting with breast cancer in whom the primary tumour may have been non-palpable and detected by screening mammography through to women with cancers over 5 cm but in whom there is no evidence of spread beyond the breast and axillary lymph nodes. The guideline includes a large spectrum of disease, ranging from ductal carcinoma in situ (DCIS) to inflammatory breast cancer, and also includes breast cancer in men, which is rare. Advanced breast cancer is the subject of another guideline. 4
## Diagnosis and preoperative assessment
- Magnetic resonance imaging (MRI) of the breast is not recommended as a routine preoperative assessment of patients with invasive breast cancer or DCIS but can help when a discrepancy exists between the clinical and radiological assessment, when breast density prevents mammographic assessment, or when breast conservation surgery to assess tumour size is being considered in lobular cancer. - Allocate patients to a named breast care nurse specialist to support them throughout their care and follow-up.
- Ensure that specialist psychological support, including psychiatric services, is readily available when necessary.
## Surgery to the breast and axilla
Surgery is the primary treatment for DCIS and early invasive breast cancer, preferably with breast conservation when possible.
- After breast conserving surgery for DCIS a minimum radial margin of excision of 2 mm is recommended, with pathological examination in line with the reporting standards of the NHS breast screening programme. If the margin is less than 2 mm consider re-excision after discussing the risks and benefits with the patient. Enter patients with screen detected DCIS into the Sloane Project (the UK prospective audit of screen detected non-invasive carcinomas of the breast). 5 Breast units should audit their recurrence rates.
- When no evidence exists of lymph node involvement by ultrasonography or a negative ultrasound guided biopsy, the axilla should be staged by minimal surgery, preferably sentinel lymph node biopsy, rather than lymph node clearance. Perform sentinel lymph node biopsy using the dual technique with isotope and blue dye. Breast units should audit their axillary recurrence rates. [Based on an overall moderate quality of evidence from randomised controlled trials, case series, and a meta-analysis of case series studies]
- Further axillary treatment, preferably by lymph node dissection as it gives additional staging information, is required if macrometastases or micrometastases are present in the sentinel lymph node or if there is histologically proved cancer in the preoperative ultrasound guided needle biopsy. Patients with isolated tumour cells in the sentinel nodes should have no further axillary surgery as they are regarded as lymph node negative.
- Discuss immediate breast reconstruction with all patients for whom mastectomy is advised, unless they have significant comorbidity or where adjuvant therapy may be compromised, and discuss the full choice of the different types of breast reconstruction, whether available locally or not. [Based on low quality evidence from observational studies and on the experience of the Guideline Development Group]
## Planning adjuvant treatment
- Measure the oestrogen receptor status of all invasive cancers using immunohistochemistry and report this quantitatively. The routine measurement of the progesterone receptor status is not needed. Assess the human epidermal growth factor receptor 2 status by using a standardised and qualitatively assured method. Ensure these results are available and recorded at the multidisciplinary team meeting to guide adjuvant treatment decisions.
- Consider adjuvant therapy at the multidisciplinary meeting for all patients with invasive breast cancer after surgery, taking into account the prognostic and predictive factors, the potential benefits and side effects, and the outcome of discussions with the patient.
- The web based tool Adjuvant! Online 6 is useful for estimating the absolute benefit of adjuvant treatment for an individual.
- Start chemotherapy or radiotherapy as soon as possible
## Endocrine therapy in invasive disease
- For postmenopausal patients with oestrogen receptor positive invasive breast cancer that is not considered to be low risk, offer an aromatase inhibitor, either anastrozole or letrozole, as initial adjuvant therapy. If tamoxifen was chosen as the primary adjuvant treatment an aromatase inhibitor, either exemestane or anastrozole, can be offered after two to three years of tamoxifen, or letrozole after five years of tamoxifen in higher risk patients. When aromatase inhibitors are poorly tolerated or contraindicated as the primary adjuvant treatment, tamoxifen should be given.
[Based on high quality randomised controlled trials]
## Trastuzumab therapy
- After surgery, chemotherapy and radiotherapy (when applicable) in patients who have breast cancer that is positive for human epidermal growth factor receptor 2 and who have satisfactory cardiac function, offer trastuzumab every three weeks for one year or until disease progression. Trastuzumab is a humanised monoclonal antibody that targets the human epidermal growth factor receptor 2, which is overexpressed in about 15% of breast cancers. Periodic follow-up of cardiac function during the year is mandatory.
## Managing bone health
- Offer baseline dual energy x ray absorptiometry to assess bone mineral density in patients starting aromatase inhibitor treatment, those who have had treatment induced menopause, or those having ovarian ablation or suppression, as all these treatments can cause considerable bone loss and consequent risk of fracture. [Based on a high quality guideline 8 and the experience of the Guideline Development Group]
- Offer bisphosphonates to patients according to UK consensus guidance for managing breast cancer treatment induced bone loss. 8
## Adjuvant radiotherapy
- Recommend breast radiotherapy after breast conservation surgery in patients with invasive disease, and consider it after surgery for DCIS.
- After mastectomy, discuss chest wall radiotherapy in higher risk patients, mainly depending on lymph node involvement.
- A dose of 40 Gy in 15 fractions using external beam radiotherapy is recommended.
- Do not irradiate the nodal areas routinely.
## Primary systemic therapy
## Complications of local treatment and menopausal symptoms
- Provide patients with information before surgery or radiotherapy on the risk of lymphoedema and factors such as infection that may cause or exacerbate it, including postoperative physiotherapy regimens. If lymphoedema develops ensure rapid access to a lymphoedema service.
- Discontinue hormone replacement therapy in all patients diagnosed with invasive breast cancer, and do not offer it routinely to women with menopausal symptoms who have a previous history of the disease. Offer support, written information, and counselling for those women who might develop menopausal symptoms as a result of their treatment.
## Follow-up
## Overcoming barriers
The challenge for clinicians and commissioners is applying this guideline in a way that provides informed choice and equity of access to services for all patients. Resources in training and infrastructure may be needed for the wider use of ultrasound and mammographic follow-up and will be necessary for identifying and supporting centres offering specialist MRI services. All women advised to have a mastectomy need advice on the appropriateness, timeliness, and types of reconstructive procedures from oncoplastic specialists, who may have to network across sites. For those whose treatments affect bone health, access to surveillance and early intervention are essential to reduce serious complications; this will require commissioner support to acquire scan time for dual energy x ray absorptiometry.
Many of these recommendations have cost implications. A costing tool developed by NICE is available, and an implementation pack will be available soon. Most of the recommendations can be implemented and audited by the multidisciplinary breast cancer teams under the supervision of the cancer networks.
## Further information on the guidance
## Current areas of inconsistency
How follow-up for patients with early and locally advanced breast cancer should be carried out has been controversial for many years. The existing NICE service guidance for "improving outcomes in breast cancer" 9 recommends that hospital based follow-up after treatment for early breast cancer should be limited to three years. However, peer review has shown considerable variation across England and Wales in implementing this recommendation 3 and has led to uncertainty about who should undertake follow-up and where it should be performed. There is great variation and conflicting advice on follow-up mammography. The new guideline has given clear advice on what individual breast cancer multidisciplinary teams should now do.
Immediate versus delayed breast reconstruction has been debated for several years. For patients who are concerned about loss of body image, immediate reconstruction has the advantage of a single breast procedure and fewer operations to obtain an acceptable and usually good cosmetic outcome. However, a large quantity of information about reconstruction has to be discussed with patients for them to make informed decisions, and this can be difficult when at the same time absorbing the diagnosis of breast cancer. Furthermore, all methods of reconstruction have potential complications that might delay subsequent adjuvant therapy. The guideline makes a sensible and pragmatic recommendation that will give more choice to patients with breast cancer who want reconstruction.
# Methods
The development of this guideline was based on methods outlined by the NICE guidelines manual. 10
Four different versions of the guideline have been produced: a full version containing all the evidence and the recommendations; a quick reference guide; a version known as the "NICE guideline," which lists the recommendations; and a lay translation of the NICE guideline for patients and the public. All the versions are available on the NICE website (www.nice.org.uk/CG80).
Future updates of the guideline will be produced as part of the NICE guideline development programme. 10
## Future research and remaining uncertainties
The Guideline Development Group also made the following research recommendations.
- What is the effectiveness of cognitive behavioural therapy compared with other psychological interventions for patients with breast cancer?
- In the absence of good data comparing clinical outcomes between axillary radiotherapy and complete axillary lymph node dissection, entry into appropriate clinical trials (such as AMAROS (after mapping of the axilla: radiotherapy or surgery), a randomised controlled trial) is recommended for patients with early breast cancer when sentinel lymph node biopsy shows metastasis in the axilla.
- How effective is trastuzumab in patients with invasive breast cancer: (a) as adjuvant therapy without chemotherapy and (b) as primary systemic treatment, in terms of quality of life, side effects, disease recurrence rates, disease-free survival, and overall survival? In patients who are also receiving or have completed chemotherapy, what is the most effective scheduling and duration of treatment with trastuzumab?
- In patients with early invasive breast cancer, how effective are (a) different hypofractionation radiotherapy regimens, (b) partial breast radiotherapy, and (c) newer radiotherapy techniques (including intensity modulated radiotherapy), in terms of long term outcomes such as quality of life, side effects, disease recurrence rates, disease-free survival, and overall survival?
- For patients who have been treated for early invasive breast cancer or DCIS, what is the optimal frequency and length of surveillance of follow-up mammography?
For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe
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Breast cancer is the commonest cancer in women, with over 40 500 new cases diagnosed each year in England and Wales.1 2 Despite a steady decline in age standardised mortality rates owing to screening and better management, the disease still causes 10 900 deaths each year in England and Wales,1 2 with a huge social and emotional impact. This article outlines the most important recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the diagnosis and treatment of early and locally advanced breast cancer.3
NICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the Guideline Development Group’s opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.
This new guideline covers women presenting with breast cancer in whom the primary tumour may have been non-palpable and detected by screening mammography through to women with cancers over 5 cm but in whom there is no evidence of spread beyond the breast and axillary lymph nodes. The guideline includes a large spectrum of disease, ranging from ductal carcinoma in situ (DCIS) to inflammatory breast cancer, and also includes breast cancer in men, which is rare. Advanced breast cancer is the subject of another guideline.4
### Diagnosis and preoperative assessment
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Outpatient Respiratory Management of Infants, Children, and Adolescents with Post-Prematurity Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline
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Outpatient Respiratory Management of Infants, Children, and Adolescents with Post-Prematurity Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline
Background: Premature birth affects millions of neonates each year, placing them at risk for respiratory disease due to prematurity. Bronchopulmonary dysplasia is the most common chronic lung disease of infancy, but recent data suggest that even premature infants who do not meet the strict definition of bronchopulmonary dysplasia can develop adverse pulmonary outcomes later in life. This post-prematurity respiratory disease (PPRD) manifests as chronic respiratory symptoms, including cough, recurrent wheezing, exercise limitation, and reduced pulmonary function. This document provides an evidence-based clinical practice guideline on the outpatient management of infants, children, and adolescents with PPRD.Methods: A multidisciplinary panel of experts posed questions regarding the outpatient management of PPRD. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations.Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations were developed for or against three common medical therapies and four diagnostic evaluations in the context of the outpatient management of PPRD.Conclusions: The panel developed recommendations for the outpatient management of patients with PPRD on the basis of limited evidence and expert opinion. Important areas for future research were identified.
## Summary of recommendations recommendation 1a
For infants, children, and adolescents with post-prematurity respiratory disease (PPRD) who do not have recurrent respiratory symptoms, we suggest that short-acting inhaled bronchodilator therapy not be routinely prescribed (conditional recommendation, very-low-certainty evidence).
## Recommendation 1b
For infants, children, and adolescents with PPRD who have recurrent respiratory symptoms (such as cough or wheeze), we suggest a trial of a short-acting inhaled bronchodilator with monitoring to assess for clinical improvement in symptoms (conditional recommendation, very-lowcertainty evidence).
## Recommendation 2a
For infants, children, and adolescents with PPRD who do not have chronic cough and recurrent wheezing, we suggest that inhaled corticosteroids not be routinely prescribed (conditional recommendation, very-lowcertainty evidence).
## Recommendation 2b
For infants, children, and adolescents with PPRD who have chronic cough or recurrent wheezing, we suggest a trial of inhaled corticosteroids with monitoring to assess for clinical improvement in symptoms (conditional recommendation, very-lowcertainty evidence).
## Recommendation 3a
For infants, children, and adolescents with PPRD, we suggest against the routine use of diuretics (conditional recommendation, verylow-certainty evidence).
## Recommendation 3b
For infants with PPRD who are discharged from the Neonatal Intensive Care Unit (NICU) on chronic diuretic therapy, we suggest discontinuation in a judicious manner (conditional recommendation, very-low-certainty evidence).
## Recommendation 4a
For infants with PPRD who are otherwise ready to be discharged from the NICU, we suggest the use of polysomnography (PSG) for patients with persistent apnea, intermittent desaturation, or bradycardia at greater than 40 weeks' postmenstrual age (PMA) (conditional recommendation, verylow-certainty evidence).
## Recommendation 4b
For infants, children, and adolescents with PPRD, we suggest the use of PSG and/or a sleep medicine referral for those with symptoms of sleep-disordered breathing (SDB), including persistent snoring, failure to thrive, or a persistent need for supplemental oxygen at 2 years of age (conditional recommendation, very-lowcertainty evidence).
## Recommendation 4c
When PSG is indicated but not available, we recommend that overnight or 24-hour oximetry be performed to screen for SDB, followed by PSG and/or a sleep medicine referral for further evaluation if needed (conditional recommendation, very-lowcertainty evidence). For infants, children, and adolescents with PPRD, we suggest a swallow evaluation (videofluoroscopic swallow study for those who are eating by mouth and have cough or persistent oxygen desaturation during feeding, suspected or confirmed vocal cord paralysis or other airway anomalies, failure to wean from oxygen therapy or ventilatory support as expected, persistent or worsening pulmonary hypertension, failure to thrive, or chronic pulmonary symptoms Introduction Use of These Guidelines Definition of PPRD Methods
# Results
Question 1: Should infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD and who have respiratory symptoms (wheezing, cough, tachypnea) receive shortacting, inhaled bronchodilators? Question 2: Should infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD and who have respiratory symptoms (wheezing, cough, tachypnea) routinely receive inhaled corticosteroids? Question 3: Should infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD and who have respiratory symptoms (wheezing, cough, tachypnea) routinely receive diuretic therapy? out of proportion to viral respiratory infections (conditional recommendation, very-low-certainty evidence).
## Recommendation 6
For infants, children, and adolescents with PPRD, we suggest airway endoscopy for those with unexplained symptoms such as chronic cough, wheezing, ventilator dependence, persistent hypoxemia, or a history of patent ductus arteriosus (PDA) ligation with stridor and weak cry (conditional recommendation, very-lowcertainty evidence).
## Recommendation 7a
For infants, children, and adolescents with PPRD who do not have symptoms suggestive of airway malacia, we suggest that dynamic airway imaging (computed tomography or magnetic resonance imaging not be used as a screening test for the routine diagnosis of tracheobronchomalacia (TBM) (conditional recommendation, very-lowcertainty evidence).
# Introduction
Worldwide, approximately 12 million neonates (10% of live births) are born prematurely and are at risk for respiratory disease, which leads to increased morbidity and mortality [bib_ref] Short-and long-term outcomes for extremely preterm infants, Patel [/bib_ref]. The most common chronic lung disease of infancy (CLDI) associated with preterm birth is bronchopulmonary dysplasia (BPD), with approximately 12-15,000 cases of BPD occurring annually in the United States alone [bib_ref] Epidemiology of bronchopulmonary dysplasia, Jensen [/bib_ref]. Premature infants who do not meet the definition of BPD may develop adverse pulmonary outcomes later in life, including cough, recurrent wheezing, exercise intolerance, hypoxemia, and reduced pulmonary function [bib_ref] Respiratory outcome in school-aged, very-low-birth-weight children in the surfactant era, Korhonen [/bib_ref] [bib_ref] Lung function and respiratory health in adolescents of very low birth weight, Anand [/bib_ref] [bib_ref] Pulmonary gas exchange and exercise capacity in adults born preterm, Farrell [/bib_ref] [bib_ref] Functional capacity during exercise in very-low-birth-weight premature children, Tsopanoglou [/bib_ref] [bib_ref] Reduced exercise capacity in children born very preterm, Smith [/bib_ref]. Disrupted lung development due to prematurity is associated with lifelong respiratory sequelae, including chronic obstructive pulmonary disease [bib_ref] Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia, Wong [/bib_ref] [bib_ref] Obstructive pulmonary disease in old age among individuals born preterm, Brostr€ Om [/bib_ref] [bib_ref] Chronic lung disease after premature birth, Baraldi [/bib_ref] [bib_ref] Disrupted lung development and bronchopulmonary dysplasia: opportunities for lung repair and regeneration, Baker [/bib_ref] [bib_ref] Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia, Husain [/bib_ref] [bib_ref] Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond, Mourani [/bib_ref] [bib_ref] Lung elastic tissue maturation and perturbations during the evolution of chronic lung..., Thibeault [/bib_ref] [bib_ref] Bronchopulmonary dysplasia, Kinsella [/bib_ref]. Children born preterm require frequent clinic visits, increased use of respiratory medications, and increased hospitalizations [bib_ref] Lungfunction trajectories leading to chronic obstructive pulmonary disease, Lange [/bib_ref] [bib_ref] Rehospitalization and growth of infants with bronchopulmonary dysplasia: a matched control study, Chye [/bib_ref] [bib_ref] Effect of preterm birth on pulmonary function at school age: a prospective..., Gross [/bib_ref] [bib_ref] Prematurity and Respiratory Outcomes Program. Bronchopulmonary dysplasia and perinatal characteristics predict 1-year..., Keller [/bib_ref] [bib_ref] Rehospitalization in the first year of life among infants with bronchopulmonary dysplasia, Smith [/bib_ref].
In 2003, the American Thoracic Society (ATS) published the "Statement on the Care of the Child with Chronic Lung Disease of Infancy and Childhood," which addressed the epidemiology, pathophysiology, and treatment of CLDI and childhood [bib_ref] Statement on the care of the child with chronic lung disease of..., Allen [/bib_ref]. This ATS statement has been a highly used clinical tool for the management of patients with CLDI. Advancements such as antenatal steroids, postnatal surfactants, and protective ventilation strategies have led to a marked increase in the survival of premature infants born much earlier in gestation. However, the increased survival of extremely preterm infants has led to a developmental arrest of alveolar and pulmonary vascular growth termed "new BPD" [bib_ref] The new bronchopulmonary dysplasia, Jobe [/bib_ref]. Thus, there was a pressing need for updated guidance to assist clinicians who care for patients born preterm in the modern era.
## Use of these guidelines
These recommendations are intended to aid clinicians in the outpatient management of infants, children, and adolescents with PPRD, regardless of the degree of prematurity, the severity of disease, the disease phenotype [bib_ref] Characterization of disease phenotype in very preterm infants with severe bronchopulmonary dysplasia, Wu [/bib_ref] , or the age of the patient at the time of presentation. Whether or not to begin a therapy or order a diagnostic study should be made on an individual basis, considering the patient's symptoms and clinical presentation.
## Definition of pprd
We have used the term "PPRD" for defining the patient population with respiratory disease that is directly associated with premature birth (less than 37 weeks' PMA), including those who were born prematurely but did not meet the definition for BPD [bib_ref] Prematurity and Respiratory Outcomes Program Investigators. Prematurity and respiratory outcomes program (PROP):..., Pryhuber [/bib_ref]. This is in contrast with the previous ATS statement, in which the term "CLDI" was used. CLDI consists of a heterogeneous group of respiratory diseases in preterm and full-term infants [bib_ref] Statement on the care of the child with chronic lung disease of..., Allen [/bib_ref]. CLDI includes BPD, other chronic respiratory diseases of prematurity not meeting the strict criteria for BPD, and chronic lung diseases in full-term infants, such as those associated with congenital diaphragmatic hernia and other forms of pulmonary hypoplasia. Although these conditions in full-term infants may be clinically similar to BPD, their underlying pathophysiology is strikingly different. For this reason, these recommendations focus on the outpatient management of patients with PPRD [bib_ref] Prematurity and Respiratory Outcomes Program Investigators. Prematurity and respiratory outcomes program (PROP):..., Pryhuber [/bib_ref].
# Methods
This clinical practice guideline was developed in accordance with ATS policies and procedures. We used the Grading of Recommendations, Assessment, Development, and Evaluation approach [bib_ref] GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables, Guyatt [/bib_ref] to formulate clinical questions, identify and summarize relevant evidence, and develop recommendations for clinical practice.
The co-chairs (A.I.C. and C.D.B.) submitted a proposal that was reviewed and approved by the ATS Assembly of Pediatrics, Program Review Subcommittee, and Board of Directors. A multidisciplinary panel of international specialists with expertise in PPRD and guideline development methodology was formed. Represented disciplines included pediatric pulmonology, neonatology, otolaryngology, sleep medicine, radiology, and nursing, and families of patients with PPRD were also included. Conflicts of interest were disclosed and managed appropriately. The committee identified seven specific questions, with three addressing the clinical management of patients with active symptoms and four addressing diagnostic methods. The patient/ intervention/comparator/outcome (PICO) format was used to formulate each question. A formal search strategy of EMBASE, Medline, the Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, and the Web of Science was performed (see the online supplement). We included studies of infants, children, and adolescents who were born preterm (less than 37 weeks' PMA) who had already been discharged from the hospital. Because of the lack of outpatient-based evidence for several questions, studies of preterm infants before NICU discharge (age greater than 36 weeks' PMA at the time of study) were included. Detailed methods are included in the online supplement.
# Results
Question 1: Should infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD and who have respiratory symptoms (wheezing, cough, tachypnea) receive short-acting, inhaled bronchodilators?
Background. Patients with PPRD are at increased risk of respiratory morbidity, cough and wheeze, and respiratory hospitalizations, and asthma is diagnosed in up to 25% [bib_ref] Rehospitalization in the first year of life among infants with bronchopulmonary dysplasia, Smith [/bib_ref] [bib_ref] Pulmonary outcomes in bronchopulmonary dysplasia, Bhandari [/bib_ref] [bib_ref] Preterm birth and childhood wheezing disorders: a systematic review and meta-analysis, Been [/bib_ref] [bib_ref] Respiratory symptoms in preterm infants: burden of disease in the first year..., Pramana [/bib_ref] [bib_ref] Lung function and respiratory symptoms at 11 years in children born extremely..., Fawke [/bib_ref]. Morbidity increases with decreasing gestational age but remains significant among children born mid-to-late preterm [bib_ref] Gestational age at birth and wheezing trajectories at 3-11 years, Leps [/bib_ref] [bib_ref] Short-and long-term outcomes of moderate and late preterm infants, Natarajan [/bib_ref]. Cohort studies demonstrate a high incidence of bronchodilator use in this population [bib_ref] Respiratory medication adherence in chronic lung disease of prematurity, Collaco [/bib_ref] [bib_ref] Prematurity and prescription asthma medication from childhood to young adulthood: a Danish..., Damgaard [/bib_ref] [bib_ref] Respiratory medications in infants, 29 weeks during the first year postdischarge: the..., Ryan [/bib_ref]. However, the overlap between respiratory disease in children born preterm and asthma is not clear [bib_ref] Pulmonary outcomes in adults with a history of bronchopulmonary dysplasia differ from..., Um-Bergstr€ Om [/bib_ref]. Although many children born preterm develop asthma-like symptoms, they are less likely to demonstrate airway hyperresponsiveness and may be less responsive to bronchodilators [bib_ref] Characteristics of asthma and airway hyper-responsiveness after premature birth, Halvorsen [/bib_ref] [bib_ref] Longitudinal evaluation of airway function 21 years after preterm birth, Narang [/bib_ref] [bib_ref] Exercise-induced bronchoconstriction in school-age children born extremely preterm, Hamon [/bib_ref]. They may have fixed airway obstruction or large airway diseases like tracheomalacia [bib_ref] Bronchoscopy in neonates with severe bronchopulmonary dysplasia in the NICU, Hysinger [/bib_ref].
Children with atopy or asthma (or a family history of these conditions) may benefit from bronchodilators [bib_ref] Management of prematurity-associated wheeze and its association with atopy, Edwards [/bib_ref]. Those born at less than 32 weeks' PMA or those with BPD may benefit differently from children without PPRD. Children with TBM can have a paradoxical response to bronchodilator therapy [bib_ref] Effect of altering smooth muscle tone on maximal expiratory flows in patients..., Panitch [/bib_ref]. Long-acting bronchodilators and anticholinergic agents, although components of asthma therapy, are infrequently used in patients with PPRD. This question focuses specifically on the use of short-acting b 2 -agonists (such as albuterol) as needed, given that this is the most common type and indication for bronchodilators in this population.
Evidence base. The outcomes considered critical or important for this review were wheezing, dyspnea, quality of life, missed school, hospital length of stay (LOS), improvement in pulmonary function test results (forced expiratory flows, airway resistance, lung volumes), tachycardia, attention deficit, airway obstruction, and hypoxemia.
The relevant medical literature described the effect of single or multiple doses of inhaled bronchodilators (online supplement). Two studies compared chronic (at least 2 wk) daily inhaled bronchodilators in children born preterm. We excluded one study whose primary outcome was peak expiratory flow (PEF), as PEF typically defines an exacerbation of respiratory disease and is not used for routine management [bib_ref] Bronchial lability and responsiveness in school children born very preterm, Pelkonen [/bib_ref]. A nonrandomized, crossover, placebocontrolled trial examined 2 weeks of twicedaily bronchodilator use (500 μg of inhaled terbutaline or placebo) in 10 preterm infants with recurrent respiratory symptoms [bib_ref] Effective bronchodilator treatment by a simple spacer device for wheezy premature infants, Yuksel [/bib_ref]. All infants (postnatal age, 12.5 mo) had experienced cough or wheezing at least 4 d/ wk for the prior month. The symptom score was significantly reduced during the treatment period. The greatest improvements were noted in wheeze and cough. The FRC increased by 32%. Although this was reported as improvement, the panel noted that this could also be due to worsening air trapping.
Supplemental evidence from studies of a single bronchodilator dose were examined. A systematic review of 21 studies of children and adolescents born preterm demonstrated a mean improvement in the FEV 1 of 4-13% after albuterol treatment [bib_ref] Effect of bronchodilators on forced expiratory volume in 1 s in preterm-born..., Kotecha [/bib_ref]. A study of 17 infants with BPD (68 weeks' PMA) demonstrated a response to albuterol in 35% of subjects [bib_ref] Pulmonary function in bronchopulmonary dysplasia, Robin [/bib_ref]. Specifically, 55% of those with recurrent wheeze responded, as compared with only 12.5% of those without wheezing. Another study of 52 preterm infants who were mechanically ventilated at birth combination if concern for anatomic abnormalities expiratory resistance in patients with BPD at 1 year of age and decreased resistance after salbutamol treatment in half of these patients [bib_ref] Response to bronchodilators in clinically stable 1-year-old patients with bronchopulmonary dysplasia, Boeck [/bib_ref]. Sixty-five percent of hospitalized infants with severe BPD were responsive to bronchodilator treatment as determined by using infant pulmonary function testing at 52 weeks' PMA [bib_ref] Infant pulmonary function testing and phenotypes in severe bronchopulmonary dysplasia, Shepherd [/bib_ref]. Finally, 75% of young children with BPD and tracheostomy were responsive to bronchodilator treatment at the ages of 6, 12, and 18 months [bib_ref] Longitudinal changes in lung function during the first three years of premature..., Mallory [/bib_ref]. Certainty of evidence. The panel's confidence in the accuracy of these estimated effects of bronchodilator administration for critical outcomes was very low. Only one small study evaluated repeated bronchodilator use, but this study was not randomized and used a nonvalidated symptom score. Evidence evaluating the effect of single doses of a bronchodilator on pulmonary function was heterogeneous. Critical outcomes such as quality of life, hospitalizations, and school absences were not described. Questions remain regarding which subpopulations with PPRD are most likely to benefit from bronchodilators.
Benefits. In preterm infants with cough and wheeze, inhaled short-acting bronchodilators improved symptoms. In addition, 27-94% of school-aged children born preterm demonstrated an improved FEV 1 after bronchodilator treatment.
Harms. A small proportion of infants may have increased airway resistance after short-acting bronchodilator administration because of underlying TBM [bib_ref] Effect of altering smooth muscle tone on maximal expiratory flows in patients..., Panitch [/bib_ref]. Patients with PPRD can also experience common adverse effects of bronchodilators, such as tachycardia, transient oxygen desaturation, and tremors [bib_ref] Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis, Ralston [/bib_ref] [bib_ref] Bronchodilators for bronchiolitis, Gadomski [/bib_ref] [bib_ref] A prospective randomized controlled blinded study of three bronchodilators in infants with..., Levin [/bib_ref].
Costs. Panel members did not consider the cost of medication to be a significant hinderance to their use but acknowledged that reducing their use when not indicated could result in significant cost savings [bib_ref] Costs of childhood asthma due to traffic-related pollution in two California communities, Brandt [/bib_ref].
Conclusions. The panel concluded that the benefits of bronchodilator administration, specifically short-acting b 2agonists, likely exceed the harms for patients born preterm with recurrent respiratory symptoms including cough and wheeze. Although the evidence is largely indirect, there is consistent evidence that inhaled b 2agonists can significantly improve airflow in patients with PPRD. Given the fact that even late-preterm infants demonstrate diminished lung function, the potential benefit of inhaled bronchodilators in the context of acute viral illness and bronchiolitis may differ from that of full-term infants, for whom routine bronchodilator administration is not recommended [bib_ref] Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis, Ralston [/bib_ref] [bib_ref] Respiratory function in healthy late preterm infants delivered at 33-36 weeks of..., Mcevoy [/bib_ref]. Forced expiratory flows in children and adolescents born preterm are abnormal and may improve with inhaled bronchodilator treatment [bib_ref] Effect of bronchodilators on forced expiratory volume in 1 s in preterm-born..., Kotecha [/bib_ref]. In addition, the harm of the intervention is likely very low, further supporting a trial of therapy. Data supporting chronic use of bronchodilators, including for airway clearance, in this population are limited. The panel also recognized that there may be individual factors, such as the presence of underlying TBM, a family history of asthma, and intercurrent lower respiratory tract bacterial infection that may impact the decision to trial bronchodilators in this patient population.
What others are saying. The 2020 European Respiratory Society (ERS) guidelines on long-term management of children with BPD made a conditional recommendation (based on consensus) for bronchodilators in certain subgroups with asthma-like symptoms, recurrent respiratory hospitalizations, exercise intolerance, or reversibility in lung function [bib_ref] European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia, Duijts [/bib_ref].
## Ats recommendations. recommendation
1A. For infants, children, and adolescents with PPRD who do not have recurrent respiratory symptoms, we suggest that shortacting inhaled bronchodilator therapy not be routinely prescribed (conditional recommendation, very-lowcertainty evidence).
RECOMMENDATION 1B. For a subgroup of patients with PPRD who have recurrent respiratory symptoms (such as cough or wheeze), we suggest a trial of shortacting inhaled bronchodilator with monitoring to assess for clinical improvement in symptoms (conditional recommendation, very-lowcertainty evidence).
Implementation. We suggest a short trial (1-2 doses) of a short-acting b 2 -agonist with continued use if there is demonstrated improvement in respiratory symptoms or pulmonary function on at least one occasion. Parental education around indications for use and training for proper administration, especially in infants and in children who have tracheostomies, should also be considered. In addition, children born preterm in whom asthma is later diagnosed may benefit from both short-acting and long-acting bronchodilators or daily controller medications as per international asthma guidelines.
Justification. This recommendation places a high value on the potential improvement of patient-important outcomes, such as quality of life, respiratory symptoms such as wheeze and dyspnea, respiratory exacerbations, and objective measures such as improvement in pulmonary function test results. In addition to the evidence above, our decision was also based on the consensus that most families would want a trial of bronchodilator therapy in their child born preterm with recurrent respiratory symptoms.
Question 2: Should Infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD and who have respiratory symptoms (wheezing, cough, tachypnea) routinely receive inhaled corticosteroids?
Background. A trial of inhaled corticosteroids is often attempted in these patients, as airway obstruction is a key feature of PPRD [bib_ref] Respiratory symptoms in preterm infants: burden of disease in the first year..., Pramana [/bib_ref] [bib_ref] Bronchial hyperresponsiveness in preterm-born subjects: a systematic review and meta-analysis, Kotecha [/bib_ref]. Up to one-third of the general preschool population has experienced wheezing in the last 6 months (63). A meta-analysis found that inhaled corticosteroids initiated at the onset of wheezing reduced the need for oral corticosteroids by 50% [bib_ref] Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and..., Chong [/bib_ref]. Asthma is diagnosed in nearly 60% of preterm infants without BPD, whereas 30% require hospitalization for respiratory complications during the first year of life [bib_ref] Prematurity as an independent risk factor for the development of pulmonary disease, Fierro [/bib_ref]. The use of inhaled corticosteroids in full-term children with intermittent wheezing reduces the need for oral corticosteroids, hospitalization rates, emergency department visits, and overall healthcare costs (66), but it is unclear whether children born preterm benefit similarly to those born full-term.
Evidence base. We identified two randomized controlled trials (RCTs), two crossover RCTs, and one prospective observational trial that compared inhaled corticosteroids with placebo in children with PPRD (67-71) (online supplement).
In an RCT, 30 infants born preterm who required supplemental oxygen at 36 weeks' PMA received fluticasone propionate or placebo for 1 year (67). There was no significant difference between study groups in the primary outcome (symptom-free days) or secondary outcomes (length of supplemental oxygen use, weight, bronchodilator use, number of hospital admissions, and LOS).
## American thoracic society documents
Another RCT compared inhaled beclomethasone dipropionate with placebo in infants with BPD from 36 weeks' PMA until 3 months after discharge [bib_ref] Inhaled hydrofluoalkane-beclomethasone dipropionate in bronchopulmonary dysplasia: a double-blind, randomized, controlled pilot study, Kugelman [/bib_ref]. There was no difference in the reported outcomes, including the length of supplemental oxygen use, bronchodilator use, weight, height, the number of hospital admissions, the LOS, oral corticosteroid use, additive inhaled or systemic corticosteroid administration, pediatric ICU days, or death before NICU discharge.
A prospective study evaluated 21 children born preterm (6 with BPD) with airway obstruction (FEV 1 , 80%, PEF , 75%, or forced expiratory flow at 50% of FVC , 62% of predicted values), increased airway hyperreactivity with responsiveness to a b-agonist, or abnormal diurnal PEF variation .20% (69). Children (10 yr of age) received budesonide for 4 months. Eighteen children completed the study, with improvement in symptom scores but no differences in spirometric measurements being shown.
A crossover RCT compared beclomethasone dipropionate with placebo in 25 infants born preterm (3-24 mo of age) with wheeze or cough on >4 d/wk that did not improve after 2 weeks of daily bronchodilator therapy [bib_ref] Randomised trial of inhaled steroids in preterm infants with respiratory symptoms at..., Yuksel [/bib_ref]. Seven infants did not complete the study; in four, this was due to worsening symptoms during placebo administration. The intervention group had significantly improved symptom scores, a significantly improved FRC, and fewer days of bronchodilator use.
Another crossover RCT compared 4 weeks of inhaled beclomethasone dipropionate with placebo in 15 school-aged children born preterm with wheezing or a troublesome cough and with a positive hyperreactive airway response to histamine [bib_ref] Increased airway responsiveness in children of low birth weight at school age:..., Chan [/bib_ref]. There was no difference in the respiratory symptom score, baseline airway function, or airway hyperreactivity between the treatment periods. There was a small but statistically insignificant increase in the FEV 1 after treatment with beclomethasone compared with placebo.
Certainty of evidence. The panel's confidence in the accuracy of the estimated effects of inhaled corticosteroid administration for critical outcomes was very low. Available studies evaluating the use of inhaled corticosteroids in children with PPRD have small cohorts and have not been adequately powered to show significant differences in the desired outcomes. Improvements in short-term symptom scores in full-term symptomatic children or children with documented airway hyperresponsiveness provide indirect evidence of a benefit.
Benefits. The two RCTs evaluating patients with BPD did not show statistically significant changes in reported outcomes, and hence did not show any benefit for the use of inhaled corticosteroids [bib_ref] Randomised double blind placebo controlled trial of inhaled fluticasone propionate in infants..., Beresford [/bib_ref] [bib_ref] Inhaled hydrofluoalkane-beclomethasone dipropionate in bronchopulmonary dysplasia: a double-blind, randomized, controlled pilot study, Kugelman [/bib_ref]. The three studies that included those with wheezing, cough, or changes in pulmonary function showed mixed results [bib_ref] Effect of inhaled budesonide therapy on lung function in schoolchildren born preterm, Pelkonen [/bib_ref] [bib_ref] Randomised trial of inhaled steroids in preterm infants with respiratory symptoms at..., Yuksel [/bib_ref] [bib_ref] Increased airway responsiveness in children of low birth weight at school age:..., Chan [/bib_ref]. However, data from full-term children with wheezing showed an improvement in symptom scores and decreased hospitalizations when subjects were treated with inhaled corticosteroids [bib_ref] Diagnosis, management, and prognosis of preschool wheeze, Ducharme [/bib_ref] [bib_ref] Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and..., Chong [/bib_ref] [bib_ref] Use of inhaled corticosteroids and healthcare costs in mild persistent asthma, Colice [/bib_ref]. Therefore, select patients with PPRD may benefit from inhaled corticosteroids.
Harms. Studies included in this review did not show evidence of harm with the use of inhaled corticosteroids. Evidence from full-term children is mixed regarding the effect of inhaled corticosteroids on growth [bib_ref] Inhaled corticosteroids in children with persistent asthma: effects of different drugs and..., Axelsson [/bib_ref] [bib_ref] Impact of inhaled corticosteroids on growth in children with asthma: systematic review..., Loke [/bib_ref]. This effect may be decreased with intermittent dosing [bib_ref] Safety of corticosteroids in young children with acute respiratory conditions: a systematic..., Fernandes [/bib_ref]. Inhaled corticosteroids increase the likelihood of sore throat and oral candidiasis, with one study finding one case of oral candidiasis for every 21 patients treated.
Parental preference. In our clinical experience, given the minimal available evidence regarding the potential benefit and toxicities, parents defer to the medical team concerning whether or not to trial inhaled corticosteroids.
Costs. The cost of daily therapy can be substantial; reducing inhaled corticosteroid use when not indicated could result in significant cost savings.
Conclusions. Given the low quality of evidence available and the lack of a significant benefit, routine use of inhaled corticosteroids has not been shown definitively to improve outcomes in patients with PPRD. However, when using data extrapolated from other populations, there may be some benefit for a trial of inhaled corticosteroids in selected patients with PPRD and chronic cough or wheezing.
What others are saying. The 2020 ERS guidelines on long-term management of children with BPD recommend against treating with inhaled corticosteroids. However, these guidelines made a conditional recommendation for a carefully monitored trial period of inhaled or systemic corticosteroids in some patients with severe BPD, severe respiratory symptoms, and/or recurrent hospitalizations and in those whose BPD was not controlled with regular bronchodilator use (60).
## Ats recommendations. recommendation
2A. For infants, children, and adolescents with PPRD who do not have chronic cough and recurrent wheezing, we suggest that inhaled corticosteroids not be routinely prescribed (conditional recommendation, very-low-certainty evidence).
RECOMMENDATION 2B. For infants, children, and adolescents with PPRD who have chronic cough or recurrent wheezing, we suggest a trial of inhaled corticosteroids with monitoring to assess for clinical improvement in symptoms (conditional recommendation, very-lowcertainty evidence).
Implementation. Before a trial of inhaled corticosteroids, the baseline status (severity of symptoms, spirometric results) should be assessed and documented. Without evidence regarding an appropriate length of time for this trial, we suggest a duration of 3 months on the basis of extrapolation from other populations and full consensus of the panel. After this, patients should be reassessed, with pulmonary function testing being conducted if possible.
Justification. This recommendation places a high value on the potential improvement of patient-important outcomes, such as quality of life, respiratory symptoms, respiratory exacerbations, and objective measures such as improvement in pulmonary function test results. Potential side effects and adverse events were taken into consideration and compared with the possible benefits of therapy.
Question 3: Should infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD and who have respiratory symptoms (wheezing, cough, tachypnea) routinely receive diuretic therapy?
Background. Most studies examining the beneficial pulmonary effects of diuretics are limited by a short length of treatment and were conducted before the widespread use of surfactants [bib_ref] Artificial surfactant therapy in hyaline-membrane disease, Fujiwara [/bib_ref] [bib_ref] Prevention of neonatal respiratory distress syndrome by tracheal instillation of surfactant: a..., Enhorning [/bib_ref] [bib_ref] Exogenous human surfactant for treatment of severe respiratory distress syndrome: a randomized..., Hallman [/bib_ref] [bib_ref] The influence of the wider use of surfactant therapy on neonatal mortality..., Hamvas [/bib_ref]. To date, no study has demonstrated an association between diuretic use and reductions in the incidence of BPD, the duration of mechanical ventilation, or NICU LOS. Diuretics, especially furosemide, are associated with comorbidities such as nephrolithiasis and AMERICAN THORACIC SOCIETY DOCUMENTS e120
American Journal of Respiratory and Critical Care Medicine Volume 204 Number 12 | December 15 2021 metabolic bone disease [bib_ref] Determinants of severe metabolic bone disease in very low-birth-weight infants with severe..., Jensen [/bib_ref] [bib_ref] Renal calcification in very low birth weight infants, Chang [/bib_ref] [bib_ref] Exposure to furosemide as the strongest risk factor for nephrocalcinosis in preterm..., Gimpel [/bib_ref] [bib_ref] Renal calcification incidence in very low birth weight infants, Jacinto [/bib_ref] [bib_ref] Nephrocalcinosis in pre-term neonates: a study of incidence and risk factors, Mohamed [/bib_ref] [bib_ref] Incidence, ultrasonic patterns and resolution of nephrocalcinosis in very low birthweight infants, Saarela [/bib_ref] [bib_ref] Etiology of nephrocalcinosis in preterm neonates: association of nutritional intake and urinary..., Schell-Feith [/bib_ref] [bib_ref] The incidence of renal calcification in preterm infants, Short [/bib_ref]. Although many infants are discharged from the NICU receiving diuretic therapy, their utility in post-NICU care remains uncertain. Evidence base. The outcomes considered important for the literature review were mortality, the burden of disease, improvement in pulmonary function tests, the duration of supplemental oxygen being required, pulmonary edema, metabolic alkalosis, dehydration, osteopenia, ototoxicity, nephrolithiasis, and electrolyte abnormalities. Included were studies that described chronic diuretic use, defined as a minimum of 1 consecutive week of scheduled therapy (online supplement).
We identified four RCTs (88-91) that were conducted between 1983 and 1992, before the widespread use of surfactants [bib_ref] History of surfactant from 1980, Halliday [/bib_ref]. As such, the infants included in these studies had "old BPD," characterized by airway injury, parenchymal fibrosis, and areas of severe hyperinflation due to oxygen toxicity and ventilator-induced lung injury [bib_ref] Pulmonary disease following respirator therapy of hyaline-membrane disease: bronchopulmonary dysplasia, Northway [/bib_ref]. Only one study describes outcomes after NICU discharge [bib_ref] Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia, Kao [/bib_ref]. These studies enlisted few patients, with the largest including 43 infants [bib_ref] Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia, Kao [/bib_ref].
Two RCTs evaluated the impact of furosemide therapy on pulmonary function, supplemental oxygen requirements, weight gain, electrolyte derangements, and hearing deficits. The first study included 11 infants born preterm, who were older than 28 days and who required continuous oxygen therapy [bib_ref] Double-blind, placebocontrolled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary..., Rush [/bib_ref]. Subjects received alternating furosemide or placebo. On Day 8, furosemide therapy was significantly associated with improved dynamic pulmonary compliance and airway resistance, a decreased FI O 2 requirement, and decreased average weight gain, with no significant difference in serum electrolytes concentrations being demonstrated when compared with placebo. In the second study of 17 mechanically ventilated infants born preterm, furosemide was administered for 7 consecutive days at 36-72 days of life [bib_ref] Controlled trial of furosemide therapy in infants with chronic lung disease, Mccann [/bib_ref]. Furosemide therapy was significantly associated with improved lung compliance and a decreased serum chloride concentration. Weight gain was greater in the placebo group (P = 0.04). At 1 year of age, all infants had normal hearing. No respiratory outcomes were evaluated at 1 year.
The remaining two RCTs evaluated the efficacy of combined thiazide and spironolactone therapy. One RCT evaluated 43 infants born preterm who were receiving spironolactone and chlorothiazide or placebo until they were weaned off oxygen therapy (within 10 wk of enrollment) [bib_ref] Randomized trial of long-term diuretic therapy for infants with oxygen-dependent bronchopulmonary dysplasia, Kao [/bib_ref]. Four weeks after the initiation of diuretics, the therapy group had significantly improved pulmonary compliance and airway resistance compared with the placebo group. However, these measures returned to prediuretic concentrations within 1 week after the completion of diuretic therapy. By 1 year of age, there was no difference in airway resistance or pulmonary compliance, the duration of supplemental oxygen being required, or the number of rehospitalizations between the two groups. The final RCT assessed 34 ventilator-dependent infants born preterm between Days of Life 31 and 40 who received both spironolactone and hydrochlorothiazide twice daily or placebo for 8 weeks [bib_ref] Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia, Albersheim [/bib_ref]. More infants were alive at NICU discharge in the diuretic group (P , 0.001). Respiratory system compliance was improved in the treatment group at 4 weeks (P = 0.016), but this difference was not significant by the end of the study. The NICU LOS, number of ventilator days, respiratory system compliance and resistance, and serum electrolytes were not significantly different.
Meta-analysis revealed a significant increase in pulmonary compliance in patients receiving diuretics at 1 and 4 weeks compared with at baseline. Compliance at 4 weeks compared with compliance at 1 week was also increased. Resistance at 4 weeks was decreased compared with resistance at 1 week. Mortality before NICU discharge was reduced, whereas rehospitalization within the first year and electrolyte supplementation were both increased in the diuretic group. No significant change was noted in the duration of supplemental oxygen use, the NICU LOS, the weight and length at 1 year, nephrolithiasis, sensorineural hearing deficits, or severe electrolyte abnormalities.
We identified 15 observational studies describing the potential harmful effects of diuretic use, including sensorineural hearing deficits or losses, nephrolithiasis, and metabolic bone disease. Six studies evaluated the rates of sensorineural hearing deficits associated with furosemide use. Of these, three studies showed that furosemide use was significantly associated with hearing impairment [bib_ref] Effects of ventilation on hearing loss in preterm neonates: nasal continuous positive..., Rastogi [/bib_ref] [bib_ref] Hyponatremia and sensorineural hearing loss in preterm infants, Ertl [/bib_ref] [bib_ref] Risk factors of sensorineural hearing loss in preterm infants, Borradori [/bib_ref]. However, the remaining studies showed no significant difference in hearing between those who received furosemide and those who did not, even in cases of furosemide exposure for greater than 28 days [bib_ref] Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee. Prolonged furosemide exposure..., Wang [/bib_ref] [bib_ref] Use of furosemide and hearing loss in neonatal intensive care survivors, Rais-Bahrami [/bib_ref] [bib_ref] Risk factors for auditory neuropathy spectrum disorder in NICU infants compared to..., Coenraad [/bib_ref]. Meta-analysis revealed a significantly increased risk of sensorineural hearing deficits in those receiving furosemide.
Eight studies assessed the risk of nephrolithiasis. Furosemide was the only diuretic used. Seven studies showed an increased incidence of nephrolithiasis with furosemide treatment [bib_ref] Renal calcification in very low birth weight infants, Chang [/bib_ref] [bib_ref] Exposure to furosemide as the strongest risk factor for nephrocalcinosis in preterm..., Gimpel [/bib_ref] [bib_ref] Renal calcification incidence in very low birth weight infants, Jacinto [/bib_ref] [bib_ref] Nephrocalcinosis in pre-term neonates: a study of incidence and risk factors, Mohamed [/bib_ref] [bib_ref] Incidence, ultrasonic patterns and resolution of nephrocalcinosis in very low birthweight infants, Saarela [/bib_ref] [bib_ref] Etiology of nephrocalcinosis in preterm neonates: association of nutritional intake and urinary..., Schell-Feith [/bib_ref] [bib_ref] The incidence of renal calcification in preterm infants, Short [/bib_ref]. The remaining study showed no difference in the detection of nephrolithiasis in infants who received furosemide [bib_ref] Nephrocalcinosis in preterm babies, Narendra [/bib_ref]. Several authors noted that a lower gestational age at birth and lower birth weight were risk factors for renal stones. Meta-analysis revealed a significant increased risk of nephrolithiasis in those receiving furosemide.
We identified only one study that evaluated severe metabolic bone disease in neonates receiving furosemide [bib_ref] Determinants of severe metabolic bone disease in very low-birth-weight infants with severe..., Jensen [/bib_ref]. For every 2 weeks of furosemide therapy, the probability of developing severe metabolic bone disease increased by 1.4% (P , 0.001).
We did not identify any studies describing the effect of early diuretic therapy on late respiratory outcomes.
Certainty of evidence. The panel's confidence in the accuracy of the estimated effects of diuretic administration for critical outcomes was very low. Evidence was considered indirect, as most studies were performed during the NICU stay and were performed before the routine use of surfactants. Several studies had incomplete outcome data. Other limitations included the lack of intention-to-treat analysis, varying chronological age at the time of testing, wide confidence intervals, potential confounders from co-interventions, bias due to missing data, and the inclusion of only infants with severe BPD in some of the studies. In addition, most studies were restricted to infants with limited comorbidities relevant to diuretic use, such as atrial septal defects and other intracardiac shunts.
Benefits. We identified no studies describing the potential beneficial effects of diuretics on important outcomes in children with PPRD after discharge from the hospital.
Harms. The use of furosemide was associated with an increased risk of nephrolithiasis and sensorineural hearing deficits. Electrolyte imbalances were also described.
Costs. Financial costs associated with diuretic use were considered to be minimal.
Conclusions. Although diuretics can improve pulmonary mechanics in the short AMERICAN THORACIC SOCIETY DOCUMENTS term, studies investigating long-term diuretic use after NICU discharge are lacking. Currently available data showed that longterm diuretic use was not associated with improvements in patient-centered outcomes; however, it was associated with an increased likelihood of harm (sensorineural hearing deficits and nephrolithiasis), especially with furosemide.
What others are saying. A recent position statement from the Thoracic Society of Australia and New Zealand reviewed the literature and concluded that no formal recommendation could be made regarding long-term diuretic therapy in infants with BPD [bib_ref] Respiratory management of infants with chronic neonatal lung disease beyond the NICU:..., Kapur [/bib_ref]. The ERS guidelines on long-term management of children with BPD provided a conditional recommendation that infants who were treated with diuretics at the time of NICU discharge should be naturally weaned by allowing the dose to decrease slowly relative to the child's weight [bib_ref] European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia, Duijts [/bib_ref].
## Ats recommendations. recommendation
3A. For infants, children, and adolescents with PPRD, we suggest against the routine use of diuretics (conditional recommendation, very-lowcertainty evidence).
RECOMMENDATION 3B. For infants with PPRD who are discharged from the NICU on chronic diuretic therapy, we suggest discontinuation in a judicious manner (conditional recommendation, verylow-certainty evidence).
## Implementation.
1. Given the short-term improvement in pulmonary mechanics, a trial of diuretics may be justified in situations in which lung compliance is believed to have acutely worsened. While administering diuretics, ongoing monitoring for electrolyte abnormalities, nephrolithiasis, and sensorineural hearing loss is recommended. 2. The timing of discontinuation should be discussed with the family and made on an individual basis. Several panelists practice discontinuation without weaning. Others decrease the diuretic dose or lengthen the time interval of administration before stopping. Few panelists described allowing children to "outgrow" the dose.
Justification. This recommendation acknowledges the potential for improvement in patient-related outcomes, while emphasizing that the long-term use of diuretics may have deleterious side effects and that adverse events may outweigh the potential, yet unlikely, benefits.
Question 4: Should all infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD undergo baseline diagnostic PSG?
Background. Infants born preterm have an increased risk of SDB [bib_ref] Episodic airway obstruction in premature infants, Dransfield [/bib_ref] [bib_ref] Cardiorespiratory events in preterm infants referred for apnea monitoring studies, Fiore [/bib_ref] [bib_ref] Sleep apnea and hypoxemia in recently weaned premature infants with and without..., Sekar [/bib_ref] [bib_ref] Effect of supplemental oxygen on sleep architecture and cardiorespiratory events in preterm..., Simakajornboon [/bib_ref]. Sleep disruption, hypoxemia, and hypercarbia can have lasting neurologic, cardiac, and behavioral effects that persist into adulthood [bib_ref] Preterm birth and risk of sleep-disordered breathing from childhood into mid-adulthood, Crump [/bib_ref] [bib_ref] Obstructive sleep apnea in the formerly preterm infant: an overlooked diagnosis, Sharma [/bib_ref] [bib_ref] Prevalence and risk factors for sleep-disordered breathing in 8-to 11-year-old children: association..., Rosen [/bib_ref].
Supplemental oxygen therapy improves hypoxemia, central apnea, and periodic breathing [bib_ref] Sleep apnea and hypoxemia in recently weaned premature infants with and without..., Sekar [/bib_ref] [bib_ref] Effect of supplemental oxygen on sleep architecture and cardiorespiratory events in preterm..., Simakajornboon [/bib_ref]. The increased risk of SDB and potential benefits of supplemental oxygen raise the question of the necessity of undergoing PSG [bib_ref] Preterm birth and risk of sleep-disordered breathing from childhood into mid-adulthood, Crump [/bib_ref] [bib_ref] Prevalence and risk factors for sleep-disordered breathing in 8-to 11-year-old children: association..., Rosen [/bib_ref]. However, costs, a lack of normative data, and the insufficient access to and limited capacity of pediatric sleep laboratories limit the ability to conduct PSG for all patients born preterm. Therefore, clinicians would benefit from guidelines regarding which infants require PSG and what alternatives may be useful when PSG is not indicated or unavailable.
Evidence base. The panel chose to focus on three clinical contexts: preterm infants before hospital discharge, preterm infants after hospital discharge, and the benefits of PSG versus overnight pulse oximetry (online supplement). We identified 32 articles relevant to the population of interest.
## Preterm infants before hospital
DISCHARGE. Nine studies evaluated the role of PSG before discharge for infants with BPD. Elder and colleagues (109) compared infants with apnea born preterm with asymptomatic neonates by using nap PSG after 35 weeks' PMA, and they observed no differences in the mean duration, type, or number of apnea events. However, the duration of the longest apnea and the degree of desaturation were greater in symptomatic cases versus controls, during both active and quiet sleep. Fajardo and colleagues (110) studied apneas in infants born preterm with and without BPD at 33 weeks' PMA. All studied infants had central events, but obstructive apnea was more frequent in the BPD group (P = 0.004). Another study evaluated the impact of a supine versus prone sleep position on respiratory events in infants born preterm with and without BPD by using nap PSG at 37 weeks' PMA [bib_ref] Effect of prone and supine position on sleep, apneas, and arousal in..., Bhat [/bib_ref]. Obstructive apnea was significantly improved, whereas central apnea was significantly increased when going from the supine to the prone position. In a study describing 76 premature infants with clinical apnea, bradycardia, or cyanosis studied by using PSG before NICU discharge, the majority of infants had some degree of obstructive apnea, but patients with bradycardia (with or without clinically witnessed apnea) were noted to have significant obstructive events at PSG [bib_ref] Episodic airway obstruction in premature infants, Dransfield [/bib_ref].
Infants with significant desaturations were noted to have improved PSG findings when treated with supplemental oxygen (104, 105) that persisted after discharge home [bib_ref] Polysomnography for the management of oxygen supplementation therapy in infants with chronic..., Kulkarni [/bib_ref]. One study compared infants with BPD who had been weaned from supplemental oxygen before PSG with agematched premature infants [bib_ref] Sleep apnea and hypoxemia in recently weaned premature infants with and without..., Sekar [/bib_ref]. Obstructive apnea or periodic breathing indices did not differ between the groups; however, infants with BPD had higher central apnea indices and lower oxygen saturation, which improved with supplemental oxygen. In another study of preterm infants who underwent PSG at 38 weeks' PMA, supplemental oxygen significantly improved the apnea index, periodic breathing, and bradycardic events (105). Kulkarni and colleagues [bib_ref] Polysomnography for the management of oxygen supplementation therapy in infants with chronic..., Kulkarni [/bib_ref] identified that infants with BPD had elevated central apnea indices and oxygen desaturation that improved with supplemental oxygen administration to degrees similar to those of healthy infants. Over sequential PSG studies, patients with BPD were noted to have consistent improvement in the apnea-hypopnea index and respiratory disturbance index without complete normalization [bib_ref] Sleep disordered breathing in bronchopulmonary dysplasia, Ortiz [/bib_ref] [bib_ref] Polysomnography in preterm infants and children with chronic lung disease, Mcgrath-Morrow [/bib_ref].
## Preterm infants after hospital
DISCHARGE. Four studies identified an increased risk of SDB in preterm patients as they age. In a prospective study of 850 children (46% premature) undergoing outpatient PSG, the prevalence of SDB was 2.2% overall and was three to five times more likely in preterm subjects [bib_ref] Prevalence and risk factors for sleep-disordered breathing in 8-to 11-year-old children: association..., Rosen [/bib_ref]. A reanalysis showed SDB in 7.3% of the preterm cohort [bib_ref] Prenatal and neonatal risk factors for sleep disordered breathing in school-aged children..., Hibbs [/bib_ref]. A cohort study of over 4 million Swedish children born over 40 years revealed SDB in 4.1% of subjects; those with preterm and extremely preterm birth had a 1.4-and 2.6-fold increased risk of SDB, respectively, from birth up to age 43 years [bib_ref] Preterm birth and risk of sleep-disordered breathing from childhood into mid-adulthood, Crump [/bib_ref]. In addition to the lasting increased risk of SDB, chronic intermittent hypoxemia has also been associated with negative cognitive and [bib_ref] Eliminating sleep-associated hypoxemia improves growth in infants with bronchopulmonary dysplasia, Moyer-Mileur [/bib_ref] [bib_ref] Awake daytime oximetry measurements in the management of infants with chronic lung..., Vermeulen [/bib_ref]. In a cohort of 63 infants with BPD and hypoxemia, there was no correlation between the 20-minute daytime and overnight oximetry studies [bib_ref] Eliminating sleep-associated hypoxemia improves growth in infants with bronchopulmonary dysplasia, Moyer-Mileur [/bib_ref]. However, in 22 infants with BPD and hypoxemia, a longer 60-minute daytime oximetry study was more accurate, with a sensitivity of 100% for predicting overnight oximetry (by PSG) and a specificity of 65% being shown [bib_ref] Awake daytime oximetry measurements in the management of infants with chronic lung..., Vermeulen [/bib_ref]. Certainty of evidence. With no RCT evaluating the use of PSG for this patient population, the panel's confidence in the accuracy of these estimated effects on the utility of PSG for critical outcomes was very low. In addition, the studies were mostly retrospective and published over 4 decades. During this time, there have been significant clinical advancements in pediatric sleep medicine and the care of premature infants that are not represented in the reviewed studies.
Benefits. PSG provides detailed information regarding SDB and evaluating respiratory effort, oxygenation, ventilation, and obstructive and central events. It also provides limited information about other organ systems, including cardiopulmonary reserve and the central nervous system with respect to the control of breathing.
Harms. PSG is a prolonged and resource-intensive diagnostic test that is not indicated or feasible for all patients born preterm. This review has shown that even asymptomatic infants can have abnormal PSG findings. Their effect on long-term development is not clear, particularly in the context of events without desaturation. There is no consensus on "normal central apnea indices" in infancy because of a lack of normative data. Therefore, PSG may lead to unnecessary interventions, increased costs, and caregiver stress when the results will not change medical management. Finally, pediatric and neonatal PSG are not available in all locations. Facility transfers or prolonged stays may be required to complete these studies.
Parental preference. PSG is performed in a sleep medicine laboratory, and the child is monitored overnight. Many parents would prefer a home sleep apnea test as compared with formal PSG. However, home sleep apnea tests are not validated or recommended for children [bib_ref] American Academy of Sleep Medicine position paper for the use of a..., Kirk [/bib_ref].
Costs. Although it is the gold standard to diagnose SDB, PSG is a resource-intensive diagnostic test [bib_ref] Diagnosis and management of childhood obstructive sleep apnea syndrome, Marcus [/bib_ref]. SDB itself is known to be associated with significant healthcare costs when diagnosis is delayed [bib_ref] Impact of diagnosing and treating obstructive sleep apnea on healthcare utilization, Walter [/bib_ref]. This emphasizes the need for timely recognition of SDB symptoms and prompt diagnosis. Clinicians may consider overnight oximetry, a less expensive alternative, as a screening tool in certain situations.
Conclusions. PSG can be a useful tool in evaluating preterm patients. However, PSG may not change clinical management. Therefore, the panel considered the utility of PSG in distinct clinical contexts. The panel determined that before NICU discharge, PSG testing should be limited to patients whose care will be affected by the study results, such as those with persistent apnea, intermittent desaturations, or bradycardia. The panel observed a higher rate of SDB after NICU discharge across early and middle childhood and into midadulthood after preterm birth. PSG should be performed in patients born preterm with snoring, hypoxemia, or secondary effects of hypoxemia, such as failure to thrive and cognitive or behavioral impairment. Finally, as PSG is costly and not universally accessible, the panel recognizes that overnight or 24-hour oximetry studies may be an appropriate alternative, with sleep medicine referral being used when indicated.
What others are saying. Guidelines from the ATS, ERS, and British Thoracic Society support treating preterm infants with supplemental oxygen to maintain normal oxygen saturation [bib_ref] European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia, Duijts [/bib_ref] [bib_ref] Home oxygen therapy for children: an official American Thoracic Society clinical practice..., Hayes [/bib_ref] [bib_ref] Paediatric Section of the Home Oxygen Guideline Development Group of the BTS..., Balfour-Lynn [/bib_ref]. However, the role of diagnostic PSG was not addressed by these panels. A position statement from the Thoracic Society of Australia and New Zealand suggested that PSG be considered when obstructive or central apnea is suspected [bib_ref] Respiratory management of infants with chronic neonatal lung disease beyond the NICU:..., Kapur [/bib_ref].
## Ats recommendations. recommendation
4A. For infants with PPRD who are otherwise ready to be discharged from the NICU, we suggest the use of PSG for patients with persistent apnea, intermittent desaturation, or bradycardia at greater than 40 weeks' PMA (conditional recommendation, very-lowcertainty evidence).
RECOMMENDATION 4B. For infants, children, and adolescents with PPRD, we suggest the use of PSG and/or sleep medicine referral for those with symptoms of SDB, including persistent snoring, failure to thrive, or a persistent need for supplemental oxygen at 2 years of age (conditional recommendation, very-lowcertainty evidence).
RECOMMENDATION 4C. When a PSG is indicated but not available, we recommend that an overnight or 24-hour oximetry be performed to screen for SDB, followed by PSG and/or a sleep medicine referral for further evaluation if needed (conditional recommendation, very-lowcertainty evidence).
Implementation. When a PSG is indicated but not readily available, clinicians must consider whether oximetry monitoring is sufficient or whether referral to a sleep medicine program is needed for clinical management.
Justification. This recommendation places a high value on the potential improvement of quality of life and other clinical outcomes as well as respiratory symptoms such as apnea or hypoxemia. Limitations such as costs, access to PSG, and the lack of normative data in these patients are also taken in consideration.
Question 5: Should all infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD undergo a swallow evaluation?
Background. Acute and chronic pulmonary aspiration in patients with PPRD carries significant morbidity. Premature infants with pulmonary disease may be more susceptible to injury from aspiration. Faster respiratory rates in premature infants can contribute to swallow dysfunction when the time between breaths is less than the time AMERICAN THORACIC SOCIETY DOCUMENTS needed to coordinate an effective swallow [bib_ref] Videofluoroscopic analysis of the infant swallow, Newman [/bib_ref]. Premature infants with airway anomalies, neurologic comorbidities, or recent viral infections may have a higher risk for aspiration [bib_ref] Previously healthy infants may have increased risk of aspiration during respiratory syncytial..., Khoshoo [/bib_ref] [bib_ref] Usefulness of upper airway endoscopy in the evaluation of pediatric pulmonary aspiration, Adil [/bib_ref]. Oral secretions, ingested liquids or solids, and gastric contents can be aspirated, leading to frequent respiratory exacerbations or infections, chronic symptoms, the development of bronchiectasis, or pulmonary hypertension [bib_ref] Non-CF bronchiectasis: does knowing the aetiology lead to changes in management?, Li [/bib_ref] [bib_ref] Evaluation and management of pulmonary hypertension in children with bronchopulmonary dysplasia, Krishnan [/bib_ref]. Clinical signs of aspiration can include cough, stridor, wheeze, tachypnea, increased secretions, and oxygen desaturation. A subset has silent aspiration, which is identified through diagnostic evaluation without clinical symptoms while feeding. Diagnosing aspiration is complex. In addition to clinical feeding evaluation, evaluating aspiration can occur via a VFSS, fiberoptic endoscopic evaluation of swallowing (FEES), upper gastrointestinal series, bronchoscopy, or chest imaging. Because upper gastrointestinal series serve primarily to evaluate esophageal anatomy and gastrointestinal function, we focused on VFSS and FEES. Bronchoscopy and chest imaging are addressed in the PICO questions that follow.
Evidence base. We identified five retrospective studies of patients with PPRD who demonstrated aspiration during a VFSS. The reported prevalence of aspiration in premature infants who underwent a VFSS ranged from 29-100% (130-134) (online supplement).
Silent aspiration was described in several studies of preterm infants [bib_ref] Infant videofluoroscopic swallow study testing, swallowing interventions, and future acute respiratory illness, Coon [/bib_ref] [bib_ref] Presenting signs and symptoms do not predict aspiration risk in children, Duncan [/bib_ref] [bib_ref] Aspiration in children with unilateral vocal fold paralysis, Irace [/bib_ref] [bib_ref] Videofluoroscopic swallowing study findings in full-term and preterm infants with dysphagia, Uhm [/bib_ref]. Those with vocal cord paralysis are at high risk for silent aspiration. One retrospective review revealed that 57% of 28 children with vocal cord paralysis referred for a VFSS had aspiration, including nine premature infants, all of whom had silent aspiration [bib_ref] Aspiration in children with unilateral vocal fold paralysis, Irace [/bib_ref].
A retrospective review compared clinical feeding evaluations with VFSSs in 412 children under 2 years of age [bib_ref] Presenting signs and symptoms do not predict aspiration risk in children, Duncan [/bib_ref]. Among those with normal clinical feeding evaluation results, approximately one-third demonstrated silent aspiration. In the subgroup of 130 preterm infants, 77% had aspiration or laryngeal penetration.
Among premature infants, an abnormal VFSS result in the first year of life is not associated with subsequent acute respiratory infections before the age of 3 years [bib_ref] Infant videofluoroscopic swallow study testing, swallowing interventions, and future acute respiratory illness, Coon [/bib_ref]. However, infants with silent aspiration who are treated with thickened feeds are at decreased risk for subsequent acute respiratory infection.
Studies differ on whether premature infants are at an increased risk for swallowing dysfunction. Two retrospective studies noted a higher incidence of feeding problems after premature birth [bib_ref] Swallowing dysfunction in infants less than 1 year of age, Mercado-Deane [/bib_ref] [bib_ref] The complexity of feeding problems in 700 infants and young children presenting..., Rommel [/bib_ref]. Yet other retrospective reviews noted similar rates of swallowing dysfunction in both preterm and term infants, although preterm infants more often experienced oxygen desaturation [bib_ref] Videofluoroscopic swallowing study findings in full-term and preterm infants with dysphagia, Uhm [/bib_ref] [bib_ref] Fluoroscopic findings of swallowing: comparison between preterm and full-term infants, Silva-Munhoz Ldef [/bib_ref].
We did not find any substantive literature describing the outcomes of using FEESs in patients with PPRD.
Certainty of evidence. The panel's confidence in the accuracy of these estimated effects of the utility of swallow evaluation for critical outcomes was very low. Studies were primarily retrospective reviews of infants referred for feeding difficulties. Symptoms of aspiration and indications for testing with a VFSS are not standardized between centers.
Benefits. Swallow studies can be used to diagnose aspiration in preterm patients. Diagnosing aspiration can make feeding safer and decrease the risk for subsequent lung disease, including obliterative bronchiolitis and bronchiectasis.
Harms. Clinical symptoms lack sensitivity and specificity for diagnosing aspiration. The degree of radiation exposure during a VFSS differs between institutions. Advanced imaging of young children and its interpretation requires specialty expertise that may not be available at all centers. For patients with PPRD, aspirating contrast can carry clinical morbidity.
Parental preference. Families may experience anxiety related to understanding swallow study results and implementing changes to feeding after swallowing dysfunction is identified. Some parents may choose to have their children followed clinically, particularly if they have concerns regarding radiation exposure.
Costs. The cost of fluoroscopic studies should be considered. When swallowing dysfunction is identified, additional procedures may also be indicated.
Conclusions. The panel concluded that the benefit of using a VFSS to identify aspiration exceeded the burden and costs associated with the procedure for symptomatic patients with PPRD.
What others are saying. The utility of swallow evaluations was not addressed in other outpatient guidelines for patients with PPRD. However, for infants without neurologic pathology with persistent wheezing not relieved by bronchodilators or corticosteroids, the 2016 ATS guidelines for infants with recurrent or persistent wheezing recommend a swallow study to evaluate for aspiration [bib_ref] Official American Thoracic Society clinical practice guidelines: diagnostic evaluation of infants with..., Ren [/bib_ref]. ATS recommendation. RECOMMENDATION 5. For infants, children, and adolescents with PPRD, we suggest a swallow evaluation (VFSS) for those who are eating by mouth and have cough or persistent oxygen desaturation during feeding, suspected or confirmed vocal cord paralysis or other airway anomalies, failure to wean from oxygen therapy or ventilatory support as expected, persistent or worsening pulmonary hypertension, failure to thrive, or chronic pulmonary symptoms out of proportion to viral respiratory infections (conditional recommendation, very-lowcertainty evidence).
Implementation. An organized, multidisciplinary team is necessary to perform quality swallowing evaluations in preterm patients. When deciding to order a swallow evaluation, clinicians should consider how the results will impact care as well as the risks and benefits. Access to appropriate radiologic and technical expertise as well as the inclusion of experienced speech and occupational therapists are critical to interpreting study results.
Justification. This recommendation places a high value on the potential quality of life gained through the enjoyment of oral feeding while balancing the potential risks of both feeding and the evaluations themselves.
Question 6: Should all infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD undergo airway endoscopy?
Background. Infants with PPRD may require prolonged mechanical ventilation, undergo multiple intubations and extubation trials, and are at high risk for airway abnormalities, including subglottic or tracheal stenosis, subglottic cysts, TBM, and vocal cord immobility after PDA ligation. Such abnormalities may prolong mechanical ventilation, impact feeding, and can be lifethreatening. Up to 50% of infants with PPRD demonstrate TBM at airway endoscopy [bib_ref] Tracheobronchial abnormalities in infants with bronchopulmonary dysplasia, Miller [/bib_ref] [bib_ref] Tracheobronchomalacia in preterm infants with chronic lung disease, Doull [/bib_ref]. Identifying airway abnormalities can guide management, including surgical correction of airway abnormalities. In the absence of a gold standard, airway endoscopy is considered the best available test to identify airway pathology. Endoscopic airway techniques consist of flexible laryngoscopy, flexible bronchoscopy, and rigid direct laryngobronchoscopy (DLB). Evidence base. In the absence of RCTs, we identified 11 observational studies assessing airway endoscopy (flexible bronchoscopy, laryngoscopy, and DLB) in children with PPRD. Six indirectly addressed diagnostic yield and prognostic data from flexible bronchoscopy. Four studies addressed flexible laryngoscopy to identify left vocal cord paralysis (LVCP) after PDA ligation in preterm infants with respiratory or feeding symptoms. One study reported findings on DLB versus flexible laryngoscopy in children with aspiration (online supplement).
Two retrospective studies addressed the prognostic value of flexible bronchoscopy in preterm infants with BPD and TBM [bib_ref] Bronchoscopy in neonates with severe bronchopulmonary dysplasia in the NICU, Hysinger [/bib_ref] [bib_ref] Children's Hospitals Neonatal Consortium. Tracheobronchomalacia is associated with increased morbidity in bronchopulmonary..., Hysinger [/bib_ref]. Three hundred fifty-three of 974 infants with BPD (36.2%) undergoing flexible bronchoscopies demonstrated malacia [bib_ref] Children's Hospitals Neonatal Consortium. Tracheobronchomalacia is associated with increased morbidity in bronchopulmonary..., Hysinger [/bib_ref]. Those with TBM more commonly underwent tracheostomy and gastrostomy, had longer mechanical ventilation and hospital LOSs, and were more likely to be mechanically ventilated at discharge. In 20 of 27 infants with severe BPD undergoing flexible bronchoscopy, airway pathologies were identified, including tracheomalacia (48%), bronchomalacia (40.7%), and airway edema (48%), often leading to changes in management (63%) [bib_ref] Bronchoscopy in neonates with severe bronchopulmonary dysplasia in the NICU, Hysinger [/bib_ref].
Three prospective studies reported flexible bronchoscopy findings in preterm infants [bib_ref] Acquired subglottic cysts in the low-birth-weight infant: characteristics, treatment, and outcome, Downing [/bib_ref] [bib_ref] Evaluation of airway complications in highrisk preterm infants: application of flexible fiberoptic..., Downing [/bib_ref] [bib_ref] Bronchoscopic findings in infants treated with high-frequency jet ventilation versus conventional ventilation, Kercsmar [/bib_ref]. Among 174 preterm infants undergoing flexible bronchoscopy, 7.5% had subglottic cysts [bib_ref] Acquired subglottic cysts in the low-birth-weight infant: characteristics, treatment, and outcome, Downing [/bib_ref]. Another study of 117 preterm infants identified TBM or subglottic stenosis (SGS) in 48 patients (15 with moderate/severe SGS; 19 with moderate/severe malacia, and two with both) [bib_ref] Evaluation of airway complications in highrisk preterm infants: application of flexible fiberoptic..., Downing [/bib_ref]. Flexible bronchoscopy of 13 mechanically ventilated preterm infants revealed vocal cord nodules (62%) and airway malacia (31%) [bib_ref] Bronchoscopic findings in infants treated with high-frequency jet ventilation versus conventional ventilation, Kercsmar [/bib_ref].
Four studies focused on flexible laryngoscopy used to identify LVCP in preterm infants after PDA ligation [bib_ref] Incidence, risk factors, and comorbidities of vocal cord paralysis after surgical closure..., Henry [/bib_ref] [bib_ref] Long-term morbidities associated with vocal cord paralysis after surgical closure of a..., Benjamin [/bib_ref] [bib_ref] Cot e JJ. Unilateral vocal cord paralysis following patent ductus arteriosus ligation..., Clement [/bib_ref] [bib_ref] Vocal fold paralysis following surgical ductal closure in extremely low birth weight..., Malcolm [/bib_ref]. A meta-analysis (33 studies; n = 4,887) showed an 11% incidence of LVCP in preterm infants, which was associated with an increased risk of BPD, gastrostomy, and mechanical ventilation days [bib_ref] Incidence, risk factors, and comorbidities of vocal cord paralysis after surgical closure..., Henry [/bib_ref]. A retrospective study showed that 22 of 55 extremely preterm infants had LVCP after PDA ligation [bib_ref] Long-term morbidities associated with vocal cord paralysis after surgical closure of a..., Benjamin [/bib_ref]. Those with LVCP were more likely to develop BPD, reactive airway disease, and gastrostomy dependence, suggesting that flexible laryngoscopy be considered for patients with respiratory or feeding difficulties after PDA ligation. A study of 23 preterm infants after PDA ligation and 12 matched preterm control subjects reported that 12 of 23 had LVCP after PDA ligation, with seven showing signs of aspiration [bib_ref] Cot e JJ. Unilateral vocal cord paralysis following patent ductus arteriosus ligation..., Clement [/bib_ref]. Finally, a study examining long-term morbidities in preterm infants after PDA ligation noted that 44% had LVCP, with most requiring gastrostomies [bib_ref] Vocal fold paralysis following surgical ductal closure in extremely low birth weight..., Malcolm [/bib_ref].
One study examined the benefit of DLB in addition to flexible laryngoscopy for 532 patients with aspiration (mean age at enrollment, 2.2 yr; 131 preterm) [bib_ref] Usefulness of upper airway endoscopy in the evaluation of pediatric pulmonary aspiration, Adil [/bib_ref] Certainty of evidence. The panel's confidence in the accuracy of these estimated effects for the utility of airway endoscopy for critical outcomes was very low. Small, observational studies often lacked a comparison group. The mode of endoscopy (flexible laryngoscopy, flexible bronchoscopy, DLB) differed between studies, limiting generalizability.
Benefits. In patients with PPRD and unexplained prolonged ventilation or chronic respiratory symptoms, airway endoscopy can be used to identify treatable anatomic abnormalities and can provide prognostic information. When possible, although not essential, airway endoscopy may be best performed by a multidisciplinary aerodigestive team, assessing all possible upper and lower airway pathologies at once without repeat anesthesia.
Harms. One study reported mild hypoxemia (an Sp O 2 less than 90% but greater than 80%) during bronchoscopy in 5 of 27 patients (18.5%), with one patient requiring bronchoscopy for severe hypoxemic events developing severe hypoxemia (Sp O 2 less than 50%) with bradycardia [bib_ref] Bronchoscopy in neonates with severe bronchopulmonary dysplasia in the NICU, Hysinger [/bib_ref]. Patients with PPRD have impaired lung function and an increased risk of cardiopulmonary sequelae (pulmonary hypertension, respiratory decompensation, atelectasis, pneumonia) after airway endoscopy [bib_ref] Measuring pediatric bronchoscopy outcomes using an electronic medical record, Deboer [/bib_ref].
Coordination of endoscopy with other procedures can increase the anesthesia time; thus, unnecessary procedures should be avoided. Complications after flexible bronchoscopy occur more frequently in children undergoing multiple same-day procedures. In a study of 1,297 bronchoscopic procedures, 27 (2.1%) unplanned outcomes occurred, with 21 of 27 patients undergoing multiple procedures [bib_ref] Measuring pediatric bronchoscopy outcomes using an electronic medical record, Deboer [/bib_ref]. However, unplanned outcomes were not different from those of flexible bronchoscopy alone in the subset with multiple procedures coordinated through a multidisciplinary aerodigestive clinic. This supports the management of such children through a collaborative aerodigestive team, when available.
The neurodevelopmental risks of general anesthesia must also be considered. In cases in which general anesthesia poses a high risk, less invasive modes of airway evaluation such as airway imaging (dynamic CT or MRI) can be considered, although the panel recognizes that imaging is not as sensitive as Parental preference. Expert opinion from the panel reported that the majority of parents prefer to proceed with coordination of all necessary airway endoscopies (flexible and rigid) to identify treatable airway abnormalities and inform future management. When parental concern regarding general anesthesia is high, nonsedated airway imaging may be preferred.
Costs. Endoscopic airway evaluations, especially those done by multiple services, are expensive. Costs need to be weighed against the costs of failing to treat airway abnormalities while accounting for the child's quality of life.
Conclusions. The panel concluded that airway endoscopy is the best available test for the identification of large airway disease. When indicated, the benefits of airway endoscopy exceed its risks. Airway endoscopy can be considered when less invasive diagnostic methods have been exhausted. Adverse outcomes are reduced AMERICAN THORACIC SOCIETY DOCUMENTS when airway evaluations are performed by a multidisciplinary aerodigestive team.
What others are saying. Other guidelines have not addressed the role of airway endoscopy in the outpatient management of preterm patients. However, the ATS guidelines for infants with recurrent or persistent wheezing recommend bronchoscopy with BAL when wheezing persists despite medical management [bib_ref] Official American Thoracic Society clinical practice guidelines: diagnostic evaluation of infants with..., Ren [/bib_ref].
ATS recommendation. RECOMMENDATION 6. For infants, children, and adolescents with PPRD, we suggest airway endoscopy for those with unexplained symptoms such as chronic cough, wheezing, ventilator dependence, persistent hypoxemia, or a history of PDA ligation with stridor and weak cry (conditional recommendation, verylow-certainty evidence).
Implementation. The optimal mode of airway endoscopy (flexible bronchoscopy, flexible laryngoscopy, DLB) is not clear in the studies reviewed. The panel suggests a collaborative approach to airway endoscopy by a multidisciplinary team. Endoscopic techniques complement each other and facilitate identification of different airway pathologies. Flexible laryngoscopy should be performed in an awake child to identify upper airway pathology (laryngomalacia, vocal cord immobility, glottic webs, stenosis). Direct or rigid laryngobronchoscopy performed with the child spontaneously breathing under anesthesia is appropriate for the identification of glottic/subglottic pathology (subglottic cysts, stenosis, laryngeal clefts) and tracheal/bronchial pathology (tracheal stenosis, TBM). Flexible bronchoscopy and sampling through BAL can be used to identify large airway disease (tracheal stenosis and TBM, as well as distal bronchial anatomic abnormalities).
Justification. This recommendation places a high priority on patient safety and the need to identify airway anomalies that could significantly impact patientcentered outcomes.
Question 7: Should all infants, children, and adolescents born preterm (gestational age less than 37 wk) with PPRD undergo diagnostic imaging for TBM?
Background. Premature infants are at risk for developing large airway disease, especially those who require prolonged positivepressure ventilation [bib_ref] Characterization of disease phenotype in very preterm infants with severe bronchopulmonary dysplasia, Wu [/bib_ref] [bib_ref] Children's Hospitals Neonatal Consortium. Tracheobronchomalacia is associated with increased morbidity in bronchopulmonary..., Hysinger [/bib_ref]. Positive pressure can distend the abnormally compliant and structurally immature airways of preterm infants, resulting in acquired or secondary TBM [bib_ref] Airway structure, function and development in health and disease, Shaffer [/bib_ref]. The adverse consequences of TBM include decreased intrathoracic airflow, cyanotic episodes, difficulty weaning from positive-pressure ventilation, and higher mortality [bib_ref] Children's Hospitals Neonatal Consortium. Tracheobronchomalacia is associated with increased morbidity in bronchopulmonary..., Hysinger [/bib_ref]. The diagnosis of TBM is important for prognostication and individualized management of patients with PPRD [bib_ref] Characterization of disease phenotype in very preterm infants with severe bronchopulmonary dysplasia, Wu [/bib_ref] [bib_ref] The clinical evaluation of severe bronchopulmonary dysplasia, Bamat [/bib_ref]. The best available test for diagnosing tracheomalacia, bronchomalacia, or TBM is airway endoscopy. However, this technique is invasive, requires sedation or anesthesia, and may not be safe for critically ill neonates with small endotracheal or tracheostomy tubes. An alternative to bronchoscopy is dynamic imaging of the large airways.
Evidence base. Ten studies of preterm infants at risk for TBM were evaluated to determine the utility of airway imaging to complement or replace airway endoscopy in the management of PPRD. Although these guidelines focus on outpatients with PPRD, studies of preterm infants before NICU discharge (age greater than 36 weeks' PMA at time of study) were included (online supplement).
Studies evaluating the use of imaging were compared with those evaluating the use of bronchoscopy, recognizing that the bronchoscopic diagnosis of airway malacia is subjective and lacks a standardized definition. Some define airway collapse of more than 50% as TBM [bib_ref] Airway structure, function and development in health and disease, Shaffer [/bib_ref]. Others have graded TBM as none (0-25% collapse), mild to moderate (26-75% collapse), or severe (greater than 75% collapse) [bib_ref] Differences in flexible and rigid bronchoscopy for assessment of tracheomalacia, Hysinger [/bib_ref].
We identified a single prospective study comparing using a tracheobronchogram with using a dynamic spiral CT scan to diagnose TBM in 16 infants (15 preterm) [bib_ref] Computed tomography versus bronchography in the diagnosis and management of tracheobronchomalacia in..., Mok [/bib_ref]. Compared with bronchography, CT was less sensitive, enabling correct identification of 10 of 16 infants with tracheomalacia and 14 of 28 infants with bronchomalacia. The dynamic CT scans resulted in an underestimation of opening pressure and required a larger radiation dose than bronchograms.
In a study of 24 infants and children, two of whom had BPD, undergoing large airway evaluation through dynamic CT with three-dimensional reconstruction, 5 had TBM, 5 had right bronchomalacia, 8 had left bronchomalacia, and 8 had lobar bronchomalacia [bib_ref] Dynamic pulmonary CT of children, Greenberg [/bib_ref]. An evaluation of the correlation with bronchoscopy results was not performed.
Several studies compared bronchoscopy and CT imaging. Ten of 17 infants less than 12 months old had airway malacia at bronchoscopy, and 50% of those infants with malacia were premature [bib_ref] Tracheobronchomalacia in infants: the use of non-breath held 3D CT bronchoscopy, Lee [/bib_ref]. The sensitivity of using CT to diagnose tracheomalacia was 37.5%, and the sensitivity for using CT to diagnose bronchomalacia was 75%. Among eight infants (50% preterm) evaluated by using dynamic volumetric CT without sedation to diagnose large airway disease, four patients had TBM at CT imaging, and there was 75% concordance with bronchoscopy results [bib_ref] Dynamic volumetric computed tomographic assessment of the young paediatric airway: initial experience..., Tan [/bib_ref]. Another study of 34 pediatric patients (35% preterm) who underwent a cine multidetector CT scan for clinical indications identified isolated tracheomalacia in four patients and right or left bronchomalacia in 10 patients (80% with a history of cardiac surgery) [bib_ref] Dynamic expiratory CT: an effective non-invasive diagnostic exam for fragile children with..., Ullmann [/bib_ref]. In the 29 patients who underwent bronchoscopy, there was complete concordance between bronchoscopy and CT results in 23 patients and partial concordance in four patients. Importantly, in two patients, the CT result was positive, whereas the bronchoscopy result was negative. Dynamic CT was calculated to be 100% sensitive and 81% specific, with a positive predictive value of 90% and a negative predictive value of 100% being demonstrated. Another retrospective study included 28 patients who underwent bronchoscopy for suspected tracheomalacia [bib_ref] Helical multi-detector CT scan as a tool for diagnosing tracheomalacia in children, Douros [/bib_ref]. Paired static end-inspiratory and endexpiratory CT was performed on 26 of 28 patients with tracheomalacia and five "control subjects" with dry cough. The CT-enabled diagnosis of tracheomalacia was determined by using the change in the crosssectional area (CSA) at the level of maximum collapse, resulting in a sensitivity of 85% and specificity of 100%. Finally, 27 children with bronchoscopic evidence of tracheomalacia and 320 control subjects were evaluated to determine the accuracy of using freebreathing cine CT for diagnosing tracheomalacia, as defined by the change in the tracheal CSA [bib_ref] Free-breathing cine CT for the diagnosis of tracheomalacia in young children, Goo [/bib_ref]. Fifty-seven percent of patients with malacia diagnosed through bronchoscopy had a significant change in the CSA, compared with 11% of control subjects, with 96% sensitivity, 97% specificity, and 97% accuracy being demonstrated.
Wu and colleagues (28) described 76 premature infants with severe BPD between 40-50 weeks' PMA by using a combination of CT with angiography and bronchoscopy/ tracheoscopy to diagnose large airway disease (defined as a .50% decrease in the tracheal or bronchial CSA from inspiration to expiration) and determined its effect on BPD-related morbidity. Large airway malacia was associated with increased risks of death before hospital discharge, tracheostomy, and home pulmonary vasodilator therapy.
An emerging area for the diagnosis of large airway disease is respiratory-gated MRI. Bates and colleagues (159) performed a retrospective study of 27 neonates by using a specialized MRI system within their NICU to evaluate for tracheomalacia. The change in the luminal CSA as determined through bronchoscopy was used to identify those with tracheomalacia. A recent study by Hysinger and colleagues (160) validated the use of ultrashort echo-time MRI for diagnosing tracheomalacia as compared with bronchoscopy. The use of MRI to diagnose airway malacia had a moderate correlation with the use of bronchoscopy.
Certainty of evidence. Overall, the quality of evidence is very low. No direct evidence answers this PICO question for patients with PPRD. With one exception, studies were retrospective, single-center studies that included small sample sizes. The available data demonstrate that using CT to diagnose large airway disease results in variable sensitivity, specificity, and concordance with using bronchoscopy. This may be due to the state dependence of imaging findings that vary according to whether the infant is calm, agitated, or in respiratory distress.
Benefits. In patients with PPRD, large airway imaging can lead to the diagnosis and treatment of surgically correctable findings. Without treatment, TBM is associated with significant morbidity [bib_ref] Children's Hospitals Neonatal Consortium. Tracheobronchomalacia is associated with increased morbidity in bronchopulmonary..., Hysinger [/bib_ref]. Large airway imaging can be used to avoid the sedation associated with bronchoscopy. Dynamic CT can provide objective data to complement bronchoscopy data. CT imaging can be used to noninvasively evaluate parenchymal and vascular pathologies that contribute to airway disease when sedated bronchoscopy is not feasible (lack of subspecialist availability, clinical instability, or prohibitively small artificial airway).
Harms. Advanced imaging of young patients and its interpretation requires specialty expertise that may not be available at all centers. CT imaging requires radiation exposure, albeit at a relatively small dose designed for pediatric imaging studies [bib_ref] Model-based iterative reconstruction in ultra-low-dose pediatric chest CT: comparison with adaptive statistical..., Kim [/bib_ref] [bib_ref] Ultrafast pediatric chest computed tomography: comparison of freebreathing vs. breath-hold imaging with..., Kino [/bib_ref] [bib_ref] Evaluation of chest CT scan in low-weight children with ultralow tube voltage..., Shi [/bib_ref] [bib_ref] Pediatric chest CT at chest radiograph doses: when is the ultralow-dose chest..., Villanueva-Meyer [/bib_ref] [bib_ref] High-pitch CT, decreasing need for sedation and its potential side effects: some..., Westra [/bib_ref] [bib_ref] Imaging the infant chest without sedation: feasibility of using single axial rotation..., Zhu [/bib_ref]. The amount of radiation is variable (0.75-1.96 mSv in the studies above). There are center-specific differences in imaging protocols, including positive endexpiratory pressure (PEEP) titration and degree of patient sedation, which can lead to decreased generalizability of the findings. Finally, in the studies referenced here and in the panelists' practices, CT and MRI are not as sensitive as bronchoscopy for diagnosing TBM and thus may not provide a definitive diagnosis.
Parental preference. Parents are understandably concerned about the radiation exposure associated with CT. Should noninvasive dynamic CT be offered without sedation and ventilation, it may be preferred to bronchoscopy. Alternatively, if reliable airway imaging requires a combination of sedation, mechanical ventilation, and radiation exposure, bronchoscopy may be preferred. Dynamic MRI of the airways, when available, is an alternative that can be performed without radiation or sedation [bib_ref] Quantitative assessment of regional dynamic airway collapse in neonates via retrospectively respiratory-gated..., Bates [/bib_ref].
Costs. There is a cost associated with airway imaging, which includes radiologist expertise for protocol design, implementation, and interpretation of the studies. We recommend unsedated CT because anesthesia is associated with increased risk and cost and affects dynamic airway collapse. Alternatively, earlier identification of large airway disease can reduce costs by allowing for PEEP titration to decrease hospital LOSs and readmissions.
Conclusions. The use of bronchoscopy is most likely to result in an accurate identification of large airway disease [see QUESTION 6: SHOULD ALL INFANTS, CHILDREN, AND ADOLESCENTS BORN PRETERM (GESTATIONAL AGE LESS THAN 37 WK) WITH PPRD UNDERGO AIRWAY ENDOSCOPY?]. Large airway CT imaging is noninvasive but requires radiation exposure and is less sensitive and specific than bronchoscopy. However, dynamic airway imaging may be useful when bronchoscopy is not possible or in cases in which imaging would identify extrinsic compression or other anatomic features causing central airway collapse. A subset of patients may require a combination of bronchoscopy and imaging [fig_ref] Figure 1: Diagnostic algorithm for patients with post-prematurity respiratory disease and concern for tracheobronchomalacia [/fig_ref].
What others are saying. The 2020 ERS guidelines for the long-term management of children with BPD recommended consideration of lung imaging for children with more severe BPD.
## Ats recommendations. recommendation
7A. For infants, children, and adolescents with PPRD who do not have symptoms suggestive of airway malacia, we suggest that dynamic airway imaging (CT or MRI) not be used as a screening test for the routine diagnosis of TBM (conditional recommendation, very-low-certainty evidence).
RECOMMENDATION 7B. We suggest that unsedated, dynamic airway imaging (CT or MRI) be used for the diagnosis or reevaluation of TBM in patients with PPRD who have recurrent symptoms suggestive of airway malacia as an alternative to bronchoscopy when the risks from anesthesia for bronchoscopy are judged to be greater than the risks from radiation or when bronchoscopy is not feasible or available (see [fig_ref] Figure 1: Diagnostic algorithm for patients with post-prematurity respiratory disease and concern for tracheobronchomalacia [/fig_ref] (conditional recommendation, verylow-certainty evidence).
Implementation. TBM is diagnosed by measuring the CSA ratio. This recommendation was informed by available literature, pediatric radiology guidelines, and expert opinion. Although technical imageacquisition details will differ by institution and device manufacturer, CT should be performed by using appropriate dosereduction techniques [bib_ref] Model-based iterative reconstruction in ultra-low-dose pediatric chest CT: comparison with adaptive statistical..., Kim [/bib_ref] , which can be as low as 0.5 mSv. Airway MRI can be performed by using dynamic cine or gating techniques (active or retrospective), with time resolutions as low as one-eighth of a respiratory cycle for retrospectively gated ultrashort echo-time sequences at high resolution [bib_ref] Quantitative assessment of regional dynamic airway collapse in neonates via retrospectively respiratory-gated..., Bates [/bib_ref]. Although dynamic airway MRI is currently limited to centers with this unique resource, this technique may represent the future of TBM diagnosis, as it does not require radiation or sedation. Sedated imaging studies are less likely to capture dynamic airway collapse and are therefore not recommended.
Justification. This recommendation accounts for the fact that dynamic airway imaging may not be available at all centers. It places a high value on properly diagnosing conditions that significantly impact clinical care. The decision to perform airway imaging in addition to or in lieu of bronchoscopy requires careful consideration by the clinician.
## Limitations and future research
Despite the frequency of PPRD in preterm infants, children, and adolescents, we were unable to make strong recommendations because all of the evidence was of very low certainty. Most studies focused on infants, AMERICAN THORACIC SOCIETY DOCUMENTS which limits their applicability and suggests that much could be learned from evaluating these therapies and diagnostic studies in older children and adolescents with PPRD. Given the frequently unrecognized risks that late-preterm infants experience, we elected to include them in the systematic review. However, differences between extremely preterm and late-preterm infants may affect clinical management.
In some cases, multicenter studies are warranted to investigate our specific recommendations more comprehensively. Studies examining the duration and weaning or discontinuation of inhaled bronchodilator and corticosteroid therapy in patients with PPRD who have respiratory symptoms (wheezing, cough, tachypnea) will be highly beneficial. However, further RCTs of diuretics in children with PPRD require careful consideration of the risks of treatment before examining the short-and long-term outcomes of this common but potentially unnecessary intervention. Further studies are needed to determine the role of diagnostic PSG in patients with PPRD. The utility of an interdisciplinary aerodigestive team approach to conducting formal evaluations of swallowing (including both VFSS and FEES), airway endoscopy, and airway imaging should be studied to determine its clinical benefit and feasibility for patients with PPRD.
Studies in areas not specifically addressed by these clinical practice guidelines may also warrant further investigation. Such topics include longitudinal assessments of pulmonary function, potentially using infant pulmonary function testing, forced oscillation techniques, spirometry, plethysmography, and other novel modalities for measuring respiratory physiology in patients with PPRD across the lifespan. The management of both acute respiratory exacerbations and chronic care warrants further study. The impact of environmental exposures, including but not limited to inhaled tobacco smoke and air pollution, on those with PPRD is likewise an important area for future research. How PPRD affects the risk of chronic obstructive pulmonary disease, emphysema, and other chronic respiratory conditions in adults remains to be determined as populations of extremely preterm neonates reach this age in the coming decades. Approaches to the prevention of these severe, life-limiting conditions should also be studied in adult cohorts with PPRD.
# Conclusions
PPRD manifests as a spectrum of disease severity. Even those with milder disease are at risk for long-term respiratory impairment [bib_ref] Expiratory airflow in late adolescence and early adulthood in individuals born very..., Doyle [/bib_ref]. Given the lack of clinical studies in infants, children, and adolescents with PPRD, this clinical practice guideline will aid primary care providers and specialists in diagnosing and treating respiratory symptoms commonly seen in this population. There are currently no medications or diagnostic testing that are universally indicated for those with PPRD. However, future studies will elucidate which subgroups of patients will benefit from targeted therapies for the prevention and treatment of PPRD in a personalized approach. As patients with PPRD enter into adulthood, additional clinical and translational research will be critical for determining the risk of cardiopulmonary disease later in life. The recommendations in this guideline were reviewed by the ATS Quality Improvement and Implementation Committee, and none are considered suitable for performance measure development.
[fig] Figure 1: Diagnostic algorithm for patients with post-prematurity respiratory disease and concern for tracheobronchomalacia. Angio = angiography; CT = computed tomography; MRI = magnetic resonance imaging; PEEP = positive end-expiratory pressure; PMA = postmenstrual age; PPV = positive-pressure ventilation.AMERICAN THORACIC SOCIETY DOCUMENTS e118American Journal of Respiratory and Critical Care Medicine Volume 204 Number 12 | December 15 2021 [/fig]
[table] 22: with BPD and 30 control subjects) demonstrated increased inspiratory or [/table]
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Background Premature birth affects millions of neonates each year, placing them at risk for respiratory disease due to prematurity. Bronchopulmonary dysplasia is the most common chronic lung disease of infancy, but recent data suggest that even premature infants who do not meet the strict definition of bronchopulmonary dysplasia can develop adverse pulmonary outcomes later in life. This post-prematurity respiratory disease (PPRD) manifests as chronic respiratory symptoms, including cough, recurrent wheezing, exercise limitation, and reduced pulmonary function. This document provides an evidence-based clinical practice guideline on the outpatient management of infants, children, and adolescents with PPRD. Methods A multidisciplinary panel of experts posed questions regarding the outpatient management of PPRD. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations. Results The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations were developed for or against three common medical therapies and four diagnostic evaluations in the context of the outpatient management of PPRD. Conclusions The panel developed recommendations for the outpatient management of patients with PPRD on the basis of limited evidence and expert opinion. Important areas for future research were identified.
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Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper
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Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper
While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers.
in Europe, and improving translational and clinical research on rare cancers.
## Basic considerations
- Rare cancers account for as many as 20% of new cancer cases [bib_ref] Rare cancers are not so rare: the rare cancer burden in Europe, Gatta [/bib_ref]. According to conventional methodologies, clinical trials need considerable numbers of patients that are difficult to collect in rare cancers. By definition, therefore, clinical evidence is more difficult to build in rare than in frequent cancers.
- Efforts to set up large collaborative clinical trials merit special attention in rare cancers. Collaborative networking is crucial and needs to be funded properly. However, the limiting factor of large collaborations may be a lack of clinical expertise. In principle, inappropriate clinical performance might flaw the outcome of a clinical trial to the same extent as methodological biases.
- It follows that alternative ways to conceive study design, analysis of data and combination of results would be exceedingly important. It is possible that some innovative solutions may imply a price to pay in terms of a higher uncertainty. However, discriminations in rare cancer patients' access to effective care are inevitable, if a higher degree of uncertainty is not accepted when compared with more frequent conditions. clinical decision making in rare cancers [bib_ref] Rare cancers are not so rare: the rare cancer burden in Europe, Gatta [/bib_ref] The problem of rare cancers is one of a higher uncertainty.
By no means does this imply that decision making in rare cancers should be conceptually different from that in more frequent conditions. As usual, it is crucial for the clinician to address decision making rationally. In the language of decision theory, this means to properly manage 'probabilities' and 'utilities' [bib_ref] Decision analysis in medicine, Thornton [/bib_ref]. Also in rare tumors, therefore, an effort should be made to shape the results of clinical research in such a way that they provide the physician, and the patient, with informative probability distributions on major expected outcomes, with the central value corresponding to the 'risk' and the distribution representing the 'uncertainty' thereof, and, when probability curves as a function of time are available, with their full shape over time made understandable. Patient's 'attitude toward risk' should be taken into account for an individualized decision making. 2) Likewise, quality of life should be incorporated as much as possible as an end point also in clinical studies on rare cancers, with the aim to let the physician describe it as precisely as possible at the patient's bedside, in order to elicit individual patient's utilities factoring their individual values and preferences. 3) Third payers, regulatory agencies and local health systems should avoid discriminations against rare cancer patients. The cost/efficacy thresholds used by any third payer for decisions on resource allocation can well be the same as for frequent cancers, but the uncertainty on quantification should be accepted as possibly higher in rare cancers. This also applies to definition of state of the art through clinical practice guidelines, and the like. 4) Rare cancer patients often argue in favor of relaxing the usual risk-averse attitude of medical decisions [bib_ref] The risks of risk aversion in drug regulation, Eichler [/bib_ref]. In fact, under an individual perspective, the trade-off between risks of side-effects deriving from a new treatment and the certainty of progressive cancer is often solved, rationally, by choosing to try the new treatment. To a reasonable extent, this should be taken into consideration also by regulatory bodies when assessing the risk/benefit ratio of new treatments in bad prognosis scenarios. 5) Innovative approaches to summarize available evidence should be encouraged [bib_ref] Evidence-based medicine for rare diseases: implications for data interpretation and clinical trial..., Behera [/bib_ref]. They should allow to make the most of all available knowledge, which is particularly critical when the direct experimental evidence is scanty, or of suboptimal methodological quality. The principles of systematic reviews should be followed. In addition to randomized clinical trials, also preclinical evidence, as well as uncontrolled trials, observational studies and analyses of retrospective case series, or anecdotal cases, should be considered when summarizing the available evidence. Medical journals should consider the rarity of diseases when shaping their editorial policies, to make sure that any additional evidence is made available. Especially in the case of very rare cancers, even evidence from similar diseases can be taken into consideration. A degree of subjectivity is inevitable under this approach. However, formal methodologies can be followed and consensus processes can be put in place, in an effort to reduce subjectivity. It has been proposed to score available studies for their validity and pertinence [bib_ref] Strategy for randomised clinical trials in rare cancers, Tan [/bib_ref].
Validity of studies is based on their design (randomized or uncontrolled, prospective or retrospective etc.) and their quality (presence of flaws in a randomized trial, existence of prespecified external controls in an uncontrolled trial etc.). Pertinence is scored according to how much the study focused on the same disease, the same treatment, the same patient subgroup, and the like. Consensus processes should be put in place to generate such scores. Methodologies should be developed to this end. However, since scores would be made explicit, the assumptions of all conclusions could be publicly reviewed and discussed. Likewise, sensitivity analyses could be made to evaluate to which extent conclusions are sensitive to the assumptions and arbitrary values incorporated in the model (i.e. by assessing how the final probability distributions are affected by changes in these assumptions and values). study designs in rare cancers 1) Clinical studies on drugs are classically divided into phases, according to their primary objective: definition of the optimal dose for phase I, drug activity for phase II and efficacy for phase III [bib_ref] Principles of clinical trial design, Piantadosi [/bib_ref]. In rare cancers, where large trials may be unfeasible, the methodology of phase II uncontrolled studies has often been applied to trials whose aim was indeed to explore efficacy, not simply antitumor activity. On the contrary, an effort should be made: (i) to identify and clearly express the true aim(s) of each trial, in order to avoid ambiguities that may compromise its validity and hamper the unequivocal interpretation of its results; (ii) to adopt the methodologies that are appropriate for these aim(s) or, whenever this is not possible, to acknowledge the suboptimal methodology of the trial while accounting for its limitations in its analysis and interpretation. 2) When the enrollment in a study of an adequate number of eligible patients is not feasible, an option is to carry out lowpower randomized clinical trials [bib_ref] Clinical trials and rare diseases, Gerss [/bib_ref]. In this way, the principle of internal controls is met, and the biases from uncontrolled studies are avoided. However, the risk of missing a moderate/small treatment effect is high, and the low power of the trial should be acknowledged in the study protocol. The minimum difference for which good power is met should be made explicit in the protocol, as well as the actual power for the expected minimum difference of clinical interest. This may allow reviewing committees to make informed decisions as to the added value of a new study. 3) Research on biomarkers should be an inherent part of research on new drugs, because it may help identify those patient populations in which the drug is able to provide remarkable benefits. Clinical studies into these selected patient populations are exposed to all problems of rare diseases, but the sample size can be lower if the expected difference is high, and a sufficient power to detect this difference can be attained even with a reasonably low number of patients. In principle, studies on small selected populations where large benefits are expected should always be preferred to large studies on unselected populations where moderate or small benefits are expected. Regulatory bodies should encourage clinical studies seeking large benefits, even if the target populations are small, possibly tolerating a higher degree of uncertainty as a result of the paucity of eligible patients [bib_ref] American Society of Clinical Oncology Perspective: raising the bar for clinical trials..., Ellis [/bib_ref].
Statistical significance per se should never be the only factor to be considered for regulatory/reimbursement as well as clinical purposes [bib_ref] Demystify statistical significance-time to move on from the p value to Bayesian..., Lee [/bib_ref]. The most likely magnitude of benefit should be regarded as a key factor for any decision. 4) If the choice is made not to plan a trial with an internal control arm, external controls must be used. Controlled studies are usually felt to be unnecessary (or unethical) when: (i) dramatic beneficial effects (e.g. cure) are likely, although in a minority of patients, in the lack of effective alternatives; (ii) an important and frequent beneficial effect was seen in a series of patients, in the presence of a clear-cut mechanism of action of the treatment; (iii) there is universal consensus on the lack of equipoise. Stringent methodological requirements are needed, including: rigorous patient selection criteria; record of refusals (inasmuch as the intent-totreat principle is even more important); identification of external controls in the protocol before any analysis; formalization of statistical considerations as in a conventional randomized trial; proper selection of end points (response, duration of response, survival). The problem of 'stage migration' with historical controls is particularly important, and the introduction of new biomarkers may amplify it. 5) Adaptive trials allow to change aspects of the study while this is ongoing, depending on analyses of data obtained from patients enrolled in the same or other studies [bib_ref] Adaptive clinical trials in oncology, Berry [/bib_ref]. Rare cancers take special benefit from adaptive trials, because of the difficulty to find patients for clinical studies and the consequently long recruitment timelines. The development of a new drug, all the more in rare cancers, can be easier and faster thanks to adaptive mechanisms, such as, for example, the intensive use of stopping rules, the transformation of a phase II into a phase III study ('seamless phase II/III designs') in case the early stage of the study was positive, or the use of 'drop-the-loser' or 'play-the-winner' designs. Appropriate statistical techniques are available to handle the following adaptations: (i) adaptations of eligibility criteria based on results of the same or other studies, or difficulties in recruitment etc.; (ii) unexpected deviations from hypothesized base risks and event occurrences; (iii) stopping rules for futility or safety reasons; (iv) changes in data analysis based on accumulating external evidence [bib_ref] Adaptive designs at European Organisation for Research and Treatment of Cancer (EORTC)..., Mauer [/bib_ref]. Other mechanisms are considered to be more problematic, such as all those based on unblinded interim analyses of efficacy.
Obstacles to adaptive designs may be the duration of treatment, as well as the time to treatment effects and use of surrogate end points. Thus, the use of adaptive mechanisms should be accurately planned by the clinical researcher and the statistician, and specified in the study protocol. Availability of an effective data monitoring committee is critical. However, it is recommended to make efforts to assess the feasibility of adaptive designs when planning clinical studies in rare cancers. Likewise, it is recommended that methodological research is promoted to address the problems still faced with adaptive studies. 6) The conventional frequentist approach to clinical studies is focused on the control of the probability of false-positive results under the null hypothesis of no treatment effect (type I error) and on the probability of a false-negative result under an alternative, prespecified hypothesis of treatment efficacy (type II error). The 'P value' represents the probability of observed (or more extreme) results in the case the null hypothesis were true. On the contrary, Bayesian-design trials are marked by the use of a prior probability distribution and the generation of a posterior probability distribution of the treatment effect [bib_ref] Strategy for randomised clinical trials in rare cancers, Tan [/bib_ref] [bib_ref] Bayesian statistics in oncology: a guide for the clinical investigator, Adamina [/bib_ref] [bib_ref] Clinical trials and rare diseases: a way out of a conundrum, Lilford [/bib_ref]. Bayesian analyses produce probability distributions of the treatment effect, that is, estimates of the probability that the true treatment effect lies between any two values (e.g. that the risk reduction is between 10% and 20% etc.) or is below or above any specified threshold (e. g. a risk reduction <5%, >30% etc.). To use Bayesian methodologies, evidence available outside the trial needs to be considered, not only in planning the trial, but also in its analysis and interpretation. In Bayesian trials, there is not a pre-fixed number of patients to enroll, the target number of patient being dictated by the desired precision of the summary estimate of treatment effect, i.e. the width of the range of its plausible values. Furthermore, probability distributions provided by a Bayesian analysis can be directly used by the clinician in the clinical decision-making process, e.g. within a formal decision analysis. The main weakness of the Bayesian approach is the dependence of its conclusions on the prior probability distribution, whose definition entails an arbitrary, though not necessarily subjective, component. In general, consensus mechanisms should be arranged before setting up a Bayesian study in a transparent way to elicit prior probability distributions, and sensitivity analyses should be foreseen . 7) reviews actual clinical practice. This is often called 'effectiveness'. In this sense, there may be an issue about the generalizability of a trial on a new treatment, i.e. as to which extent efficacy demonstrated in the trial can be converted into effectiveness in real life. However, clinical research is done to improve clinical practice, which then has to change according to the new results of research. Therefore, the lack of generalizability of a new treatment when a trial has shown its superiority should be properly addressed by finding ways to transfer it into clinical practice and should not be viewed as an obstacle in principle to the introduction of the new treatment. This is all the more true of rare cancers, where the expertise is less accessible and the driving force of the market is lower to attract for-profit players. 8) It has been claimed that the availability of electronic patient records, which can be connected through wide data networks, gives rise to the opportunity to measure effectiveness in real conditions. Particularly in rare and very rare cancers, the substantial amount of data generated thereby is felt as a great opportunity to evaluate the effectiveness of available treatments in real conditions. In principle, there is no qualitative difference between the efficacy and the effectiveness of a new treatment, and the latter simply represents the actual translation in real conditions of the former, which in a sense is an 'unobservable' property of the treatment. Therefore, the same biases which hamper the estimation of efficacy outside a formal trial (and also within trials) prevent the use of routine clinical data to provide unbiased estimates of effectiveness. In other words, estimates of treatment effectiveness obtained from observational studies are exposed to major biases, and the statistical methods used to adjust imbalances in baseline factors cannot take into account unknown or unmeasured confounders, and therefore cannot assure that patients who received different treatments are actually comparable. As a consequence, clinical data extracted from current clinical practice can be used: (i) to provide information of the appropriateness of patient management in the real world, through the use of indicators consisting of surrogate end points (e.g. response rate etc.) and of markers of quality of care (e.g. early mortality etc.); (ii) to generate specific hypotheses to be tested in future trials (e.g. on treatment efficacy in specific subgroups); (iii) to create historical series of consecutive, unselected patients that provide information on time trends in prognosis and occurrence of specific outcomes in the general population. These series can be used as controls in subsequent uncontrolled studies, or to compare periods where different treatment approaches were used, whenever radical prognostic changes due to the introduction of a new treatment are assumed to be plausible.
surrogate end points in rare cancers 1) Surrogate end points are those which can replace the natural clinical end points by having the property of being measured sooner and/or easier (e.g. relapse-free survival, in the adjuvant setting, or progression-free survival, in the advanced).
In addition, their effect may be amplified in comparison to natural end points (e.g. differences in tumor response are likely to be of a higher magnitude than corresponding differences in survival). However, they require to be validated in order to be used appropriately [bib_ref] Biomarkers and surrogate end points-the challenge of statistical validation, Buyse [/bib_ref]. Validation needs high numbers, which are the problem of rare cancers. On the other hand, sometimes surrogate end points can be the only way to show improvements timely. In addition, some of them may recapitulate properties which might be perceived by patients as a value in se, as, for example freedom from progression or freedom from relapse inasmuch as quality of life is concerned, so that they may not require any formal validation in specific presentations. A new treatment could also be used temporarily, under the assumption that the surrogate end point is valid, while waiting for final results. 2) While validation of surrogate end points is problematic in rare cancers, their use is of great value in the clinic, as a tool to better describe and evaluate treatment benefits at the patient's bedside, and also to modulate therapies. Conceptually, any benefit in terms of antitumor activity actually observed in the individual patient increases the likelihood of an efficacy advantage in that patient (e.g. a patient who responds to a medical therapy is more likely to take some benefit on a longer time span, in comparison to a nonresponding patient). Therefore, a given treatment could be administered for a short time span and continued only provided a short-term effect on a surrogate end point, such as any kind of 'tumor response', is observed. This may be relevant to overcome regulatory and reimbursement limitations to patient access to new treatments in rare cancers. For example 'pay-by-result' approaches, and the like, may well help optimize cost/efficacy on a population basis. 3) Tumor response is the most typical indicator of antitumor activity. Unfortunately, it was originally conceived as a dichotomous tool to screen drugs worth testing in a phase III setting, essentially aiming at its reproducibility [bib_ref] Meaningful clinical classification of therapeutic responses to anticancer drugs, Karnofsky [/bib_ref] [bib_ref] New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eisenhauer [/bib_ref]. This may explain its limitations as a surrogate end point for clinical efficacy. Currently, an additional difficulty is given by the possibly nondimensional nature of tumor response to many molecularly targeted agents, while standard response criteria are mainly based on tumor shrinkage. Sometimes, they may slow down tumor progression, though progression is not avoided, so that tumor response and progression-free intervals may not be fit to render the whole potential benefit of the drug. It is recommended that methodological research addresses the problem of tumor response in medical oncology, trying to redefine it as an indicator which may have clinical meaning, in addition to being reproducible. Modern medical imaging, including functional imaging, should be fully exploited. Given the mechanism of action of new molecularly targeted drugs, nondichotomous definitions of tumor response may be useful, as well as those catching the impact on the growth rate of the tumor [bib_ref] Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and..., Eisenhauer [/bib_ref].
critical organizational aspects of clinical research in rare cancers 1) Collaborative health care 'reference networks' involving centers of expertise along with other centers able to provide good quality of care are a crucial instrument to improve quality of care in the field of rare cancers [bib_ref] Creating a European Union framework for actions in the field of rare..., Moliner [/bib_ref]. Quality control programs should be in place in order to make sure that quality of care is evenly distributed across the network. Reference networks on rare cancers improve health care and improve accrual in trials, as well as clinical quality within clinical trials. 2) Patient information about trials should be made widely available. Patients should be aware that there is always an added value in entering a trial. On the other side, patient communities should be involved as much as possible in the conception of new clinical trials, particularly in regard to study design and the selection of study end points. 3) Rare cancer trials need to be rich in information in order to maximize their efficiency. For example a long follow-up for each patient would be crucial to generate information on the natural history of the disease etc. This applies also to biological information. Limitations to the duration of follow-up of patients enrolled in clinical trials should be overcome. Likewise, limitations to the opportunity to share the results across trials should be overcome. Efforts should be made toward clinical trial database sharing [bib_ref] How should clinical trial data be shared?, Tucker [/bib_ref].
Regulations, including those on data protection, should remove obstacles. New models regarding 'precompetitive collaborations' and in general collaboration across pharma companies, should be explored. 4) The review of pathologic diagnosis, if not made at reference centers, is crucial in rare cancers, to make sure that the quality of care is high [bib_ref] Second-opinion pathologic review is a patient safety mechanism that helps reduce error..., Middleton [/bib_ref] [bib_ref] Histopathologic diagnosis of pediatric neoplasms: a review of international consultations, Santiago [/bib_ref] [bib_ref] Sarcoma: concordance between initial diagnosis and centralized expert review in a population-based..., Ray-Coquard [/bib_ref]. This obviously applies to clinical trials and to clinical databases suitable to be used for retrospective research. Telepathology, expert panels, dedicated training facilities are useful tools in this direction. 5) There have been patient-driven efforts to feed databases of studies and of cancer registries, which may become a formidable tool to gain new knowledge in rare conditions. This implies methodological challenges, which should be addressed. 6) Incentives for orphan drugs encourage pharmaceutical companies to launch clinical studies on new agents in rare cancers. However, given the inherently low number of patients, the risk of failing approval due to lack of evidence may all the same discourage from developing drugs in most rare cancers. In addition, screening of new drugs in rare cancers is by definition less likely to happen, since phase I studies will privilege frequent cancers (more likely to be enrolled in comparison to any single rare cancer in any phase I study), and hints of activity from the phase I setting will be therefore lacking in rare cancers. It is recommended that mechanisms are put in place to regularly screen new drugs also in rare cancers. This could be achieved through formal collaborations among reference centers by using framework study protocols on specific rare cancers liable to be exploited to test sequentially new drugs in their phase II stage of development. Bayesian approaches could be used, in order to efficiently formalize probabilities of activity for new agents in specific rare cancers. Mechanisms of conditional approval and 'adaptive licensing' should be actively exploited, because they may allow rare cancer patients earlier access to drugs with potentials of efficacy and at the same time generate new evidence [bib_ref] Adaptive licensing: taking the next step in the evolution of drug approval, Eichler [/bib_ref]. For this use of new drugs, patients should be referred to centers and networks of expertise, scientific and ethical scrutiny should be arranged and publication of all results should be foreseen. 7) The compassionate and off-label use of new drugs is more widespread in rare cancers [bib_ref] The off-label use of drugs in oncology: a position paper by the..., Casali [/bib_ref]. Regulations thereof should be harmonized as much as possible, by acknowledging the likelihood that orphan indications may not be properly and timely covered by approval and reimbursement. In return for some relaxation in rules on compassionate and off-label use of drugs in rare cancers, this could be exploited to generate data in ways close to what is done in formal clinical studies. Also for this use of new drugs, patients should be referred to centers and networks of expertise, scientific and ethical scrutiny should be arranged and publication of all results should be foreseen. [bib_ref] American Society of Clinical Oncology Perspective: raising the bar for clinical trials..., Ellis [/bib_ref] In rare cancers, national, international, even global collaborations should be pursued to make investigator-driven studies possible. These are vital, for example to provide hints of activity of new agents in very rare cancers, which could be tested within industry-sponsored trials in case of a positive result from early low-cost studies. They are vital also to assess the value of new treatment strategies, with special regard to multidisciplinary approaches. Currently, the main obstacles to investigator-driven wide collaborations are regulatory and need to be overcome as much as possible. 9) Biobanks for medical research are crucial to advance the development of new treatments in rare cancers. They should be maintained by dedicated personnel in a centralized way, to realize good quality control, proper access, regulatory and ethical competence and harmonization and standardization. Currently, major obstacles have to do with data protection. While data confidentiality needs to be protected by putting in place all reasonable available means, the right of patients to donate their tissues for research, if they will, should be protected as well. The patient should be able to give a 'broad consent' for his/her data and tissues to be used for research purposes by the treating institutions, avoiding the need to reconsent whenever a new retrospective research is decided [bib_ref] Can broad consent be informed consent?, Sheehan [/bib_ref] [bib_ref] Broad consent versus dynamic consent in biobank research: is passive participation an..., Steinsbekk [/bib_ref]. Of course, proper ethics and scientific reviewing mechanisms for new researches should be in place. [bib_ref] Adaptive clinical trials in oncology, Berry [/bib_ref] In rare cancers, all cases may be useful to advance science.
Thus, prospective clinical databases, registries and connection of electronic patient records on a network basis should be encouraged. Collaborative reference networks focusing on health care should be implemented and properly funded for quality of care reasons, but their added value in terms of generating new evidence should always be factored. 11) Cancer registries are essential because they provide vital data on incidence, prevalence and survival. Population cancer registries may allow to conduct high-resolution studies on selected topics. Proper derogations from the requirement of patient's informed consent are needed for population-based cancer registries to survive as crucial public health facilities [bib_ref] Cancer registration, public health and the reform of the European data protection..., Andersen [/bib_ref]. 12) Observational clinical studies on selected patient subgroups should be encouraged, because they can allow to gain vital information on the natural history and clinical characteristics of entities which sometimes are described only pathologically, and can generate external controls for uncontrolled clinical studies. Data generated by health care databases should be exploited, overcoming unneeded regulatory constraints. 13) Given the key role played by regulatory bodies through their scientific advices to pharmaceutical companies embarking into development of new drugs in cancers, regular consultations between these bodies and the rare cancer-based communities (both patient-and physiciandriven) would be vital to tailor the way new drugs are developed in rare cancers. Confidentiality issues and conflicts of interest should be managed. In principle, the value of the disease-based communities should be acknowledged and regulatory/reimbursement bodies should view them as active partners in establishing criteria for approval of new treatments in rare cancers.
# Disclosure
The authors have declared no conflicts of interest.
references
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http://www.annalsofoncology.org/article/S0923753419313705/pdf
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While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to stepwisely test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers .
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Cardiac imaging in congenital heart disease during the coronavirus disease-2019 pandemic: recommendations from the Working Group on Congenital Heart Disease of the Italian Society of Cardiology
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Cardiac imaging in congenital heart disease during the coronavirus disease-2019 pandemic: recommendations from the Working Group on Congenital Heart Disease of the Italian Society of Cardiology
# Introduction
The 2019 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that is responsible for coronavirus disease-2019 (COVID-19) has been recently declared a pandemic by WHO and is critically affecting the provision of healthcare services.Among Western countries, Italy was the first to be deeply affected by SARS-CoV-2, currently being the one with the largest number of infected people after China, and the country with the highest number of deaths.
Evidence suggest that, compared with adult patients, clinical manifestations of children's COVID-19 may be less severe. However, young children, particularly infants, are vulnerable to infection and, furthermore, they may play a pivotal role in interfamilial and human-tohuman virus transmission. [bib_ref] Epidemiology of COVID-19 Among Children in China, Dong [/bib_ref] [bib_ref] SARS-CoV-2 infection in children: transmission dynamics and clinical characteristics, Cao [/bib_ref] Furthermore, SARS-CoV-2 is thought to infect host cells through ACE2 to cause COVID-19, and to provoke direct damage to the myocardium resulting in virus-related myocarditis. [bib_ref] COVID-19 and the cardiovascular system, Zheng [/bib_ref] [bib_ref] Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin, Hu [/bib_ref] This will turn into multiple requests for transthoracic echocardiograms and/or cardiac diagnostic work-up of positive patients.
Healthcare workers are at higher risk of infection especially in the event of close contact with suspected or confirmed cases, such as during physical examination and investigations (i.e. echocardiographic studies). According to statistics from the Italian Report of Istituto Superiore di Sanità (ISS) of 19 March 2020, 3559 (10%) out of 35 731 SARS-CoV-2-infected patients were healthcare workers.Sonographers, nurses, and physicians involved in the Paediatric Echo Lab and in performing echocardiographic exams have to reduce their own risk of infection and prevent the spread of the disease.
The aim of this position paper is to provide recommendations on how to manage challenges faced by the different cardiac imaging modalities in the evaluation of patients with congenital heart disease (CHD), during the pandemic. However, these indications must be considered as expert opinion because of the lack of evidence-based scientific data on this subject.
## Indications for echocardiography
In suspected or confirmed paediatric COVID-19 cases, echocardiography should only be performed if there is a strong clinical indication, and the result may provide a clear benefit or may have a crucial impact on clinical management. In particular, the Echo-Lab leading team along with referring physicians should identify all those investigations that have an urgent/emergent indication and reschedule all the elective ones, especially for patients at higher risk of infection and low priority for echocardiogram.High priority (1) First echocardiographic study in a newborn/infant with a strong clinical suspicion of CHD (cyanosis, cardiac murmur, cardiomegaly at chest X-ray, abnormal arterial pulses, respiratory distress not otherwise explained, failure to thrive) or with an antenatal diagnosis of critical CHD, who is likely to require a surgical/interventional procedure in the near future (e.g. D-Transposition of Great Arteries, Tetralogy of Fallot, pulmonary atresia, aortic coarctation, univentricular hearts, pulmonary or aortic valve critical stenosis). (2) Known CHD patients (e.g. Fontan circulation, Eisenmenger syndrome) or patients with known cardiomyopathy (e.g. hypertrophic, dilated, restrictive), presenting to the emergency department with signs and/or symptoms suggesting hemodynamic deterioration and/or worsening of their underlining cardiac condition. (3) Patients presenting to the emergency department or referred by a local paediatrician with a high suspicion of cardiovascular disease based on history, physical examination, electrocardiogram, chest X-ray (e.g. myocarditis, dilated cardiomyopathy, hypertrophic cardiomyopathy, infective endocarditis, left or right heart obstruction, aortic arch disease).
## Medium priority
(1) Scheduled echocardiogram in a patient with known CHD who underwent recent surgical/interventional procedure and/or medical therapy modification, but is otherwise clinically stable. (2) Scheduled echocardiogram in known CHD patient whose cardiac status has changed from previous ultrasound investigation but is otherwise clinically stable.
Low priority (1) Scheduled outpatient echocardiogram in a known CHD patient without a clear change in clinical status from previous ultrasound investigation.
(2) Scheduled outpatient echocardiogram, requested after incidental murmur detection in a child otherwise clinically stable.
Transesophageal echocardiogram (TEE) deserves special consideration in determining when and whether it should be performed. In fact, TEEs carry a higher risk of the SARS-CoV-2 infection's spread, as they can cause the aerosolization of droplets containing virus. In addition, especially in children or young adults, the transthoracic acoustic window is generally good for minimizing the need for TEE. Therefore, TEEs should be postponed or canceled if they are unlikely to change the clinical management, and/or if an alternative imaging modality [e.g. ultrasound enhancing agent with TTE, cardiac computed tomography (CT) or cardiac magnetic resonance (CMR)] can provide the necessary information (see below in Guidance for advanced imaging).
## Special cases
(1) Adult patients with CHD (ACHD) should be managed according to SIECVI recommendation. 9 (2) Fetal echocardiography screening and follow-up, if indicated, should be pursued according to local guidelines without exceptions or delays, even during the pandemic. However, in the circumstances of pregnant women with suspected or confirmed COVID-19 infection, all the precautions regarding personal protection (see below) should be followed in order to minimize the contagion. It would be appropriate to counsel the parent using technologies allowing a reduction in the time spent in physical proximity to the patient (e.g. video conferencing, phone calls).
## Suggested echocardiographic scan protocol
Echocardiogram execution Echocardiographic studies performed on paediatric patients with suspected or confirmed COVID-19 should be as focused as necessary to be of any diagnostic value. Each exam should be planned in advance after review of images from past exams and/or other imaging modalities. In fact, prolonged scanning time can expose the operator to added risk. However, thorough investigation may be necessary in some circumstances (e.g. first scan in a newborn). In order to minimize the scanning time, these exams should be executed by experienced sonographers and measurements should be performed offline.
Echocardiogram should take place inside an isolated room with dedicated machine whenever possible. The echo machine must be covered with special protections in order to avoid/minimize contamination. Nontouch screen systems should be preferred as the touching system once covered is less efficient, thus increasing the scanning time. Sterile single-use ultrasound gel packets are preferable to nonsterile gel. Unless crucial, ECG leads should not be used.
Ideally, the child should be placed in the left lateral position with the operator positioned on the right side of the bench, in this manner the distance patient-to-imager would increase, minimizing the exposition of the operator to droplets. However, changing the preferred patient position should be balanced against potential tradeoffs in lower image quality and longer scanning time.
The number of personnel involved in the exam execution should be reduced to a minimum. Restriction should be applied to all students, residents, fellows and practicing physicians who are not essential to scan performance and interpretation. Only one caregiver should be allowed to stay in the room during the scan.
## Outpatient setting
In the outpatient setting, the child and one caregiver should be triaged by phone the day before the appointment and triaged verbally on the day of the exam to check for any symptoms of infection or close contact with infected people. Among those who have criteria for suspected COVID-19 infection, the elective studies must be deferred. In case of a nondeferrable patient, this should be screened and tested for infection according to local protocols and methods for quarantine. Before accessing the outpatient department, the patient and the caregiver would undergo temperature measurement. In addition, they would be invited to wash their hands and wear a surgical facemask.
## Inpatient setting
In the case of an echocardiogram in a suspected or confirmed COVID-19 hospital inpatient, a bedside investigation with a portable machine in the isolated room should be preferred, avoiding moving patients within the clinic or hospital. The echo machine should undergo a comprehensive cleaning protocol with specific products before next use. For each COVID-19 ward a dedicated echo machine should be identified and must not be moved from that location. The identification of the optimal location for the echocardiographic study should also take into account the monitoring capabilities and staffing of different locations.
Only one caregiver should be allowed for every patient, and she/he should be always the same during the whole hospital stay. All caregivers and patients (when applicable) should be invited to wear a facemask and wash their hands frequently. In some institutions (e.g. University Hospital of Padua) patients and caregivers, regardless of symptoms and infection risk, would undergo a nasopharyngeal swab test the day before the admission.
## Personal protection of healthcare workers
As a general protocol, all healthcare workers should undergo a temperature check before starting their working day. They should frequently and meticulously wash/ sanitize their hands during their working time.
Furthermore, they should always wear a surgical facemask inside the hospital and respect the social distancing, except during physical examination or medical procedures.
Guidance on personal protective equipment (PPE) to manage patients with low risk of infection:
(1) Wash hands (2) Wear disposable gown (3) Put on nonsterile gloves and surgical face mask Guidance on donning PPE to manage COVID-19 suspected or confirmed patients:
(1) Put on special work clothes and work shoes (2) Wash hands (3) Put on disposable surgical cap (4) Put on medical protective mask (FFP2 or FFP3) (5) Put on inner disposable nitrite/latex gloves (6) Put on goggles and protective clothing (including waterproof boot covers, disposable isolation gown and face shield) (7) Put on outer disposable latex gloves Guidance on removing PPE to manage COVID-19 suspected or confirmed patients:
(1) Wash hands and remove visible bodily fluids/blood contaminants on the outer surfaces of both hands (2) Wash hands and replace outer gloves with new gloves (3) Remove full-face shield (4) Wash hands and remove disposable gowns along with outer gloves (5) Wash hands and put on new outer gloves (6) Remove protective clothing along with outer gloves (for gloves and protective clothing, turn inside out, while rolling them down) and remove the waterproof boot covers (7) Wash hands and remove goggles (8) Wash hands and remove facemask (9) Wash hands and remove cap (10) Wash hands and remove inner disposable latex gloves (11) Wash hands and leave removal area 10
## Echocardiographic machine protection and cleaning
Whenever possible it would be ideal to set a machine for use with suspected or confirmed patients. After donning of the operator and before entering the room, probes and machine consoles should be covered with disposable plastic. After the echocardiogram, the machine and probes should be thoroughly cleaned, ideally in the patient's room and again outside. All the surfaces of objects should be wiped with 1000 mg/l chlorine-containing disinfectant or wipes with effective chlorine; after 30 min, they should be rinsed with clean water. However, before initiating the cleaning process, the operator should consult vendors' disinfecting guidelines available online, as procedures vary and could affect the functionality of machines and probes. Smaller, laptop-sized portable machines should be preferred as they are more easily cleaned; however, the operator should take into account the inferior image quality and functionality compared with conventional machines.
## Guidance for advanced imaging (cardiac ct and cmr)
Chest CT is a key component of the diagnostic work-up for patients with suspected infection with SARS-CoV-2, 11 even though it is rarely performed in the paediatric population because of the less severe lung involvement and for safety reasons. [bib_ref] Chinese Pediatric Novel Coronavirus Study Team. SARS-CoV-2 infection in children, Lu [/bib_ref] If a patient with an underlying heart condition and suspected/confirmed COVID-19 needs additional anatomical cardiac assessment (most likely presurgical and postsurgical assessment, newborn with nonconclusive echocardiographic diagnosis, coronary assessment, suspected pulmonary embolism), cardiac CT can be an option. [bib_ref] COVID-19) outbreak: what the department of radiology should know, Kooraki [/bib_ref] The evaluation can be performed either as a targeted cardiovascular study, or as a combined cardiothoracic assessment if lung information is required because of respiratory impairment. CT equipment to perform a comprehensive cardiac examination must include a multirow detector CT scanner, ECG cardiac synchronization and iodinate contrast injector system. Apart from the urgent scans (presurgical/postsurgical, new diagnosis, recent hemodynamic deterioration), all the elective exams planned in clinically stable subjects should be postponed.
Cardiac Magnetic Resonance (CMR) is rarely a mandatory exam, so in suspected or confirmed SARS-CoV-2 infection, CMR can almost always be delayed, and all the elective studies should be re-scheduled.
The most likely clinical scenario where CMR can be considered is in case of suspected myocarditis. In this setting (suspected/confirmed COVID-19 and signs of myocarditis), CMR can be performed, considering the risk/benefit ratio according to the patient's hemodynamic status and exam's therapeutic impact. Other less common possible CMR indications in this setting might be advanced presurgical hemodynamic assessment in patients with complex CHD (e.g. complex intracardiac shunt assessment, borderline ventricle assessment), and subjects with recent diagnosis of myocardial mass.
Both for cardiac CT and CMR, all the nonurgent scans planned as outpatients, even in patients with no suspicion of infection, should be postponed in accordance with the referring physician because of the risk of infection in the hospital setting.
If the exam (CT or CMR) is indicated, the number of people involved in the procedure execution should be reduced to a minimum, limiting access to all those who are not essential for scan performance and interpretation. All the people involved (physicians, nurses, technicians) should wear protective equipment including respiratory protection with use of a medical mask, disposable isolation gown with fluid-resistant characteristics, disposable gloves with coverage over gown cuffs, eye protection with goggles and probably a face mask over goggles. [bib_ref] COVID-19) outbreak: what the department of radiology should know, Kooraki [/bib_ref] Patients should wear a surgical mask during transport to and from the department. CT and MR machine gantries, and reporting stations (monitor, mouse and keyboards) should be sanitized after every contact with suspected patients. [bib_ref] COVID-19) outbreak: what the department of radiology should know, Kooraki [/bib_ref] © 2020 Italian Federation of Cardiology -I.F.C. All rights reserved.
Journal of Cardiovascular Medicine 2020, Vol 00 No 00 © 2020 Italian Federation of Cardiology -I.F.C. All rights reserved.
Journal of Cardiovascular Medicine 2020, Vol 00 No 00 © 2020 Italian Federation of Cardiology -I.F.C. All rights reserved.
All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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The recent outbreak of 2019 severe acute respiratory syndrome coronavirus-2 is having major repercussions on healthcare services provision in Italy and worldwide. Data suggest the virus has a strong impact on the cardiovascular system, and cardiac imaging will play an important role in patients affected by coronavirus disease-2019. Although paediatric patients are mildly affected, they represent a clear accelerator in spreading the virus, and healthcare workers are at higher risk of infection. The aim of this position paper is to provide clinical recommendation regarding the execution of imaging investigations for the cardiac diagnostic work-up of paediatric patients with suspected or confirmed infection.
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0b5efa8a85d5b0f529693da27643bcbfdec2d626
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pubmed
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Osteosarcoma
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Osteosarcoma
Osteosarcoma is the most common malignant bone tumour found in children and young adults. The annual incidence is 65 cases per year which represents 5% of all childhood cancers (0.5 cases per 100 000 per year). Non-metastatic osteosarcoma is currently curable in about 70% of cases.These guidelines do not relate to radiation-induced osteosarcoma or that occurring in Paget's disease. They were validated in December 1998 and will be updated according to the publication of new data.DIAGNOSISPlain X-rays of bone remain indispensable for confirming the presence of bone pathology. Lesions are typically localized in the metaphyseal region of long bones, as mixed osteolytic osteoblastic lesions or cortical lytic lesions, with periosteal reaction and adjacent soft-tissue mass.Technetium bone scanning is used to detect the growth plates, and also skip metastases and distant spread. The examination should be done in three phases to study the functional characteristics of the radio-isotope uptake over time. A thoracic CT scan detects lung metastases not visible on chest X-ray. Thin (about 1 cm) cuts should be taken, if possible by spiral scanning (level of evidence B). MRI and bone scan must be done before surgical biopsy to avoid artefacts from haemorrhage, oedema and bone healing. CT scanning and arteriography are no longer used routinely to study the primary tumour. An arteriogram done immediately preoperatively can in some cases identify venous tumour emboli, provided this is a dynamic scan.
## Diagnosis
The biopsy must be taken by the surgeon who is to eventually do the definitive surgery. He/she must be experienced in this type of surgery. The biopsy should be of adequate size and representative of the tumour. Surgical drainage should be avoided. The incision must be placed in an area that will be excised at the time of eventual resection. In some very specialized units, a core-needle biopsy may be sufficient to make a firm diagnosis, but this requires particular expertise with regard to interpretation and is not yet standard practice. The role of the pathologist is very important for both the diagnosis and in evaluating the subsequent response to chemotherapy (level of evidence A).
## Staging
Patients are generally classified as having metastatic or non-metastatic disease. Age, tumour volume and site of tumour have been reported as prognostic variables, but these are not consistent.
Alkaline phosphatase, LDH, renal function and cardiac echogram should be documented prior to therapy.
## Treatment modalities
Children should be treated according to an appropriate multicentre trial, such as SFOP and adults within FNCLCC or EORTC protocols.
## Chemotherapy
Protocols combining neo-adjuvant chemotherapy and adjuvant chemotherapy have superior efficacy to protocols of adjuvant chemotherapy alone (level of evidence B). However, there are no randomized trials comparing these therapeutic options. Chemotherapy must be given by teams experienced in the use of aggressive and toxic protocols with provision of full medical and haematological supportive care. Preoperative chemotherapy generally combines a number of agents (standard). A variety of protocols can be proposed: high-dose methotrexate + doxorubicin, doxorubicin + cisplatin, high-dose methotrexate + cisplatin + doxorubicin, ifosfamide + cisplatin .
High-dose methotrexate is effective and widely used in children (level of evidence B). It is generally given at a dose of at least 12 g m -2 to children. In adults, a test dose may be used to define the dose that will give an identical area under the concentration curve for all patients, and is usually at least 8 g m -2 . In general, the scheduling of methotrexate is identical in adults to children. It must be possible to measure methotrexate levels and to support with dialysis if necessary. The methods of high-dose methotrexate administration will vary according to different protocols, but facilities to provide rigorous hydration, clinical surveillance, regular blood tests and folinic acid rescue must be in place at all times.
Randomized trials have suggested a combination of cisplatin and doxorubicin may be comparable to more complex multiagent regimens (level of evidence B).
## Surgery
Surgery must be undertaken by an experienced surgeon who is familiar with the indications for amputation if conservative surgery is contraindicated. For localized disease, the biopsy scar should be resected and the tumour removed 'en bloc' without being opened (level of evidence B) . The limits of excision must be wide and clear histologically. A sample of the proximal marrow must be taken for analysis. Several surgical options are possible: reconstructive surgery using prostheses, reconstruction using bone graft, either autologous or allogeneic, and rotationplasty. The result of primary chemotherapy is documented by Huvos' histological grading on excised tumour [fig_ref] Figure 3: Postoperative treatment [/fig_ref]. Good and bad responders to chemotherapy are defined. At present in France, the definition of a good response is if there is less than 10% of viable tumour cells in the sample. The response to preoperative chemotherapy is the single most important prognostic factor (level of evidence B). Various medical imaging techniques are under evaluation to determine the efficacy of chemotherapy. These include MRI, PET and Thallium scans. The results are at present unreliable in predicting response (level of evidence A). These tests should only be done in the context of an evaluable protocol.
The existence of metastases at presentation, in particular if they are single, should not lead to abandoning the possibility of curative treatment (level of evidence B). Amputation of limbs is only done under exceptional circumstances. Aggressive surgery to lung metastases following primary chemotherapy may be appropriate .
## Radiotherapy
Radiotherapy may be indicated in the case of inoperable tumour. Options for irradiation include high dose, between 55-70 Gy according to site, and also photon or neutron therapy. Radiotherapy may also be useful for palliation of locally recurrent disease.
## Follow-up
Few studies have compared the method and timing of follow up for osteosarcoma. Recommendations are as follows (level of evidence B):
- Chest X-ray every 2 months, for years 1 and 2, every 3 months for years 3 and 4, every 6 months for years 5 and 6, then annually.
- CT scan (if there were lung metastases at presentation) every 6 months for the first year and then every year until the fourth year.
- Plain X-ray of bone and MRI are only done in the case of local symptoms. Technetium bone scan may be done every 4 months for years 1 and 2, every 6 months for years 3 and 4 and then only in the case of symptoms. The role of bone scan remains debatable, however, as there is no useful therapeutic intervention in the event of distant bone metastases.
## Internal reviewers
BN Bui (Institut Bergonié, Bordeaux), MC Demaille (Centre Oscar Lambret, Lille), C. Kalifa (Institut Gustave Roussy, Villejuif), P. Pouillart (Institut Curie, Paris), J. Stines (Centre Alexis Vautrin, Nancy) and JM Zucker (Institut Curie, Paris). local treatment (see Metastatic disease: local treatment (see
## Figure 1 preoperative chemotherapy for osteosarcoma
## Non-metastatic disease: local treatment
Presurgical post-chemotherapy evaluation: reassessment using the same modalities as at presentation
[fig] T: Philip 1 , JY Blay 1 , M Brunat-Mentigny 1 , C Carrie 1 , P Chauvot 1 , F Farsi 1 , B Fervers 1,2 , JC Gentet 3 , F Giammarile 1 , R Kohler 4 , S Mathoulin 5 , LM Patricot 6 and P hiesse 1 [/fig]
[fig] Figure 3: Postoperative treatment [/fig]
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https://www.qeios.com/read/FR8H08/pdf
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Osteosarcoma is the most common malignant bone tumour f in children and young adults. The annual incidence is 65 case year which represents 5% of all childhood cancers (0.5 case 100 000 per year). Non-metastatic osteosarcoma is curr curable in about 70% of cases. These guidelines do not relate to radiation-induced osteo coma or that occurring in Paget’s disease. They were validat December 1998 and will be updated according to the publica of new data.
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